Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.

A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.

Universality in long-distance geometry and quantum complexity.

In physics, two systems that radically differ at short scales can exhibit strikingly similar macroscopic behaviour: they are part of the same long-distance universality class1. Here we apply this viewpoint to geometry and initiate a program of classifying homogeneous metrics on group manifolds2 by their long-distance properties. We show that many metrics on low-dimensional Lie groups have markedly different short-distance properties but nearly identical distance functions at long distances, and provide evidence that this phenomenon is even more robust in high dimensions. An application of these ideas of particular interest to physics and computer science is complexity geometry3-7-the study of quantum computational complexity using Riemannian geometry. We argue for the existence of a large universality class of definitions of quantum complexity, each linearly related to the other, a much finer-grained equivalence than typically considered. We conjecture that a new effective metric emerges at larger complexities that describes a broad class of complexity geometries, insensitive to various choices of microscopic penalty factors. We discuss the implications for recent conjectures in quantum gravity.

Genome-wide and targeted CRISPR screens identify RNF213 as a mediator of interferon gamma-dependent pathogen restriction in human cells.

To define cellular immunity to the intracellular pathogen Toxoplasma gondii, we performed a genome-wide CRISPR loss-of-function screen to identify genes important for (interferon gamma) IFN-γ-dependent growth restriction. We revealed a role for the tumor suppressor NF2/Merlin for maximum induction of Interferon Stimulated Genes (ISG), which are positively regulated by the transcription factor IRF-1. We then performed an ISG-targeted CRISPR screen that identified the host E3 ubiquitin ligase RNF213 as necessary for IFN-γ-mediated control of T. gondii in multiple human cell types. RNF213 was also important for control of bacterial (Mycobacterium tuberculosis) and viral (Vesicular Stomatitis Virus) pathogens in human cells. RNF213-mediated ubiquitination of the parasitophorous vacuole membrane (PVM) led to growth restriction of T. gondii in response to IFN-γ. Moreover, overexpression of RNF213 in naive cells also impaired growth of T. gondii. Surprisingly, growth inhibition did not require the autophagy protein ATG5, indicating that RNF213 initiates restriction independent of a previously described noncanonical autophagy pathway. Mutational analysis revealed that the ATPase domain of RNF213 was required for its recruitment to the PVM, while loss of a critical histidine in the RZ finger domain resulted in partial reduction of recruitment to the PVM and complete loss of ubiquitination. Both RNF213 mutants lost the ability to restrict growth of T. gondii, indicating that both recruitment and ubiquitination are required. Collectively, our findings establish RNF213 as a critical component of cell-autonomous immunity that is both necessary and sufficient for control of intracellular pathogens in human cells.

Transcriptional control of leukemogenesis by the chromatin reader SGF29.

ABSTRACT: Aberrant expression of stem cell-associated genes is a common feature in acute myeloid leukemia (AML) and is linked to leukemic self-renewal and therapy resistance. Using AF10-rearranged leukemia as a prototypical example of the recurrently activated "stemness" network in AML, we screened for chromatin regulators that sustain its expression. We deployed a CRISPR-Cas9 screen with a bespoke domain-focused library and identified several novel chromatin-modifying complexes as regulators of the TALE domain transcription factor MEIS1, a key leukemia stem cell (LSC)-associated gene. CRISPR droplet sequencing revealed that many of these MEIS1 regulators coordinately controlled the transcription of several AML oncogenes. In particular, we identified a novel role for the Tudor-domain-containing chromatin reader protein SGF29 in the transcription of AML oncogenes. Furthermore, SGF29 deletion impaired leukemogenesis in models representative of multiple AML subtypes in multiple AML subtype models. Our studies reveal a novel role for SGF29 as a nononcogenic dependency in AML and identify the SGF29 Tudor domain as an attractive target for drug discovery.

Engineering an Escherichia coli based in vivo mRNA manufacturing platform.

Synthetic mRNA is currently produced in standardized in vitro transcription systems. However, this one-size-fits-all approach has associated drawbacks in supply chain shortages, high reagent costs, complex product-related impurity profiles, and limited design options for molecule-specific optimization of product yield and quality. Herein, we describe for the first time development of an in vivo mRNA manufacturing platform, utilizing an Escherichia coli cell chassis. Coordinated mRNA, DNA, cell and media engineering, primarily focussed on disrupting interactions between synthetic mRNA molecules and host cell RNA degradation machinery, increased product yields >40-fold compared to standard "unengineered" E. coli expression systems. Mechanistic dissection of cell factory performance showed that product mRNA accumulation levels approached theoretical limits, accounting for ~30% of intracellular total RNA mass, and that this was achieved via host-cell's reallocating biosynthetic capacity away from endogenous RNA and cell biomass generation activities. We demonstrate that varying sized functional mRNA molecules can be produced in this system and subsequently purified. Accordingly, this study introduces a new mRNA production technology, expanding the solution space available for mRNA manufacturing.

Inter-software and inter-scan variability in measurement of epicardial adipose tissue: a three-way comparison of a research-specific, a freeware and a coronary application software platform.

OBJECTIVES: Epicardial adipose tissue (EAT) is a proposed marker of cardiovascular risk; however, clinical application may be limited by variability in post-processing software platforms. We assessed inter-vendor agreement of EAT volume (EATv) and attenuation on both contrast-enhanced (CE) and non-contrast CT (NCT) using a standard coronary CT reporting software (Vitrea), an EAT research-specific software (QFAT) and a freeware imaging software (OsiriX). METHODS: Seventy-six consecutive patients undergoing simultaneous CE and NCT had complete volumetric EAT measurement. Between-software, within-software NCT vs. CE, and inter- and intra-observer agreement were evaluated with analysis by ANOVA (with post hoc adjustment), Bland-Altman with 95% levels of agreement (LoA) and intraclass correlation coefficient (ICC). RESULTS: Mean EATv (freeware 53 ± 31 mL vs. research 93 ± 43 mL vs. coronary 157 ± 64 mL) and attenuation (freeware - 72 ± 25 HU vs. research - 75 ± 3 HU vs. coronary - 61 ± 10 HU) were significantly different between all vendors (ANOVA p < 0.001). EATv was consistently higher in NCT vs. CE for all software packages, with most reproducibility found in research software (bias 26 mL, 95% LoA: 2 to 56 mL), compared to freeware (bias 11 mL 95% LoA: - 46 mL to 69 mL) and coronary software (bias 10 mL 95% LoA: - 127 to 147 mL). Research software had more comparable NCT vs. CE attenuation (- 75 vs. - 72 HU) compared to freeware (- 72 vs. - 57 HU) and coronary (- 61 vs. - 39 HU). Excellent inter-observer agreement was seen with research (ICC 0.98) compared to freeware (ICC 0.73) and coronary software (ICC 0.75) with narrow LoA on Bland-Altman analysis. CONCLUSION: There are significant inter-vendor differences in EAT assessment. Our study suggests that research-specific software has better agreement and reproducibility compared to freeware or coronary software platforms. KEY POINTS: • There are significant differences between EAT volume and attenuation values between software platforms, regardless of scan type. • Non-contrast scans routinely have higher mean EAT volume and attenuation; however, this finding is only consistently seen with research-specific software. • Of the three analyzed packages, research-specific software demonstrates the highest reproducibility, agreement, and reliability for both inter-scan and inter-observer agreement.

Enlarging Paravisceral Aortic Aneurysm Treated With In Situ Laser Fenestration of Physician-Modified Stent Graft for Preservation of Accessory Renal Arteries.

PURPOSE: In situ laser fenestration (LISF) was performed as a bailout procedure to ensure renal perfusion during complex aortic aneurysm repair. CASE REPORT: A 69 year-old male patient with previous repair of abdominal aortic aneurysm who presented with increasing lower back pain and an enlarging, 6-cm, perivisceral aortic aneurysm that required urgent repair. Given potential complications and risks of redo open repair, we performed endovascular repair via deployment of a 5-vessel fenestrated physician modified stent graft (PMEG) with stent placement to the celiac, superior mesenteric, right renal, and 2 of the larger 3 left renal arteries. The renal artery planned for sacrifice was found intraoperatively to be perfusing a large portion of the kidney. Subsequently, LISF was used to cannulate and salvage perfusion to the third renal artery. Completion aortogram demonstrated patency of all renal visceral vessels with no vessel leak. Follow-up CT angiogram 1 year later demonstrated aortic graft with all visceral stents patent, no endoleak, and a reduction in residual aneurysm sac. CONCLUSION: Even with careful planning and design of a physician modified stent graft, in situ laser fenestration provides an option to successfully create additional stents intraoperatively in order to preserve perfusion to critical visceral organs. CLINICAL IMPACT: In situ laser fenestration will provide surgeons with a valuable intra-operative method to create additional stents when organ perfusion would otherwise be lost. As more surgeons develop this technical ability and more long-term outcomes are studied, this method has the possibility to not only be used for urgent and emergent cases but may one day be an acceptable variation to standard practice.

Randomized Controlled Study in the Use of Aromatherapy for Pain Reduction and to Reduce Opioid Use in the Emergency Department.

INTRODUCTION: This study aimed to evaluate the effects of aromatherapy on emergency department patients' perception of pain and its ability to reduce the use of opioids in an emergency department. METHODS: This randomized, controlled, single-blinded study was conducted in a suburban/rural freestanding emergency department with a therapeutic group, sham group, and control group. RESULTS: A total of 230 patients, 171 females and 59 males, completed the study. Of those who received the therapeutic agent, an average reduction in pain of 1.04 points on the pain scale was reported, whereas the sham group averaged 0.38 and the control group 0.23. There was a statistically significant reduction of pain scores in the therapeutic group. A total of 13 received opioid pain medication during their visit. Of these, the therapeutic group averaged a total of 2.67 morphine milligram equivalents for their visit compared with 3.63 in the sham group and 4.36 in the control group; however, statistical significance was not achieved. DISCUSSION: This study supported what other studies have found, indicating that aromatherapy is effective in reducing pain. A difference between the placebo effect and a true therapeutic effect was seen by using a control group apart from the sham and therapeutic groups. Despite the small effect size (0.3), implementation of aromatherapy into standard practice may be practical considering the anxiolytic effects that have been shown in other studies. Aromatherapy with essential oils should be considered as another tool to use in a multimodal approach in the treatment of pain in the emergency department setting.

Increasing student engagement with course content in graduate public health education: A pilot randomized trial of behavioral nudges.

Digital advances in the learning space have changed the contours of student engagement as well as how it is measured. Learning management systems and other learning technologies now provide information about student behaviors with course materials in the form of learning analytics. In the context of a large, integrated and interdisciplinary Core curriculum course in a graduate school of public health, this study undertook a pilot randomized controlled trial testing the effect of providing a "behavioral nudge" in the form of digital images containing specific information derived from learning analytics about past student behaviors and performance. The study found that student engagement varied significantly from week to week, but nudges linking coursework completion to assessment grade performance did not significantly change student engagement. While the a priori hypotheses of this pilot trial were not upheld, this study yielded significant findings that can guide future efforts to increase student engagement. Future work should include a robust qualitative assessment of student motivations, testing of nudges that tap into these motivations and a richer examination of student learning behaviors over time using stochastic analyses of data from the learning management system.

Forest regeneration within Earth system models: current process representations and ways forward.

Earth system models must predict forest responses to global change in order to simulate future global climate, hydrology, and ecosystem dynamics. These models are increasingly adopting vegetation demographic approaches that explicitly represent tree growth, mortality, and recruitment, enabling advances in the projection of forest vulnerability and resilience, as well as evaluation with field data. To date, simulation of regeneration processes has received far less attention than simulation of processes that affect growth and mortality, in spite of their critical role maintaining forest structure, facilitating turnover in forest composition over space and time, enabling recovery from disturbance, and regulating climate-driven range shifts. Our critical review of regeneration process representations within current Earth system vegetation demographic models reveals the need to improve parameter values and algorithms for reproductive allocation, dispersal, seed survival and germination, environmental filtering in the seedling layer, and tree regeneration strategies adapted to wind, fire, and anthropogenic disturbance regimes. These improvements require synthesis of existing data, specific field data-collection protocols, and novel model algorithms compatible with global-scale simulations. Vegetation demographic models offer the opportunity to more fully integrate ecological understanding into Earth system prediction; regeneration processes need to be a critical part of the effort.

Simulating environmentally-sensitive tree recruitment in vegetation demographic models.

Vegetation demographic models (VDMs) endeavor to predict how global forests will respond to climate change. This requires simulating which trees, if any, are able to recruit under changing environmental conditions. We present a new recruitment scheme for VDMs in which functional-type-specific recruitment rates are sensitive to light, soil moisture and the productivity of reproductive trees. We evaluate the scheme by predicting tree recruitment for four tropical tree functional types under varying meteorology and canopy structure at Barro Colorado Island, Panama. We compare predictions to those of a current VDM, quantitative observations and ecological expectations. We find that the scheme improves the magnitude and rank order of recruitment rates among functional types and captures recruitment limitations in response to variable understory light, soil moisture and precipitation regimes. Our results indicate that adopting this framework will improve VDM capacity to predict functional-type-specific tree recruitment in response to climate change, thereby improving predictions of future forest distribution, composition and function.

Plaque contact surface area and lumen volume predict stroke risk in extracranial carotid artery stenosis.

BACKGROUND: The standard indication for intervention in asymptomatic disease is currently percent stenosis in the internal carotid artery as measured by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method, which remains limited in discriminating power. Computed tomography angiography (CTA) is widely used to calculate NASCET stenosis, but also offers the opportunity to analyze carotid artery plaques from a morphological perspective that has not been widely used. We aim to improve stroke risk stratification of patients with carotid artery stenosis using plaque three-dimensional (3D) modeling and image analysis. METHODS: Patients with computed tomography angiographies appropriate for 3D reconstruction were identified from a National Institutes of Health-designated stroke center database, and carotid arteries were segmented and analyzed using software algorithms to calculate contact surface area (CSA) between the plaque and blood flow, and volume of the flow lumen within the region of the plaque (lumen volume [LV]). These novel parameters factor in the 3D morphometry inherent to each carotid plaque and were compared between stroke and nonstroke groups. RESULTS: A total of 134 carotid arteries were analyzed, 33 of which were associated with an ipsilateral stroke. Plaques associated with stroke demonstrated statistically significant increases in average CSA (541.52 mm2) and LV (394.64 mm3) when compared with those not associated with stroke (371.18 mm2 and 245.92 mm3, respectively). When comparing area under the receiver operating characteristics curve between NASCET (0.65) percent stenosis, CSA (0.74), and LV (0.77), both CSA and LV demonstrated more favorable values in predicting stroke risk in patients with carotid stenosis. CONCLUSIONS: The data presented here demonstrate morphological features of carotid plaques that are independent of NASCET criteria stratification and may present an improved method in assessing stroke risk in patients with carotid artery stenosis.

Diabetes mellitus is independently associated with early stent thrombosis in patients undergoing drug eluting stent implantation: Analysis from the Victorian cardiac outcomes registry.

BACKGROUND: Diabetes mellitus (DM) is a predictor of restenosis and late stent thrombosis (ST) in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting-stents (DES). Real-world data on rates of early ST is lacking. We compared clinical outcomes of patients with and without DM from the Victorian cardiac outcomes registry. METHODS: Consecutive patients undergoing PCI with DES were analyzed with primary outcome being ST at 30-days. Secondary outcomes including major adverse cardiovascular events (MACE) and all-cause mortality. RESULTS: Of 43,209 patients included, 9730 (22.5%) had DM. At 30 days, DM was independently associated with higher rates of early ST (0.7% vs. 0.5%) OR 1.41 (95% confidence interval; 1.05-1.87, p = 0.02), MACE (4.1% vs. 3.5%, p = 0.004) and mortality (1.9% vs. 1.5%, p = 0.01). Increased risk was not simply due to treatment. Patients with DM requiring insulin were equally affected in regard to MACE (4.7% vs. 3.9%, p = 0.069) and mortality (1.9%, vs. 1.8%, p = 0.746). On National Death Index linkage, patients with DM had increased all-cause mortality over five-year follow-up (OR 1.69 CI 1.55-1.83, p = < 0.001). CONCLUSION: In this large real-world-registry, DM was an independent predictor of early ST, MACE and mortality at 30 days. These data suggest additional therapeutic strategies are required to reduce the risk of early complications in patients with DM undergoing PCI with DES.

Coronary imaging of cardiac allograft vasculopathy predicts current and future deterioration of left ventricular function in patients with orthotopic heart transplantation.

BACKGROUND: Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) improve sensitivity of cardiac allograft vasculopathy (CAV) detection compared to invasive coronary angiography (ICA), but their ability to predict clinical events is unknown. We determined whether severe CAV detected with ICA, IVUS, or OCT correlates with graft function. METHODS: Comparison of specific vessel parameters between IVUS and OCT on 20 patients attending for angiography 12-24 months post-orthotopic heart transplant. Serial left ventricular ejection fraction (EF) was recorded prospectively. RESULTS: Analyzing 55 coronary arteries, OCT and IVUS correlated well for vessel CAV characteristics. A mean intimal thickness (MIT)OCT  > .25 mm had a sensitivity of 86.7% and specificity of 74.3% at detecting Stanford grade 4 CAV. Those with angiographically evident CAV had significant reduction in graft EF over 7.3 years follow-up (median ΔEF -2% vs +1.5%, P = .03). Patients with MITOCT  > .25 mm in at least one vessel had a lower median EF at time of surveillance (57% vs 62%, P = .014). Two MACEs were noted. CONCLUSION: Imaging with OCT correlates well with IVUS for CAV detection. Combined angiography and OCT to screen for CAV within 12-24 months of transplant predicts concurrent and future deterioration in graft function.

PTSD is not the emblematic disorder of the COVID-19 pandemic; adjustment disorder is.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been hailed by some as the emblematic mental disorder of the COVID-19 pandemic, assuming that PTSD's life-threat criterion was met de facto. More plausible outcomes like adjustment disorder (AD) have been overlooked. METHODS: An online cross-sectional survey was launched in the initial stage of the pandemic using a convenience sample of 5 913 adults to compare the prevalence of COVID-related probable PTSD versus probable AD. The abridged Impact of Event Scale - Revised (IES-6) assessed the severity of trauma- and stressor-related symptoms over the previous week. Demographic and pandemic-related data (e.g., receiving a formal diagnosis of COVID-19, job loss, loss of loved one, confinement, material hardship) were collected. A Classification and Regression Tree analysis was conducted to uncover the pandemic experiences leading to clinical 'caseness'. Caseness was defined by a score > 9 on the IES-6 symptom measure and further characterized as PTSD or AD depending on whether the Peritraumatic Distress Inventory's life-threat item was endorsed or not. RESULTS: The participants were predominantly Caucasian (72.8%), women (79.2%), with a university degree (85%), and a mean age of 42.22 (SD = 15.24) years; 3 647 participants (61.7%; 95%CI [60.4, 63.0]) met the threshold for caseness. However, when perceived life-threat was accounted for, only 6.7% (95%CI [6.1, 7.4]) were classified as PTSD cases, and 55% (95%CI [53.7, 56.2]) as AD cases. Among the AD cases, three distinct profiles emerged marked by the following: (i) a worst personal pandemic experience eliciting intense fear, helplessness or horror (in the absence, however, of any life-threat), (ii) a pandemic experience eliciting sadness/grief, and (iii) worrying intensely about the safety of significant others. CONCLUSIONS: Studies considering the life-threat criterion as met de facto during the pandemic are confusing PTSD for AD on most counts. This misconception is obscuring the various AD-related idioms of distress that have emerged during the pandemic and the actual treatment needs.

Prescribing Trends and Health Care Expenditure of P2Y12 Prescriptions in Australia Over the Last Decade.

BACKGROUND: Dual antiplatelet therapy (DAPT) is guideline therapy following acute coronary syndrome (ACS). Novel, potent P2Y12 inhibitors have been developed and studied but it is unclear how this evidence has been incorporated into patient care. We sought to describe the prescribing trends and health care costs of P2Y12therapy in Australia over the last decade. METHOD: The latest statistical data collected by the Pharmaceutical Benefit Scheme (PBS), Australia, was reviewed. PBS codes for coronary indications were selected. Yearly total prescriptions and cost were then compared between all three P2Y12 inhibitors. Linear trend modelling was used to observe general trends over the data collection period. RESULTS: Total yearly P2Y12 scripts have more than doubled between 2010 (403,880 scripts) and 2020 (994,826 scripts). Clopidogrel is the most prescribed P2Y12 inhibitor and has been for the last decade. Ticagrelor represents 26.2% of total prescriptions but accounts for 75% of PBS spending. More than $30 million is spent on ticagrelor every year with a cost per MACE prevented of $72,637. Prasugrel was the least prescribed agent but was 41% cheaper per major adverse cardiac event (MACE) prevented than ticagrelor before being removed from the Australian market. Without prasugrel available, clopidogrel scripts have increased 10% and ticagrelor scripts remain stable. CONCLUSION: Clopidogrel remains the most prescribed P2Y12 agent in Australia, despite emergence of more potent P2Y12 inhibitors. Ticagrelor is increasingly prescribed but represents a disproportionately large burden of spending. Whilst prasugrel is the most efficacious, cheaper than ticagrelor and guideline recommended P2Y12 inhibitor after ACS, it represented the minority of scripts before being withdrawn. Rather than use of a potent P2Y12 agent, clinicians are reverting to prescribing clopidogrel.

Trauma and Maternal Caregivers as Risks for Executive Function Deficits Among Youth Who Have Sexually Harmed.

Despite robust research linking trauma events to the commission of sexual harm by youth, the majority of victims do not become victimizers, imploring us to study potential interceding influences. Some research indicates that intermediary factors like attachment characteristics, trauma symptomatology, and executive functioning may be critical in understanding sexual harm committed by youth. This study explored relationships between trauma events, trauma symptoms, and attachment characteristics, and their relationship to executive functioning in a sample of 196 youth who committed sexual harm. Results revealed bivariate associations between trauma events, symptomatology, and maternal attachment characteristics. Structural equation modeling revealed numerous direct and indirect effects on the path to deficits in executive functioning, and that sexual abuse, above and beyond other forms of traumatic events, contributed to executive functioning deficits via trauma symptoms. The results are contextualized and implications are discussed.

Comparative analyses of two primate species diverged by more than 60 million years show different rates but similar distribution of genome-wide UV repair events.

BACKGROUND: Nucleotide excision repair is the primary DNA repair mechanism that removes bulky DNA adducts such as UV-induced pyrimidine dimers. Correspondingly, genome-wide mapping of nucleotide excision repair with eXcision Repair sequencing (XR-seq), provides comprehensive profiling of DNA damage repair. A number of XR-seq experiments at a variety of conditions for different damage types revealed heterogenous repair in the human genome. Although human repair profiles were extensively studied, how repair maps vary between primates is yet to be investigated. Here, we characterized the genome-wide UV-induced damage repair in gray mouse lemur, Microcebus murinus, in comparison to human. RESULTS: We derived fibroblast cell lines from mouse lemur, exposed them to UV irradiation, and analyzed the repair events genome-wide using the XR-seq protocol. Mouse lemur repair profiles were analyzed in comparison to the equivalent human fibroblast datasets. We found that overall UV sensitivity, repair efficiency, and transcription-coupled repair levels differ between the two primates. Despite this, comparative analysis of human and mouse lemur fibroblasts revealed that genome-wide repair profiles of the homologous regions are highly correlated, and this correlation is stronger for highly expressed genes. With the inclusion of an additional XR-seq sample derived from another human cell line in the analysis, we found that fibroblasts of the two primates repair UV-induced DNA lesions in a more similar pattern than two distinct human cell lines do. CONCLUSION: Our results suggest that mouse lemurs and humans, and possibly primates in general, share a homologous repair mechanism as well as genomic variance distribution, albeit with their variable repair efficiency. This result also emphasizes the deep homologies of individual tissue types across the eukaryotic phylogeny.

Ancestral patterns of recessive dystrophic epidermolysis bullosa mutations in Hispanic populations suggest sephardic ancestry.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis caused by mutations in the gene coding for type VII collagen (COL7A1). More than 800 different pathogenic mutations in COL7A1 have been described to date; however, the ancestral origins of many of these mutations have not been precisely identified. In this study, 32 RDEB patient samples from the Southwestern United States, Mexico, Chile, and Colombia carrying common mutations in the COL7A1 gene were investigated to determine the origins of these mutations and the extent to which shared ancestry contributes to disease prevalence. The results demonstrate both shared European and American origins of RDEB mutations in distinct populations in the Americas and suggest the influence of Sephardic ancestry in at least some RDEB mutations of European origins. Knowledge of ancestry and relatedness among RDEB patient populations will be crucial for the development of future clinical trials and the advancement of novel therapeutics.