Genome-Wide Association Study Identifies Single Nucleotide Polymorphism Markers Associated with Mycelial Growth (at 15, 20, and 25°C), Mefenoxam Resistance, and Mating Type in Phytophthora infestans.

Phenotypic diversity among individuals defines the potential for evolutionary selection in a species. Phytophthora infestans epidemics are generally thought to be favored by moderate to low temperatures, but temperatures in many locations worldwide are expected to rise as a result of global climate change. Thus, we investigated variation among individuals of P. infestans for relative growth at different temperatures. Isolates of P. infestans came from three collections: (i) individual genotypes recently dominant in the United States, (ii) recently collected individuals from Central Mexico, and (iii) progeny of a recent sexual recombination event in the northeastern United States. In general, these isolates had optimal mycelial growth rates at 15 or 20°C. However, two individuals from Central Mexico grew better at higher temperatures than did most others and two individuals grew relatively less at higher temperatures than did most others. The isolates were also assessed for mefenoxam sensitivity and mating type. Each collection contained individuals of diverse sensitivities to mefenoxam and individuals of the A1 and A2 mating type. We then searched for genomic regions associated with phenotypic diversity using genotyping-by-sequencing. We found one single nucleotide polymorphism (SNP) associated with variability in mycelial growth at 20°C, two associated with variability in mycelial growth at 25°C, two associated with sensitivity to mefenoxam, and one associated with mating type. Interestingly, the SNPs associated with mefenoxam sensitivity were found in a gene-sparse region, whereas the SNPs associated with growth at the two temperatures and mating type were found both at more gene-dense regions.

Epilepsy genetics: Current knowledge, applications, and future directions.

The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease.

Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma.

Background: Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma. Patients and methods: We carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial. Results: Mutant BRAF or NRAS ctDNA was detected (≥1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval [DFI; hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.79-5.47; P < 0.0001] and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80-5.79; P < 0.0001) versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status and disease stage (DFI: HR 3.26, 95% CI 1.83-5.83, P < 0.0001; DMFI: HR 3.45, 95% CI 1.88-6.34, P < 0.0001). Five-year overall survival rate for patients with detectable ctDNA was 33% (95% CI 14%-55%) versus 65% (95% CI 56%-72%) for those with undetectable ctDNA. Overall survival was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.40-4.96); P = 0.003) and remained significant after adjustment for performance status (HR 2.50, 95% CI 1.32-4.74, P = 0.005). Conclusion: ctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy. Clinical trial number: ISRCTN 81261306.

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

Assessment of bulbar function in amyotrophic lateral sclerosis: validation of a self-report scale (Center for Neurologic Study Bulbar Function Scale).

BACKGROUND AND PURPOSE: Impaired bulbar functions of speech and swallowing are among the most serious consequences of amyotrophic lateral sclerosis (ALS). Despite this, clinical trials in ALS have rarely emphasized bulbar function as an endpoint. The rater-administered Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) or various quality-of-life measures are commonly used to measure symptomatic benefit. Accordingly, we sought to evaluate the utility of measures specific to bulbar function in ALS. METHODS: We assessed bulbar functions in 120 patients with ALS, with clinicians first making direct observations of the degree of speech, swallowing and salivation impairment in these subjects. Clinical diagnosis of bulbar impairment was then compared with ALSFRS-R scores, speech rate, time to swallow liquids and solids, and scores obtained when patients completed visual analog scales (VASs) and the newly-developed 21-question self-administered Center for Neurologic Study Bulbar Function Scale (CNS-BFS). RESULTS: The CNS-BFS, ALSFRS-R, VAS and timed speech and swallowing were all concordant with clinician diagnosis. The self-report CNS-BFS and ALSFRS-R bulbar subscale best predicted clinician diagnosis with misclassification rates of 8% and 14% at the optimal cut-offs, respectively. In addition, the CNS-BFS speech and swallowing subscales outperformed both the bulbar component of the ALSFRS-R and speech and swallowing VASs when correlations were made between these scales and objective measures of timed reading and swallowing. CONCLUSIONS: Based on these findings and its relative ease of administration, we conclude that the CNS-BFS is a useful metric for assessing bulbar function in patients with ALS.

Phytophthora betacei, a new species within Phytophthora clade 1c causing late blight on Solanum betaceum in Colombia.

Over the past few years, symptoms akin to late blight disease have been reported on a variety of crop plants in South America. Despite the economic importance of these crops, the causal agents of the diseases belonging to the genus Phytophthora have not been completely characterized. In this study, a new Phytophthora species was described in Colombia from tree tomato (Solanum betaceum), a semi-domesticated fruit grown in northern South America. Comprehensive phylogenetic, morphological, population genetic analyses, and infection assays to characterize this new species, were conducted. All data support the description of the new species, Phytophthora betacei sp. nov. Phylogenetic analyses suggest that this new species belongs to clade 1c of the genus Phytophthora and is a close relative of the potato late blight pathogen, P. infestans. Furthermore, it appeared as the sister group of the P. andina strains collected from wild Solanaceae (clonal lineage EC-2). Analyses of morphological and physiological characters as well as host specificity showed high support for the differentiation of these species. Based on these results, a complete description of the new species is provided and the species boundaries within Phytophthora clade 1c in northern South America are discussed.

The Expression of PHOSPHO1, nSMase2 and TNAP is Coordinately Regulated by Continuous PTH Exposure in Mineralising Osteoblast Cultures.

Sustained exposure to high levels of parathyroid hormone (PTH), as observed in hyperparathyroidism, is catabolic to bone. The increase in the RANKL/OPG ratio in response to continuous PTH, resulting in increased osteoclastogenesis, is well established. However, the effects of prolonged PTH exposure on key regulators of skeletal mineralisation have yet to be investigated. This study sought to examine the temporal expression of PHOSPHO1, TNAP and nSMase2 in mineralising osteoblast-like cell cultures and to investigate the effects of continuous PTH exposure on the expression of these enzymes in vitro. PHOSPHO1, nSMase2 and TNAP expression in cultured MC3T3-C14 cells significantly increased from day 0 to day 10. PTH induced a rapid downregulation of Phospho1 and Smpd3 gene expression in MC3T3-C14 cells and cultured hemi-calvariae. Alpl was differentially regulated by PTH, displaying upregulation in cultured MC3T3-C14 cells and downregulation in hemi-calvariae. PTH was also able to abolish the stimulatory effects of bone morphogenic protein 2 (BMP-2) on Smpd3 and Phospho1 expression. The effects of PTH on Phospho1 expression were mimicked with the cAMP agonist forskolin and blocked by the PKA inhibitor PKI (5-24), highlighting a role for the cAMP/PKA pathway in this regulation. The potent down-regulation of Phospho1 and Smpd3 in osteoblasts in response to continuous PTH may provide a novel explanation for the catabolic effects on the skeleton of such an exposure. Furthermore, our findings support the hypothesis that PHOSPHO1, nSMase2 and TNAP function cooperatively in the initiation of skeletal mineralisation.

Incretin-based medications for type 2 diabetes: an overview of reviews.

AIMS: To summarize evidence from and assess the quality of published systematic reviews evaluating the safety, efficacy and effectiveness of incretin-based medications used in the treatment of type 2 diabetes. METHODS: We identified systematic reviews of randomized controlled trials or observational studies published in any language that evaluated the safety and/or effectiveness of glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl-peptidase-4 (DPP-4) inhibitors. Data sources used include the Cochrane Library, PubMed, EMBASE, Web of Science, International Pharmaceutical Abstracts, table of contents of diabetes journals, and hand-searching of reference lists and clinical practice guidelines. The methodological quality of systematic reviews was independently assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Our study protocol was registered with PROSPERO (2013:CRD42013005149). The primary outcomes were pooled treatment effect estimates for glycaemic control, macrovascular and microvascular complications, and hypoglycaemic events. RESULTS: We identified 467 unique citations of which 84 systematic reviews met our inclusion criteria. There were 51 reviews that evaluated GLP-1 receptor agonists and 64 reviews that evaluated DPP-4 inhibitors. The median (interquartile range) AMSTAR score was 6 (3) out of 11 for quantitative and 1 (1) for non-quantitative reviews. Among the 66 quantitative systematic reviews, there were a total of 718 pooled treatment effect estimates reported for our primary outcomes and 1012 reported pooled treatment effect estimates for secondary outcomes. CONCLUSIONS: Clinicians and policy makers, when using the results of systematic reviews to inform decision-making with regard to round clinical care or healthcare policies for incretin-based medications, should consider the variability in quality of reviews.

Five Reasons to Consider Phytophthora infestans a Reemerging Pathogen.

Phytophthora infestans has been a named pathogen for well over 150 years and yet it continues to "emerge", with thousands of articles published each year on it and the late blight disease that it causes. This review explores five attributes of this oomycete pathogen that maintain this constant attention. First, the historical tragedy associated with this disease (Irish potato famine) causes many people to be fascinated with the pathogen. Current technology now enables investigators to answer some questions of historical significance. Second, the devastation caused by the pathogen continues to appear in surprising new locations or with surprising new intensity. Third, populations of P. infestans worldwide are in flux, with changes that have major implications to disease management. Fourth, the genomics revolution has enabled investigators to make tremendous progress in terms of understanding the molecular biology (especially the pathogenicity) of P. infestans. Fifth, there remain many compelling unanswered questions.

Phenotypic Characterization of Recent Clonal Lineages of Phytophthora infestans in the United States.

Phytophthora infestans, the causal agent of late blight disease, has been reported in the United States and Canada since the mid-nineteenth century. Due to the lack of or very limited sexual reproduction, the populations of P. infestans in the United States are primarily reproducing asexually and, thus, show a simple genetic structure. The emergence of new clonal lineages of P. infestans (US-22, US-23, and US-24) responsible for the late blight epidemics in the northeastern region of the United States in the summers of 2009 and 2010 stimulated an investigation into phenotypic traits associated with these genotypes. Mating type, differences in sensitivity to mefenoxam, differences in pathogenicity on potato and tomato, and differences in rate of germination were studied for clonal lineages US-8, US-22, US-23, and US-24. Both A1 and A2 mating types were detected. Lineages US-22, US-23, and US-24 were generally sensitive to mefenoxam while US-8 was resistant. US-8 and US-24 were primarily pathogenic on potato while US-22 and US-23 were pathogenic on both potato and tomato. Indirect germination was favored at lower temperatures (5 and 10°C) whereas direct germination, though uncommon, was favored at higher temperatures (20 and 25°C). Sporangia of US-24 released zoospores more rapidly than did sporangia of US-22 and US-23. The association of characteristic phenotypic traits with genotype enables the prediction of phenotypic traits from rapid genotypic analyses for improved disease management.

The 2009 Late Blight Pandemic in the Eastern United States - Causes and Results.

The tomato late blight pandemic of 2009 made late blight into a household term in much of the eastern United States. Many home gardeners and many organic producers lost most if not all of their tomato crop, and their experiences were reported in the mainstream press. Some CSAs (Community Supported Agriculture) could not provide tomatoes to their members. In response, many questions emerged: How did it happen? What was unusual about this event compared to previous late blight epidemics? What is the current situation in 2012 and what can be done? It's easiest to answer these questions, and to understand the recent epidemics of late blight, if one knows a bit of the history of the disease and the biology of the causal agent, Phytophthora infestans.

Late-onset Leclercia adecarboxylata bacteraemia in a premature infant in the NICU.

UNLABELLED: Late-onset sepsis is a unique entity in the neonatal intensive care unit (NICU), as organisms involved are, by definition, nosocomial. As such, a limited number of microbes are characteristically involved. Leclercia adecarboxylata is a gram-negative bacillus rarely cultured in a clinical context, with the few published cases primarily involving immunocompromised adults. We present an ex-26-week newborn girl who developed late-onset sepsis with Leclercia adecarboxylata bacteraemia in the NICU. The infection was successfully treated with gentamicin and cefotaxime. This is the fifth paediatric report of Leclercia adecarboxylata infection, and the first in a neonate. The case raises the possibility that prior courses of antibiotics may have predisposed this individual to a rare infection essentially limited to immunocompromised individuals. CONCLUSION: Leclercia adecarboxylata is a rare infection, particularly in immunocompetent individuals. In neonates, the clinical course can be good with timely initiation of appropriate antibiotics.

On the effect of irregular uterine activity during a vaginal delivery using an electro-chemo-mechanical constitutive model.

During a normal vaginal delivery, the muscle cells propagate electrical signals throughout the uterine wall, resulting in uterine contractions. However, uncoordinated uterine activity may disturb the uterine contractions pattern and negatively impact fetal and maternal health. Some of the abnormalities identified by the specialists are excessively short resting intervals and tachysystole. This work aims to investigate the influence of abnormal uterine activity in terms of maximum principal stress distribution and collagen fibers stretch in the uterine tissue during vaginal delivery with (i) excessively short resting intervals without changing the contraction time, and (ii) tachysystole (contraction and reduced resting times). These patterns are compared with a normal uterine contraction pattern. To achieve our aims, a biomechanical model was developed, including finite element models of the uterus and the fetus, and an electro-chemo-mechanical constitutive model. Generally, the excessively short resting intervals exhibit higher average maximum principal stresses during the contraction and resting stages, lower average fibers stretch values in the longitudinal direction and higher stretch in the circumferential direction. On the other hand, the tachysystole exhibit generally lower stress values during the uterine contraction and higher stress values during the resting stages, higher stretch in the longitudinal direction, and lower stretch in the circumferential direction.

The swelling behavior of the mouse cervix: Changing kinetics with osmolarity and the role of hyaluronan in pregnancy.

The cervical remodeling process during pregnancy is characterized by progressive compositional and structural changes in the tissues extra-cellular matrix (ECM). Appropriately timed remodeling is critical for healthy gestation and prevention of premature cervical softening leading to preterm birth (PTB). Modification of the ECM glycosaminoglycans (GAGs) content with advancing pregnancy, especially the non-sulfated GAG hyaluronan (HA), is a fundamental change associated with cervical remodeling. While GAGs have numerous physiological roles, the mechanical consequence of evolving GAG content on cervical structure-function behavior remains an open question. Additionally, an understanding of cervical swelling properties, postulated to be regulated in part by GAGs, is required for the appropriate definition of a reference configuration for mechanical tests and to enhance biological understanding. To investigate cervical swelling, osmotic loading tests are conducted on isolated wild type mouse cervices throughout pregnancy. These tests are performed in various osmolarity solutions to assess the influence of the media on swelling kinetics. A genetically altered strain of mice with depletion of cervical HA is also tested to elucidate the contribution of HA to tissue swelling. Results show ex vivo cervical swelling is significant with volume changes ranging from 20 to 100% after 3h of free swelling. The swelling kinetics depend highly on osmolarity of the media and is altered with advancing pregnancy. The contribution of HA to swelling is only significant in hypo-osmotic solution when HA cervical content is high at the end of pregnancy. In summary, it is critical to account for swelling deformation mechanisms after excision in mechanical experiments. STATEMENT OF SIGNIFICANCE: The cervical extracellular matrix (ECM) undergoes drastic changes to fulfill the functional change of the cervix during pregnancy. Inappropriate timing for this transformation can result in preterm birth, a severe clinical challenge. One of the fundamental changes of the cervical ECM is the significant modification of the glycosaminoglycan content, especially hyaluronan (HA), which is thought to contribute significantly to the swelling and mechanical properties of the cervix. This study aims to measure the swelling kinetics of cervical tissue during pregnancy and to investigate the role of HA in these swelling tendencies. Results show the significant swelling of cervical tissue, which evolves as pregnancy progresses, highlighting a key material property feature of the remodeled cervix. Using a mouse strain with a cervical HA depletion, this work shows HA contributes to the swelling trends of late-term cervical tissue, in a hypo-osmotic solution.

Changing lives, dynamic plans: Prospective assessment of 12-month changes in pregnancy timing intentions and personal circumstances using data from HER Salt Lake.

OBJECTIVES: To explore the association between changes in personal circumstances and shifts in pregnancy intentions. STUDY DESIGN: New start contraceptive clients, who desired to prevent pregnancy for at least one year enrolled in the survey arm of the HER Salt Lake Contraceptive Initiative (September 2015 -March 2017) and responded to the question "What are your future pregnancy plans?" at enrollment and 12-month follow-up. We estimated multivariable binary logistic fixed-effects regressions to examine the association between changes in personal circumstances and a change from never desiring a pregnancy at enrollment to considering one in the future at 12-month follow-up. RESULTS: The majority of the 2825 participants (2246, 79%) maintained their pregnancy timing intention over the 12-month study period. Multivariable analyses of the 208 participants who changed from never desiring a pregnancy to considering pregnancy in the future at 12-month follow-up indicated that entering cohabitation (aOR 3.14, 95% CI 1.30-7.58), increased household income (aOR 1.06, 95% CI 1.00-1.13), and changes from unemployment to full-time employment (aOR 5.94, 95% CI 1.29-27.36) are associated with increased the odds of desiring a future pregnancy after never wanting one a year prior. CONCLUSIONS: Pregnancy intentions are dynamic over twelve months and covary with partner status, household income, and employment status. Pregnancy intentions are linked to changes in life circumstances. Health care providers need to frequently assess pregnancy intentions and resulting contraceptive or preconception needs.

Mechanical Effects of a Maylard Scar During a Vaginal Birth After a Previous Caesarean.

Caesarean section is one of the most common surgeries worldwide, even though there is no evidence supporting maternal and perinatal long-term benefits. Furthermore, the mechanical behavior of a caesarean scar during a vaginal birth after caesarean (VBAC) is not well understood since there are several questions regarding the uterine wound healing process. The aim of this study is to investigate the biomechanical Maylard fiber reorientation and stiffness influence during a VBAC through computational methods. A biomechanical model comprising a fetus and a uterus was developed, and a chemical-mechanical constitutive model that triggers uterine contractions was used, where some of the parameters were adjusted to account for the matrix and fiber stiffness increase in the caesarean scar. Several mechanical simulations were performed to analyze different scar fibers arrangements, considering different values for the respective matrix and fibers stiffness. The results revealed that a random fiber arrangement in the Maylard scar has a much higher impact on its mechanical behavior during a VBAC than the common fibers arrangement present in the uninjured uterine tissue. An increase of the matrix scar stiffness exhibits a lower impact, while an increase of the fiber's stiffness has no significant influence.

Effect of elasticity on subbandage pressure of three layer tubular compression bandages in healthy volunteers: a RCT.

OBJECTIVE: To estimate the difference between mean interface sub-bandage pressures of two multilayer compression bandage systems in healthy volunteers when supine, standing, exercising and during recovery. METHOD: Inelastic and elastic compression bandages were randomised to opposite limbs of each participant. Sub-bandage interface pressures for both bandages were compared within person. Participants and study staff were aware of the treatment. A pressure transducer measured sub-bandage pressures on the medial aspect of the lower leg, at the transition of the gastrocnemius muscle into the Achilles tendon (B1). The difference in interface pressure for the two different compression bandages was measured at level B1 during supine resting, standing, exercise and recovery. We defined the pressure difference between active standing and lying as a measure of stiffness, and amplitude as the range of pressures during plantar flexion while standing. The two bandage systems (inelastic and elastic) were applied from the base of the toes to just below knee and remained in place for the duration of the experiment. Elastic bandage consisted of three layers of graduated tubular bandage (83% cotton, 9% Lycra, 8% polyamide). Inelastic or short-stretch bandage consisted of 100% cotton crepe bandage. RESULTS: Interface sub-bandage pressures varied during different activities, but the mean difference in interface pressures between inelastic and elastic bandages was consistently at least 13 mm Hg. Stiffness was 7.3 mm Hg higher in the inelastic group (95% CI 5.1-9.5). The estimated difference in amplitude of sub-bandage pressure between the bandages during exercise was 15.5 mm Hg (95% CI 12.2-18.9). CONCLUSION: We found in vivo interface sub-bandage pressures varied with the type of bandage and activity phase. Inelastic bandages resulted in an increased mean interface sub-bandage pressure when resting and recovering, which was further increased when standing or exercising. Bandage stiffness and amplitude were also greater for inelastic compared with elastic bandages. CONFLICT OF INTEREST: None.

CT metal artifact reduction algorithms: Toward a framework for objective performance assessment.

PURPOSE: Although several metal artifact reduction (MAR) algorithms for computed tomography (CT) scanning are commercially available, no quantitative, rigorous, and reproducible method exists for assessing their performance. The lack of assessment methods poses a challenge to regulators, consumers, and industry. We explored a phantom-based framework for assessing an important aspect of MAR performance: how applying MAR in the presence of metal affects model observer performance at a low-contrast detectability (LCD) task This work is, to our knowledge, the first model observer-based framework for the evaluation of MAR algorithms in the published literature. METHODS: We designed a numerical head phantom with metal implants. In order to incorporate an element of randomness, the phantom included a rotatable inset with an inhomogeneous background. We generated simulated projection data for the phantom. We applied two variants of a simple MAR algorithm, sinogram inpainting, to the projection data, that we reconstructed using filtered backprojection. To assess how MAR affected observer performance, we examined the detectability of a signal at the center of a region of interest (ROI) by a channelized Hotelling observer (CHO). As a figure of merit, we used the area under the ROC curve (AUC). RESULTS: We used simulation to test our framework on two variants of the MAR technique of sinogram inpainting. We found that our method was able to resolve the difference in two different MAR algorithms' effect on LCD task performance, as well as the difference in task performances when MAR was applied, vs not. CONCLUSION: We laid out a phantom-based framework for objective assessment of how MAR impacts low-contrast detectability, that we tested on two MAR algorithms. Our results demonstrate the importance of testing MAR performance over a range of object and imaging parameters, since applying MAR does not always improve the quality of an image for a given diagnostic task. Our framework is an initial step toward developing a more comprehensive objective assessment method for MAR, which would require developing additional phantoms and methods specific to various clinical applications of MAR, and increasing study efficiency.

MRNIP is a replication fork protection factor.

The remodeling of stalled replication forks to form four-way DNA junctions is an important component of the replication stress response. Nascent DNA at the regressed arms of these reversed forks is protected by RAD51 and the tumor suppressors BRCA1/2, and when this function is compromised, stalled forks undergo pathological MRE11-dependent degradation, leading to chromosomal instability. However, the mechanisms regulating MRE11 functions at reversed forks are currently unclear. Here, we identify the MRE11-binding protein MRNIP as a novel fork protection factor that directly binds to MRE11 and specifically represses its exonuclease activity. The loss of MRNIP results in impaired replication fork progression, MRE11 exonuclease-dependent degradation of reversed forks, persistence of underreplicated genomic regions, chemosensitivity, and chromosome instability. Our findings identify MRNIP as a novel regulator of MRE11 at reversed forks and provide evidence that regulation of specific MRE11 nuclease activities ensures protection of nascent DNA and thereby genome integrity.