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The surveillance of translation is critical for the fitness of organisms from bacteria to humans. Ribosome-associated Quality Control (RQC) is a surveillance mechanism that promotes the elimination of truncated polypeptides, byproducts of ribosome stalling during translation. In canonical mammalian RQC, NEMF binds to the large ribosomal subunit and recruits the E3 ubiquitin ligase Listerin, which marks the nascent-chains for proteasomal degradation. NEMF additionally extends the nascent-chain's C-terminus with poly-alanine ('Ala-tail'), exposing lysines in the ribosomal exit tunnel for ubiquitination. In an alternative, Listerin-independent RQC pathway, released nascent-chains are targeted by Ala-tail-binding E3 ligases. While mutations in Listerin or in NEMF selectively elicit neurodegeneration in mice and humans, the physiological significance of Ala-tailing and its role in disease have remained unknown. Here, we report the analysis of mice in which NEMF's Ala-tailing activity was selectively impaired. Whereas the Nemf homozygous mutation did not affect lifespan and only led to mild motor defects, genetic interaction analyses uncovered its synthetic lethal phenotype when combined with the lister neurodegeneration-causing mutation. Conversely, the lister phenotype was markedly improved when Ala-tailing capacity was partially reduced by a heterozygous Nemf mutation. Providing a plausible mechanism for this striking switch from early neuroprotection to subsequent neurotoxicity, we found that RQC substrates that evade degradation form amyloid-like aggregates in an Ala-tail dependent fashion. These findings uncover a critical role for Ala-tailing in mammalian proteostasis, and deepen our molecular understanding of pathophysiological roles of RQC in neurodegeneration.

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Diagnostic multiparametric MRI of the prostate has steadily evolved over the last three decades and can now reliably depict the dominant tumor in most men with prostate cancer. In response, several methods of targeted biopsy to direct tissue sampling of suspected tumor foci seen at multiparametric MRI have been developed and successfully tested in recent years, including software-assisted MRI-ultrasound (US) fusion biopsy and direct MRI-guided in-bore biopsy. These advances are leading to a sea change in the approach to prostate cancer diagnosis, with the traditional approach of blind systematic biopsy increasingly being replaced by MRI directed targeted biopsy. This review aims to describe the current status of targeted biopsy, with an emphasis on the relative accuracy of different techniques. The results of several critical large multicenter trials are presented, while unanswered questions that require more research are highlighted.

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ABSTRACT: We describe early ex vivo proof-of-concept testing of a novel system composed of a disposable endorectal coil and converging multichannel needle guide with a reusable clamp stand, embedded electronics, and baseplate to allow for endorectal magnetic resonance (MR) imaging and in-bore MRI-targeted biopsy of the prostate as a single integrated procedure. Using prostate phantoms imaged with standard T 2 -weighted sequences in a Siemens 3T Prisma MR scanner, we measured the signal-to-noise ratio in successive 1-cm distances from the novel coil and from a commercially available inflatable balloon coil and measured the lateral and longitudinal deviation of the tip of a deployed MR compatible needle from the intended target point. Signal-to-noise ratio obtained with the novel system was significantly better than the inflatable balloon coil at each of five 1-cm intervals, with a mean improvement of 78% ( P < 0.05). In a representative sampling of 15 guidance channels, the mean lateral deviation for MR imaging-guided needle positioning was 1.7 mm and the mean longitudinal deviation was 2.0 mm. Our ex vivo results suggest that our novel system provides significantly improved signal-to-noise ratio when compared with an inflatable balloon coil and is capable of accurate MRI-guided needle deployment.

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BACKGROUND: Bariatric surgery is a proven effective method of reducing obesity and reversing or preventing obesity-related comorbidities. The aim of this study is to describe the development of a tool to assist with the prioritization of patients with obesity for bariatric surgery. The tool would meet the criteria for being evidence-based, fair, implementable and transparent. METHODS: The development of the tool involved a validated step-by-step process based on the consensus of clinical judgement of the New Zealand Ministry of Health working party. The process involved elicitation of criteria, clinical ranking of vignettes and creation of weightings using the 1000Minds® tool. The concurrent validity was tested by comparing tool rankings of vignettes to clinical judgement rankings. RESULTS: Four major criteria (impact on life, likelihood of achieving maximum benefit with respect to control of diabetes, duration of benefit and surgical risk) are used to characterize the need and potential to benefit. The impact on life criterion has the largest weighting (up to 44.3%). There was good concurrent validity with a correlation coefficient r = 0.67. CONCLUSION: The tool as presented is evidence-based, transparent and internally valid. The next step is to assess the predictive validity of the tool using real patient data to evaluate the effectiveness of the tool and determine what modifications may be required.

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Gastric cancer is globally the fifth leading cause of cancer death. We present a case report describing the unique genomic characteristics of an Epstein-Barr virus-negative gastric cancer with esophageal invasion and regional lymph node metastasis. Genomic tests were performed first with the stomach biopsy using platforms FoundationOne, OncoDNA, and Oncopanel at Dana Farber Institute. Following neoadjuvant chemotherapy, residual tumor was resected and the stomach and esophageal residual tumor samples were compared with the initial biopsy by whole exome sequencing and molecular pathway analysis platform Oncobox. Copy number variation profiling perfectly matched the whole exome sequencing results. A moderate agreement was seen between the diagnostic platforms in finding mutations in the initial biopsy. Final data indicate somatic activating mutation Q546K in PIK3CA gene, somatic frameshifts in PIH1D1 and FBXW7 genes, stop-gain in TP53BP1, and a few somatic mutations of unknown significance. RNA sequencing analysis revealed upregulated expressions of MMP7, MMP9, BIRC5, and PD-L1 genes and strongly differential regulation of several molecular pathways linked with the mutations identified. According to test results, the patient received immunotherapy with anti-PD1 therapy and is now free of disease for 2 years. Our data suggest that matched tumor and normal tissue analyses have a considerable advantage over tumor biopsy-only genomic tests in stomach cancer.

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We report that fluoroquinolone-resistant Escherichia coli are found in feces of 8.8% of healthy women, with most bacteria belonging to pandemic multidrug-resistant ST131-H30R or ST1193 clonal groups. Moreover, these highly uropathogenic clonal groups demonstrate an especially prolonged gut persistence and high rate of bacteriuria without documented urinary tract infection.

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INTRODUCTION: Balance loss and falls are a common and multifactorial finding in persons with Parkinson's Disease (pwPD). Objective fatigability is thought to contribute to falls in other neurologic conditions, but its impact on balance in pwPD is not known. The two-fold purpose of this study was to: 1) establish that a 6-minute walk (6MWFast) is a stimulus to subjective fatigue for pwPD; and, 2) determine if the Mini Balance Evaluation Systems Test (MBT) is sensitive to change that was induced by a fatiguing condition. METHODS: Using a randomized crossover design, 19 research participants performed a Mini Balance Evaluation Systems Test (MBT) before and after either a 'fast' 6-minute walk (6MWFast) to induce fatigue or a 6-minute rest. RESULTS: VASF scores increased after the 6MWFast. Total MBT scores in research participants with Modified Hoehn and Yahr (H&Y) scores of 3.0 and above differed significantly before and after the 'fast' 6-minute walk (p = .007, n = 9) while participants with H&Y scores of 1.5 to 2.5 (p = .084, n = 10) did not, suggesting that more disabled pwPD were more likely to experience fatigability that interfered with balance. CONCLUSIONS: A 6MWFast is a sufficient stimulus to induce subjective fatigue in pwPD and to decrease total MBT scores for more disabled pwPD. Balance evaluations should occur when pwPD are in fatigued and unfatigued states to determine whether fatigue has an impact on balance performance.

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We describe the rapid and ongoing emergence across multiple US cities of a new multidrug-resistant Escherichia coli clone-sequence type (ST) 1193-resistant to fluoroquinolones (100%), trimethoprim-sulfamethoxazole (55%), and tetracycline (53%). ST1193 is associated with younger adults (age <40 years) and currently comprises a quarter of fluoroquinolone-resistant clinical E. coli urine isolates.

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Reports of a role of postmenopausal estrogen replacement therapy in the development of breast cancer have been inconsistent. Although many epidemiologic studies have failed to show an association between short-term use of estrogen and breast cancer, there are indications that long-term use may present an increased risk. We undertook a long-term, retrospective cohort study of the incidence of breast cancer in women who had taken long-term estrogen (average 17.2 years), compared to women who had not taken estrogen. Subjects were 454 women born between 1900 and 1915, who were members of a large health maintenance organization in northern California. By the end of 1995, 26 (11.2%) of estrogen users developed breast cancer, as did 9 (4.1%) of the nonusers; the relative risk (RR) for estrogen use was 2.8 [95% confidence interval (95% CI) 1.3-5.9]. Adjustment for age and multiple breast cancer risk factors, including breast cancer surveillance, reduced the RR for estrogen to 2.0 (95% CI 0.9-4.5). We conclude that long-term estrogen use is associated with a substantially increased risk of breast cancer.

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Primary care physicians experience high rates of burnout, which results in diminished quality of life, poorer quality of care, and workforce attrition. In this randomized controlled trial, our primary aim was to examine the impact of a brief mindfulness-based intervention (MBI) on burnout, stress, mindfulness, compassion, and resilience among physicians. A total of 33 physicians completed the baseline assessment and were randomized to the Mindful Medicine Curriculum (MMC; n = 17) or waitlist control group (n = 16). Participants completed self-report measures at baseline, post-MBI, and 3-month follow-up. We also analyzed satisfaction with doctor communication (DCC) and overall doctor rating (ODR) data from patients of the physicians in our sample. Participants in the MMC group reported significant improvements in stress (P < .001), mindfulness (P = .05), emotional exhaustion (P = .004), and depersonalization (P = .01) whereas in the control group, there were no improvements on these outcomes. Although the MMC had no impact on patient-reported DCC or ODR, among the entire sample at baseline, DCC and ODR were significantly correlated with several physician outcomes, including resilience and personal achievement. Overall, these findings suggest that a brief MBI can have a positive impact on physician well-being and potentially enhance patient care.

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BACKGROUND: The perceived benefits of Roux-en-Y laparoscopic gastric bypass (LRYGB) surgery in the ≥60s are regarded as being significantly less than in the younger population. This study examined a New Zealand population who underwent LRYGB and analysed the mortality rate, complications and postoperative weight loss. METHODS: This was a retrospective cohort study of patients who underwent LRYGB over a 12-year period and had attended up to 1 year of follow-up clinic. The study population was from a single centre in New Zealand. RESULTS: A total of 1362 patients were eligible. Demographic analysis showed the <60 to have 83% female majority, mean age of 43 years and a mean body mass index of 46. The ≥60 group had a 76% female majority, mean age of 63 years and a mean body mass index of 45. The % excess weight loss, % weight loss and weight loss at 1 year all showed a significant difference. Analysis of the % excess weight loss at 1 year in the ≥60s showed a mean of 79% and a median of 78% (95% confidence interval: 69%, 85%). In the <60s the mean was 84% and the median 84% (95% confidence interval: 83%, 85%). Comparison between the groups showed a significant difference (Kruskal-Wallis test, P = 0.0064). The complication frequency of the groups was not significantly different (chi-square test, P = 0.7605). CONCLUSION: LRYGB is an effective weight loss operation in the <60s and ≥60s. LRYGB is safe, with a low complication rate and 30-day postoperative mortality rate. LRYGB should not be restricted on the basis of age alone.

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In July 2011, the observation of a massive phytoplankton bloom underneath a sea ice-covered region of the Chukchi Sea shifted the scientific consensus that regions of the Arctic Ocean covered by sea ice were inhospitable to photosynthetic life. Although the impact of widespread phytoplankton blooms under sea ice on Arctic Ocean ecology and carbon fixation is potentially marked, the prevalence of these events in the modern Arctic and in the recent past is, to date, unknown. We investigate the timing, frequency, and evolution of these events over the past 30 years. Although sea ice strongly attenuates solar radiation, it has thinned significantly over the past 30 years. The thinner summertime Arctic sea ice is increasingly covered in melt ponds, which permit more light penetration than bare or snow-covered ice. Our model results indicate that the recent thinning of Arctic sea ice is the main cause of a marked increase in the prevalence of light conditions conducive to sub-ice blooms. We find that as little as 20 years ago, the conditions required for sub-ice blooms may have been uncommon, but their frequency has increased to the point that nearly 30% of the ice-covered Arctic Ocean in July permits sub-ice blooms. Recent climate change may have markedly altered the ecology of the Arctic Ocean.

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Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited polyneuropathies. Mutations in 80 genetic loci can cause forms of CMT, resulting in demyelination and axonal dysfunction. The clinical presentation, including sensory deficits, distal muscle weakness, and atrophy, can vary greatly in severity and progression. Here, we used mouse models of CMT to demonstrate genetic interactions that result in a more severe neuropathy phenotype. The cell adhesion molecule Nrcam and the Na+ channel Scn8a (NaV1.6) are important components of nodes. Homozygous Nrcam and heterozygous Scn8a mutations synergized with both an Sh3tc2 mutation, modeling recessive demyelinating Charcot-Marie-Tooth type 4C, and mutations in Gars, modeling dominant axonal Charcot-Marie-Tooth type 2D. We conclude that genetic variants perturbing the structure and function of nodes interact with mutations affecting the cable properties of axons by thinning myelin or reducing axon diameter. Therefore, genes integral to peripheral nodes are candidate modifiers of peripheral neuropathy.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Using TDP-43(A315T) mice, an ALS and FTD model with marked cortical pathology, we found that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PNs) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PNs and alleviated neurodegeneration, suggesting a new therapeutic target for ALS and FTD.

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We present Visualization-by-Sketching, a direct-manipulation user interface for designing new data visualizations. The goals are twofold: First, make the process of creating real, animated, data-driven visualizations of complex information more accessible to artists, graphic designers, and other visual experts with traditional, non-technical training. Second, support and enhance the role of human creativity in visualization design, enabling visual experimentation and workflows similar to what is possible with traditional artistic media. The approach is to conceive of visualization design as a combination of processes that are already closely linked with visual creativity: sketching, digital painting, image editing, and reacting to exemplars. Rather than studying and tweaking low-level algorithms and their parameters, designers create new visualizations by painting directly on top of a digital data canvas, sketching data glyphs, and arranging and blending together multiple layers of animated 2D graphics. This requires new algorithms and techniques to interpret painterly user input relative to data "under" the canvas, balance artistic freedom with the need to produce accurate data visualizations, and interactively explore large (e.g., terabyte-sized) multivariate datasets. Results demonstrate a variety of multivariate data visualization techniques can be rapidly recreated using the interface. More importantly, results and feedback from artists support the potential for interfaces in this style to attract new, creative users to the challenging task of designing more effective data visualizations and to help these users stay "in the creative zone" as they work.

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We present a modelling study of processes controlling the summer melt of the Arctic sea ice cover. We perform a sensitivity study and focus our interest on the thermodynamics at the ice-atmosphere and ice-ocean interfaces. We use the Los Alamos community sea ice model CICE, and additionally implement and test three new parametrization schemes: (i) a prognostic mixed layer; (ii) a three equation boundary condition for the salt and heat flux at the ice-ocean interface; and (iii) a new lateral melt parametrization. Recent additions to the CICE model are also tested, including explicit melt ponds, a form drag parametrization and a halodynamic brine drainage scheme. The various sea ice parametrizations tested in this sensitivity study introduce a wide spread in the simulated sea ice characteristics. For each simulation, the total melt is decomposed into its surface, bottom and lateral melt components to assess the processes driving melt and how this varies regionally and temporally. Because this study quantifies the relative importance of several processes in driving the summer melt of sea ice, this work can serve as a guide for future research priorities.

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Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole-genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing.

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