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The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

BackgroundGermline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.MethodsCDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories.ResultsUpdated CDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing.ConclusionsThe development and evolution of CDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.

UNLABELLED: This study provides extended seasonal predictions for the Upper Colorado River Basin (UCRB) precipitation in boreal spring using an artificial neural network (ANN) model and a stepwise linear regression model, respectively. Sea surface temperature (SST) predictors are developed taking advantage of the correlation between the precipitation and SST over three ocean basins. The extratropical North Pacific has a higher correlation with the UCRB spring precipitation than the tropical Pacific and North Atlantic. For the ANN model, the Pearson correlation coefficient between the observed and predicted precipitation exceeds 0.45 (p-value  40% for lead times less than 8 months. This study highlights the advantage of oceanic climate signals in extended seasonal predictions for the UCRB spring precipitation and supports the improvement of the UCRB streamflow prediction and related water resource decisions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00382-022-06422-x.

To estimate snowpack water storage in mountain basins, this study presents a framework that couples a deep-learning long short-term memory (LSTM) model and a zonal bias-correction approach for assimilating ground snow observations. We explored the framework's ability for snow water equivalent (SWE) mapping and forecasting in a domain, including the Feather, Yuba-Bear, and American River basins in California's Sierra Nevada. Through a series of different modeling experiments, performances of the LSTM model and bias-correction approach were independently investigated. The LSTM model trained with meteorological forcing (precipitation and temperature), landscape attributes, and antecedent lagged snow conditions, showed good agreement with SWE reanalysis data (Nash-Sutcliffe efficiency, NSE = 0.99). However, for continuous SWE projection without using SWE reanalysis as the antecedent snow condition, the LSTM model underestimated basin-scale and site-scale SWE (NSE = 0.19), reflecting large discrepancies since model bias accumulates over time. Thus, a zonal inverse-distance-weighting (IDW) bias-correction approach was proposed to assimilate ground observations and correct model trajectory. With the bias correction, SWE estimates were significantly improved (NSE = 0.79). The zonal IDW approach accounts for snow differences across different areas by zonal distance, based on historical snow patterns, showing better predictions than the original IDW, which showed larger biases in complex terrain with a rain shadow. We observed that SWE estimates from the framework were not sensitive to the difference in precipitation and temperature forcings between observation-based data and one-day-ahead weather forecasts, suggesting that the framework can use weather-forecast forcing for snowpack forecasting. Comparison between results from monthly and daily bias corrections showed that increasing bias-correction frequency and integrating more snow observations can further improve SWE estimates. Using the continuous SWE products, analyses of 170 precipitation events showed that snowmelt often occurred when daily temperature was above 3.7 °C, augmenting runoff. The proposed framework leverages ground observations and a deep-learning model to provide daily gridded snowpack estimates, which are important for runoff forecasting and water supply.

Monoclonal antibody therapeutics to treat coronavirus disease (COVID-19) have been authorized by the US Food and Drug Administration under Emergency Use Authorization (EUA). Many barriers exist when deploying a novel therapeutic during an ongoing pandemic, and it is critical to assess the needs of incorporating monoclonal antibody infusions into pandemic response activities. We examined the monoclonal antibody infusion site process during the COVID-19 pandemic and conducted a descriptive analysis using data from 3 sites at medical centers in the United States supported by the National Disaster Medical System. Monoclonal antibody implementation success factors included engagement with local medical providers, therapy batch preparation, placing the infusion center in proximity to emergency services, and creating procedures resilient to EUA changes. Infusion process challenges included confirming patient severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity, strained staff, scheduling, and pharmacy coordination. Infusion sites are effective when integrated into pre-existing pandemic response ecosystems and can be implemented with limited staff and physical resources.

This study reports on a blending approach using snowpack measurements from a wireless-sensor network, gauge precipitation, and atmospheric-moisture data to estimate mountain precipitation amount and phase. We applied the approach in California's American River basin, using dense measurements from a network consisting of over 130 sensor nodes distributed across the upper, more snow-dominated part of the basin (≥1,500 m elevation). Analysis of 60 precipitation events in water years 2014–2017 showed that the approach provides estimates of precipitation and orographic enhancement that reduce uncertainty from apparent snow undercatch by limited gauges. This approach also infers total precipitation based on snow measurements during rain-on-snow events. The sensor network and blending approach yielded median upper-basin orographic precipitation gradients (OPGs) of 0.57 km−1, smaller than the also-positive lower-basin (

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

Categorization is a fundamental cognitive strategy employed to ease information processing and to aid memory formation. Past research on how humans categorize objects has used images of objects as experimental stimuli. Concurrently, studies in the past 10 years have found differences in the processing of images as compared to real-world objects. One proposed explanation is that these results are due to differences in the affordances of images versus objects. Using a similarity judgement paradigm, we explored the effect of affordances in a categorization task including words (object names), images, and objects. Consistent with previous research, we found significant differences in how participants made similarity judgements of images and objects. Moreover, we found that similarity judgments using object names were much more similar to the judgments of pictures than of objects. An exploratory cluster analysis opens the possibility of framing such differences as affordance driven. These results suggest a need for more ecologically valid categorization tasks, more conservative inferences when using images as stimuli in these tasks, and the need for further exploring the role of affordances in categorization.

Sleep's role in memory consolidation is widely acknowledged, but its role in weakening memories is still debated. Memory weakening is evolutionary beneficial and makes an integral contribution to cognition. We sought evidence on whether sleep-based memory reactivation can facilitate memory suppression. Participants learned pairs of associable words (e.g., DIET-CREAM) and were then exposed to hint words (e.g., DIET) and instructed to either recall ("think") or suppress ("no-think") the corresponding target words (e.g., CREAM). As expected, suppression impaired retention when tested immediately after a 90-min nap. To test if reactivation could selectively enhance memory suppression during sleep, we unobtrusively presented one of two sounds conveying suppression instructions during sleep, followed by hint words. Results showed that targeted memory reactivation did not enhance suppression-induced forgetting. Although not predicted, post-hoc analyses revealed that sleep cues strengthened memory, but only for suppressed pairs that were weakly encoded before sleep. The results leave open the question of whether memory suppression can be augmented during sleep, but suggest strategies for future studies manipulating memory suppression during sleep. Additionally, our findings support the notion that sleep reactivation is particularly beneficial for weakly encoded information, which may be prioritized for consolidation.

To provide complementary information on the hydrologically important rain–snow-transition elevation in mountain basins, this study provides two estimation methods using ground measurements from basin-scale wireless sensor networks: one based on wet-bulb temperature Twet and the other based on snow-depth measurements of accumulation and ablation. With data from 17 spatially distributed clusters (178 nodes) from two networks, in the American and Feather River basins of California’s Sierra Nevada, we analyzed transition elevation during 76 storm events in 2014–18. A Twet threshold of 0.58C best matched the transition elevation defined by snow depth. Transition elevations using Twet in upper elevations of the basins generally agreed with atmospheric snow level from radars located at lower elevations, while radar snow level was;100 m higher due to snow-level lowering on windward mountainsides during orographic lifting. Diurnal patterns of the difference between transition elevation and radar snow level were observed in the American basin, related to diurnal ground-temperature variations. However, these patterns were not found in the Feather basin due to complex terrain and higher uncertainties in transition-elevation estimates. The American basin tends to exhibit 100-m-higher transition elevations than does the Feather basin, consistent with the Feather basin being about 18 latitude farther north. Transition elevation averaged 155 m higher in intense atmospheric river events than in other events; meanwhile, snow-level lowering was enhanced with a 90-m-larger difference between radar snow level and transition elevation. On-the-ground continuous observations from distributed sensor networks can complement radar data and provide important ground truth and spatially resolved information on transition elevations in mountain basins.

AbstractTo provide complementary information on the hydrologically important rain–snow-transition elevation in mountain basins, this study provides two estimation methods using ground measurements from basin-scale wireless sensor networks: one based on wet-bulb temperature Twet and the other based on snow-depth measurements of accumulation and ablation. With data from 17 spatially distributed clusters (178 nodes) from two networks, in the American and Feather River basins of California’s Sierra Nevada, we analyzed transition elevation during 76 storm events in 2014–18. A Twet threshold of 0.5°C best matched the transition elevation defined by snow depth. Transition elevations using Twet in upper elevations of the basins generally agreed with atmospheric snow level from radars located at lower elevations, while radar snow level was ~100 m higher due to snow-level lowering on windward mountainsides during orographic lifting. Diurnal patterns of the difference between transition elevation and radar snow level were observed in the American basin, related to diurnal ground-temperature variations. However, these patterns were not found in the Feather basin due to complex terrain and higher uncertainties in transition-elevation estimates. The American basin tends to exhibit 100-m-higher transition elevations than does the Feather basin, consistent with the Feather basin being about 1° latitude farther north. Transition elevation averaged 155 m higher in intense atmospheric river events than in other events; meanwhile, snow-level lowering was enhanced with a 90-m-larger difference between radar snow level and transition elevation. On-the-ground continuous observations from distributed sensor networks can complement radar data and provide important ground truth and spatially resolved information on transition elevations in mountain basins.

BackgroundNitric oxide (NO) plays an important role in normal postnatal transition. Our aims were to determine whether adding inhaled NO (iNO) decreases supplemental oxygen exposure in preterm infants requiring positive pressure ventilation (PPV) during resuscitation and to study iNO effects on heart rate (HR), oxygen saturation (SpO2), and need for intubation during the first 20 min of life.MethodsThis was a pilot, double-blind, randomized, placebo-controlled trial. Infants 25 0/7-31 6/7 weeks' gestational age requiring PPV with supplemental oxygen during resuscitation were enrolled. PPV was initiated with either oxygen (FiO2-0.30) + iNO at 20 ppm (iNO group) or oxygen (FiO2-0.30) + nitrogen (placebo group). Oxygen was titrated targeting defined SpO2 per current guidelines. After 10 min, iNO/nitrogen was weaned stepwise per protocol and terminated at 17 min.ResultsTwenty-eight infants were studied (14 per group). The mean gestational age in both groups was similar. Cumulative FiO2 and rate of exposure to high FiO2 (>0.60) were significantly lower in the iNO group. There were no differences in HR, SpO2, and need for intubation.ConclusionsAdministration of iNO as an adjunct during neonatal resuscitation is feasible without side effects. It diminishes exposure to high levels of supplemental oxygen.

BackgroundNitric oxide (NO) plays an important role in normal postnatal transition. Our aims were to determine whether adding inhaled NO (iNO) decreases supplemental oxygen exposure in preterm infants requiring positive pressure ventilation (PPV) during resuscitation and to study iNO effects on heart rate (HR), oxygen saturation (SpO2), and need for intubation during the first 20 min of life.MethodsThis was a pilot, double-blind, randomized, placebo-controlled trial. Infants 25 0/7-31 6/7 weeks' gestational age requiring PPV with supplemental oxygen during resuscitation were enrolled. PPV was initiated with either oxygen (FiO2-0.30) + iNO at 20 ppm (iNO group) or oxygen (FiO2-0.30) + nitrogen (placebo group). Oxygen was titrated targeting defined SpO2 per current guidelines. After 10 min, iNO/nitrogen was weaned stepwise per protocol and terminated at 17 min.ResultsTwenty-eight infants were studied (14 per group). The mean gestational age in both groups was similar. Cumulative FiO2 and rate of exposure to high FiO2 (>0.60) were significantly lower in the iNO group. There were no differences in HR, SpO2, and need for intubation.ConclusionsAdministration of iNO as an adjunct during neonatal resuscitation is feasible without side effects. It diminishes exposure to high levels of supplemental oxygen.

ObjectiveTo determine the implications of car ownership for physical activity and weight in a global city.DesignQuasi-experimental cross sectional study.SettingBeijing, China, 2011-15.ParticipantsPeople aged 18 and older from a random sample of households who had entered a permit lottery to purchase a vehicle between January 2011 and November 2015.InterventionsPermit allowing purchase of a vehicle within six months of permit issuance.Main outcome measuresTransit use (number of subway and bus rides each week), physical activity (minutes of walking or bicycling each day), and weight, measured once in early 2016.ResultsOf 937 people analysed in total, 180 had won a permit to purchase a new vehicle. Winning the permit lottery resulted in the purchase of an additional vehicle 91% of the time (95% confidence interval 89% to 94%; P

BACKGROUND: Vegetatively propagated clones accumulate somatic mutations. The purpose of this study was to better appreciate clone diversity and involved defining the nature of somatic mutations throughout the genome. Fifteen Zinfandel winegrape clone genomes were sequenced and compared to one another using a highly contiguous genome reference produced from one of the clones, Zinfandel 03. RESULTS: Though most heterozygous variants were shared, somatic mutations accumulated in individual and subsets of clones. Overall, heterozygous mutations were most frequent in intergenic space and more frequent in introns than exons. A significantly larger percentage of CpG, CHG, and CHH sites in repetitive intergenic space experienced transition mutations than in genic and non-repetitive intergenic spaces, likely because of higher levels of methylation in the region and because methylated cytosines often spontaneously deaminate. Of the minority of mutations that occurred in exons, larger proportions of these were putatively deleterious when they occurred in relatively few clones. CONCLUSIONS: These data support three major conclusions. First, repetitive intergenic space is a major driver of clone genome diversification. Second, clones accumulate putatively deleterious mutations. Third, the data suggest selection against deleterious variants in coding regions or some mechanism by which mutations are less frequent in coding than noncoding regions of the genome.

BACKGROUND:Vegetatively propagated clones accumulate somatic mutations. The purpose of this study was to better appreciate clone diversity and involved defining the nature of somatic mutations throughout the genome. Fifteen Zinfandel winegrape clone genomes were sequenced and compared to one another using a highly contiguous genome reference produced from one of the clones, Zinfandel 03. RESULTS:Though most heterozygous variants were shared, somatic mutations accumulated in individual and subsets of clones. Overall, heterozygous mutations were most frequent in intergenic space and more frequent in introns than exons. A significantly larger percentage of CpG, CHG, and CHH sites in repetitive intergenic space experienced transition mutations than in genic and non-repetitive intergenic spaces, likely because of higher levels of methylation in the region and because methylated cytosines often spontaneously deaminate. Of the minority of mutations that occurred in exons, larger proportions of these were putatively deleterious when they occurred in relatively few clones. CONCLUSIONS:These data support three major conclusions. First, repetitive intergenic space is a major driver of clone genome diversification. Second, clones accumulate putatively deleterious mutations. Third, the data suggest selection against deleterious variants in coding regions or some mechanism by which mutations are less frequent in coding than noncoding regions of the genome.

BACKGROUND:Vegetatively propagated clones accumulate somatic mutations. The purpose of this study was to better appreciate clone diversity and involved defining the nature of somatic mutations throughout the genome. Fifteen Zinfandel winegrape clone genomes were sequenced and compared to one another using a highly contiguous genome reference produced from one of the clones, Zinfandel 03. RESULTS:Though most heterozygous variants were shared, somatic mutations accumulated in individual and subsets of clones. Overall, heterozygous mutations were most frequent in intergenic space and more frequent in introns than exons. A significantly larger percentage of CpG, CHG, and CHH sites in repetitive intergenic space experienced transition mutations than in genic and non-repetitive intergenic spaces, likely because of higher levels of methylation in the region and because methylated cytosines often spontaneously deaminate. Of the minority of mutations that occurred in exons, larger proportions of these were putatively deleterious when they occurred in relatively few clones. CONCLUSIONS:These data support three major conclusions. First, repetitive intergenic space is a major driver of clone genome diversification. Second, clones accumulate putatively deleterious mutations. Third, the data suggest selection against deleterious variants in coding regions or some mechanism by which mutations are less frequent in coding than noncoding regions of the genome.

ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, settings, and participantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.ExposuresGenetic variants associated with primary open-angle glaucoma.Main outcomes and measuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P

ObjectiveTo determine the implications of car ownership for physical activity and weight in a global city.DesignQuasi-experimental cross sectional study.SettingBeijing, China, 2011-15.ParticipantsPeople aged 18 and older from a random sample of households who had entered a permit lottery to purchase a vehicle between January 2011 and November 2015.InterventionsPermit allowing purchase of a vehicle within six months of permit issuance.Main outcome measuresTransit use (number of subway and bus rides each week), physical activity (minutes of walking or bicycling each day), and weight, measured once in early 2016.ResultsOf 937 people analysed in total, 180 had won a permit to purchase a new vehicle. Winning the permit lottery resulted in the purchase of an additional vehicle 91% of the time (95% confidence interval 89% to 94%; P

Improving the nutritional content of public school meals is a topic of intense policy interest. A main motivation is the health of school children, and, in particular, the rising childhood obesity rate. Medical and nutrition literature has long argued that a healthy diet can have a second important impact: improved cognitive function. In this paper, we test whether offering healthier meals affects student achievement as measured by test scores. Our sample includes all California (CA) public schools over a five-year period. We estimate difference-in-differences style regressions using variation that takes advantage of frequent meal-vendor contract turnover. Students at schools that contract with a healthy school-meal vendor score higher on CA state achievement tests. We do not find any evidence that healthier school meals lead to a decrease in obesity rates. The test score gains, while modest in magnitude, come at very low cost.

Employers and colleges value individuals with leadership service, but there is limited evidence on whether leadership service itself creates skills. Identification in this context has proved di cult because settings in which leadership service accrues to individuals for ostensibly random reasons are rare. In this study we estimate the e ects of random assignment to classroom leadership positions in a Chinese secondary school. We find that leadership service increases test scores, increases students’ political popularity in the classroom, makes students more likely to take initiative, and shapes students’ beliefs about the determinants of success. The results suggest that leadership service may impact human capital and is not solely a signal of preexisting skills.

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.

Spending on big-time college athletics is often justified on the grounds that athletic success attracts students and raises donations. We exploit data on bookmaker spreads to estimate the probability of winning each game for college football teams. We then condition on these probabilities using a propensity score design to estimate the effects of winning on donations, applications, and enrollment. The resulting estimates represent causal effects under the assumption that, conditional on bookmaker spreads, winning is uncorrelated with potential outcomes. We find that winning reduces acceptance rates and increases donations, applications, academic reputation, in-state enrollment, and incoming SAT scores.

Grapevine red blotch-associated virus (GRBaV) is a major threat to the wine industry in the USA. GRBaV infections (aka red blotch disease) compromise crop yield and berry chemical composition, affecting the flavor and aroma properties of must and wine. In this study, we combined genome-wide transcriptional profiling with targeted metabolite analyses and biochemical assays to characterize the impact of the disease on red-skinned berry ripening and metabolism. Using naturally infected berries collected from two vineyards, we were able to identify consistent berry responses to GRBaV across different environmental and cultural conditions. Specific alterations of both primary and secondary metabolism occurred in GRBaV-infected berries during ripening. Notably, GRBaV infections of post-véraison berries resulted in the induction of primary metabolic pathways normally associated with early berry development (e.g. thylakoid electron transfer and the Calvin cycle), while inhibiting ripening-associated pathways, such as a reduced metabolic flux in the central and peripheral phenylpropanoid pathways. We show that this metabolic reprogramming correlates with perturbations at multiple regulatory levels of berry development. Red blotch caused the abnormal expression of transcription factors (e.g. NACs, MYBs, and AP2-ERFs) and elements of the post-transcriptional machinery that function during red-skinned berry ripening. Abscisic acid, ethylene, and auxin pathways, which control both the initiation of ripening and stress responses, were also compromised. We conclude that GRBaV infections disrupt normal berry development and stress responses by altering transcription factors and hormone networks, which result in the inhibition of ripening pathways involved in the generation of color, flavor, and aroma compounds.

Grapevine red blotch-associated virus (GRBaV) is a major threat to the wine industry in the USA. GRBaV infections (aka red blotch disease) compromise crop yield and berry chemical composition, affecting the flavor and aroma properties of must and wine. In this study, we combined genome-wide transcriptional profiling with targeted metabolite analyses and biochemical assays to characterize the impact of the disease on red-skinned berry ripening and metabolism. Using naturally infected berries collected from two vineyards, we were able to identify consistent berry responses to GRBaV across different environmental and cultural conditions. Specific alterations of both primary and secondary metabolism occurred in GRBaV-infected berries during ripening. Notably, GRBaV infections of post-véraison berries resulted in the induction of primary metabolic pathways normally associated with early berry development (e.g. thylakoid electron transfer and the Calvin cycle), while inhibiting ripening-associated pathways, such as a reduced metabolic flux in the central and peripheral phenylpropanoid pathways. We show that this metabolic reprogramming correlates with perturbations at multiple regulatory levels of berry development. Red blotch caused the abnormal expression of transcription factors (e.g. NACs, MYBs, and AP2-ERFs) and elements of the post-transcriptional machinery that function during red-skinned berry ripening. Abscisic acid, ethylene, and auxin pathways, which control both the initiation of ripening and stress responses, were also compromised. We conclude that GRBaV infections disrupt normal berry development and stress responses by altering transcription factors and hormone networks, which result in the inhibition of ripening pathways involved in the generation of color, flavor, and aroma compounds.

Finger gnosis (the ability to identify which finger has beentouched) and magnitude comparison (the ability to determinewhich of two numbers is larger) are surprisingly correlated.We present a spiking neuron model of a common componentthat could be used in both tasks: an array of pointers. Weshow that if the model's single tuned parameter is set to matchhuman accuracy performance in one task, then it also matcheson the other task (with the exception of one data point). Thisprovides a novel explanation of the relation, and proposes acommon component that could be used across cognitive tasks.

Congestion plays a central role in urban and transportation economics. Existing estimates of congestion costs rely on stated or revealed preferences studies. We explore a complementary measure of congestion costs based on self-reported happiness. Exploiting quasi-random variation in daily congestion in Beijing that arises because of superstitions about the number four, we estimate a strong effect of daily congestion on self-reported happiness. When benchmarking this effect against the relationship between income and self-reported happiness we compute implied congestion costs that are several times larger than conventional estimates. Several factors, including the value of reliability and externalities on non-travelers, can reconcile our alternative estimates with the existing literature.

Congestion plays a central role in urban and transportation economics. Existing estimates of congestion costs rely on stated or revealed preferences studies. We explore a complementary measure of congestion costs based on self-reported happiness. Exploiting quasi-random variation in daily congestion in Beijing that arises because of superstitions about the number four, we estimate a strong effect of daily congestion on self-reported happiness. When benchmarking this effect against the relationship between income and self-reported happiness we compute implied congestion costs that are several times larger than conventional estimates. Several factors, including the value of reliability and externalities on non-travelers, can reconcile our alternative estimates with the existing literature.

Anthropogenic climate change amounts to a rapidly approaching, “new” stressor in the Sacramento–San Joaquin Delta system. In response to California’s extreme natural hydroclimatic variability, complex water-management systems have been developed, even as the Delta’s natural ecosystems have been largely devastated. Climate change is projected to challenge these management and ecological systems in different ways that are characterized by different levels of uncertainty. For example, there is high certainty that climate will warm by about 2°C more (than late-20th-century averages) by mid-century and about 4°C by end of century, if greenhouse-gas emissions continue their current rates of acceleration. Future precipitation changes are much less certain, with as many climate models projecting wetter conditions as drier. However, the same projections agree that precipitation will be more intense when storms do arrive, even as more dry days will separate storms. Warmer temperatures will likely enhance evaporative demands and raise water temperatures. Consequently, climate change is projected to yield both more extreme flood risks and greater drought risks. Sea level rise (SLR) during the 20th century was about 22 cm, and is projected to increase by at least 3-fold this century. SLR together with land subsidence threatens the Delta with greater vulnerabilities to inundation and salinity intrusion. Effects on the Delta ecosystem that are traceable to warming include SLR, reduced snowpack, earlier snowmelt and larger storm-driven streamflows, warmer and longer summers, warmer summer water temperatures, and water-quality changes. These changes and their uncertainties will challenge the operations of water projects and uses throughout the Delta’s watershed and delivery areas. Although the effects of of climate change on Delta ecosystems may be profound, the end results are difficult to predict, except that native species will fare worse than invaders. Successful preparation for the coming changes will require greater integration of monitoring, modeling, and decision making across time, variables, and space than has been historically normal.

While all forms of glaucoma are characterized by a specific pattern of retinal ganglion cell death, they are clinically divided into several distinct subclasses, including normal tension glaucoma, primary open angle glaucoma, congenital glaucoma, and secondary glaucoma. For each type of glaucoma there are likely numerous molecular pathways that control susceptibility to the disease. Given this complexity, a single animal model will never precisely model all aspects of all the different types of human glaucoma. Therefore, multiple animal models have been utilized to study glaucoma but more are needed. Because of the powerful genetic tools available to use in the laboratory mouse, it has proven to be a highly useful mammalian system for studying the pathophysiology of human disease. The similarity between human and mouse eyes coupled with the ability to use a combination of advanced cell biological and genetic tools in mice have led to a large increase in the number of studies using mice to model specific glaucoma phenotypes. Over the last decade, numerous new mouse models and genetic tools have emerged, providing important insight into the cell biology and genetics of glaucoma. In this review, we describe available mouse genetic models that can be used to study glaucoma-relevant disease/pathobiology. Furthermore, we discuss how these models have been used to gain insights into ocular hypertension (a major risk factor for glaucoma) and glaucomatous retinal ganglion cell death. Finally, the potential for developing new mouse models and using advanced genetic tools and resources for studying glaucoma are discussed.

The bacteriophage population is large, dynamic, ancient, and genetically diverse. Limited genomic information shows that phage genomes are mosaic, and the genetic architecture of phage populations remains ill-defined. To understand the population structure of phages infecting a single host strain, we isolated, sequenced, and compared 627 phages of Mycobacterium smegmatis. Their genetic diversity is considerable, and there are 28 distinct genomic types (clusters) with related nucleotide sequences. However, amino acid sequence comparisons show pervasive genomic mosaicism, and quantification of inter-cluster and intra-cluster relatedness reveals a continuum of genetic diversity, albeit with uneven representation of different phages. Furthermore, rarefaction analysis shows that the mycobacteriophage population is not closed, and there is a constant influx of genes from other sources. Phage isolation and analysis was performed by a large consortium of academic institutions, illustrating the substantial benefits of a disseminated, structured program involving large numbers of freshman undergraduates in scientific discovery.

Many believe that classroom interactions play an important role in students’ academic achievement, but there is little evidence on peer effects within subclassroom groups. We exploit random seat assignment in a Chinese middle school to estimate how the gender of neighboring students affects a student’s academic achievement. We find that being surrounded by five females rather than five males increases a female’s test scores by 0.2-0.3 standard deviations but has no significant effects on a male’s test scores. These results suggest a low-cost way to potentially improve performance within the world’s largest school system.

Public transit accounts for 1 percent of US passenger miles traveled but attracts strong public support. Using a simple choice model, we predict that transit riders are likely to be individuals who commute along routes with severe roadway delays. These individuals' choices thus have high marginal impacts on congestion. We test this prediction with data from a strike in 2003 by Los Angeles transit workers. Estimating a regression discontinuity design, we find that average highway delay increases 47 percent when transit service ceases. We find that the net benefits of transit systems appear to be much larger than previously believed. (JEL H76, J52, L92, R41).

Health insurance affects the rate at which individuals visit hospitals and emergency departments (EDs). We identify the causal effect of losing health insurance using a regression discontinuity design. We compare individuals just before and after their twenty third birthday, which insurers have used as a cutoff after which students are no longer eligible for their parents' health insurance: 1.5% of young adults lose their health insurance upon turning 23, and this transition leads to a 1.6% decrease in ED visits and a 0.8% decrease in hospital stays. We discuss why these estimates are larger than those observed among teenage populations. © 2014 by the President and Fellows of Harvard College and the Massachusetts Institute of Technology.

Heavier vehicles are safer for their own occupants but more hazardous for other vehicles. Simple theory thus suggests that an unregulated vehicle fleet is inefficiently heavy. Using three separate identification strategies we show that, controlling for own-vehicle weight, being hit by a vehicle that is 1000 pounds heavier generates a 40–50% increase in fatality risk. These results imply a total accident-related externality that exceeds the estimated social cost of US carbon emissions and is equivalent to a gas tax of $0.97 per gallon ($136 billion annually). We consider two policies for internalizing this external cost, a weight-varying mileage tax and a gas tax, and find that they are similar for most vehicles. The findings suggest that European gas taxes may be much closer to optimal levels than the US gas tax.

Heavier vehicles are safer for their own occupants but more hazardous for other vehicles. Simple theory thus suggests that an unregulated vehicle fleet is inefficiently heavy. Using three separate identification strategies we show that, controlling for own-vehicle weight, being hit by a vehicle that is 1000 pounds heavier generates a 40–50% increase in fatality risk. These results imply a total accident-related externality that exceeds the estimated social cost of US carbon emissions and is equivalent to a gas tax of $0.97 per gallon ($136 billion annually). We consider two policies for internalizing this external cost, a weight-varying mileage tax and a gas tax, and find that they are similar for most vehicles. The findings suggest that European gas taxes may be much closer to optimal levels than the US gas tax.

We have obtained a 1.55-Å crystal structure of a hammerhead ribozyme derived from Schistosoma mansoni under conditions that permit detailed observations of Na(+) ion binding in the ribozyme's active site. At least two such Na(+) ions are observed. The first Na(+) ion binds to the N7 of G10.1 and the adjacent A9 phosphate in a manner identical with that previously observed for divalent cations. A second Na(+) ion binds to the Hoogsteen face of G12, the general base in the hammerhead cleavage reaction, thereby potentially dissipating the negative charge of the catalytically active enolate form of the nucleotide base. A potential but more ambiguous third site bridges the A9 and scissile phosphates in a manner consistent with that of previous predictions. Hammerhead ribozymes have been observed to be active in the presence of high concentrations of monovalent cations, including Na(+), but the mechanism by which monovalent cations substitute for divalent cations in hammerhead catalysis remains unclear. Our results enable us to suggest that Na(+) directly and specifically substitutes for divalent cations in the hammerhead active site. The detailed geometry of the pre-catalytic active-site complex is also revealed with a new level of precision, thanks to the quality of the electron density maps obtained from what is currently the highest-resolution ribozyme structure in the Protein Data Bank.

We have obtained a 1.55-Å crystal structure of a hammerhead ribozyme derived from Schistosoma mansoni under conditions that permit detailed observations of Na(+) ion binding in the ribozyme's active site. At least two such Na(+) ions are observed. The first Na(+) ion binds to the N7 of G10.1 and the adjacent A9 phosphate in a manner identical with that previously observed for divalent cations. A second Na(+) ion binds to the Hoogsteen face of G12, the general base in the hammerhead cleavage reaction, thereby potentially dissipating the negative charge of the catalytically active enolate form of the nucleotide base. A potential but more ambiguous third site bridges the A9 and scissile phosphates in a manner consistent with that of previous predictions. Hammerhead ribozymes have been observed to be active in the presence of high concentrations of monovalent cations, including Na(+), but the mechanism by which monovalent cations substitute for divalent cations in hammerhead catalysis remains unclear. Our results enable us to suggest that Na(+) directly and specifically substitutes for divalent cations in the hammerhead active site. The detailed geometry of the pre-catalytic active-site complex is also revealed with a new level of precision, thanks to the quality of the electron density maps obtained from what is currently the highest-resolution ribozyme structure in the Protein Data Bank.

ARTICLES:1. Does Yelp Affect Restaurant Demand?2. Immigration Reform 2013: Implications for California Agriculture.3. Some Impacts of Recession on California’s Nursery and Floral Industry.

1. Does Yelp Affect Restaurant Demand?2. Immigration Reform 2013: Implications for California Agriculture.3.Some Impacts of Recession on California’s Nursery and Floral Industry.

The ability to direct our thought processes influences not only what we do, but also what we remember later. Here we sought to identify the brain network that supports the ability to control memory retrieval and to understand the neural basis of age-related changes and individual differences in the capacity for mnemonic control. To this end, we collected functional MRI data from 43 children and young adults while they attempted to retrieve or suppress retrieval of previously learned associations. Seed-based functional connectivity analyses revealed a largely right-lateralized dorsolateral prefrontal cortex-cingulate-parietal-hippocampal network that exhibited strongly correlated activity during retrieval suppression. Regardless of age, individuals who were able to suppress memory retrieval exhibited tighter coupling between key nodes in this dorsolateral prefrontal cortex-cingulate-parietal-hippocampal network than individuals who did not. Further, only those capable of mnemonic control exhibited tighter coupling during successful retrieval suppression (intentional forgetting) than during unsuccessful retrieval (unintentional forgetting). Across both children and adults, individual differences in retrieval suppression were best explained by the strength of these network interactions.

The ability to direct our thought processes influences not only what we do, but also what we remember later. Here we sought to identify the brain network that supports the ability to control memory retrieval and to understand the neural basis of age-related changes and individual differences in the capacity for mnemonic control. To this end, we collected functional MRI data from 43 children and young adults while they attempted to retrieve or suppress retrieval of previously learned associations. Seed-based functional connectivity analyses revealed a largely right-lateralized dorsolateral prefrontal cortex-cingulate-parietal-hippocampal network that exhibited strongly correlated activity during retrieval suppression. Regardless of age, individuals who were able to suppress memory retrieval exhibited tighter coupling between key nodes in this dorsolateral prefrontal cortex-cingulate-parietal-hippocampal network than individuals who did not. Further, only those capable of mnemonic control exhibited tighter coupling during successful retrieval suppression (intentional forgetting) than during unsuccessful retrieval (unintentional forgetting). Across both children and adults, individual differences in retrieval suppression were best explained by the strength of these network interactions.