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UC Davis Previously Published Works

Dietary resistant starch supplementation increases gut luminal deoxycholic acid abundance in mice

(2024)

Bile acids (BA) are among the most abundant metabolites produced by the gut microbiome. Primary BAs produced in the liver are converted by gut bacterial 7-α-dehydroxylation into secondary BAs, which can differentially regulate host health via signaling based on their varying affinity for BA receptors. Despite the importance of secondary BAs in host health, the regulation of 7-α-dehydroxylation and the role of diet in modulating this process is incompletely defined. Understanding this process could lead to dietary guidelines that beneficially shift BA metabolism. Dietary fiber regulates gut microbial composition and metabolite production. We tested the hypothesis that feeding mice a diet rich in a fermentable dietary fiber, resistant starch (RS), would alter gut bacterial BA metabolism. Male and female wild-type mice were fed a diet supplemented with RS or an isocaloric control diet (IC). Metabolic parameters were similar between groups. RS supplementation increased gut luminal deoxycholic acid (DCA) abundance. However, gut luminal cholic acid (CA) abundance, the substrate for 7-α-dehydroxylation in DCA production, was unaltered by RS. Further, RS supplementation did not change the mRNA expression of hepatic BA producing enzymes or ileal BA transporters. Metagenomic assessment of gut bacterial composition revealed no change in the relative abundance of bacteria known to perform 7-α-dehydroxylation. P. ginsenosidimutans and P. multiformis were positively correlated with gut luminal DCA abundance and increased in response to RS supplementation. These data demonstrate that RS supplementation enriches gut luminal DCA abundance without increasing the relative abundance of bacteria known to perform 7-α-dehydroxylation.

Cover page of Helping Faculty Teach Software Performance Engineering

Helping Faculty Teach Software Performance Engineering

(2024)

Over the academic year 2022–23, we discussed the teaching of software performance engineering with more than a dozen faculty across North America and beyond. Our outreach was centered on research-focused faculty with an existing interest in this course material. These discussions revealed an enthusiasm for making software performance engineering a more prominent part of a curriculum for computer scientists and engineers. Here, we discuss how MIT’s longstanding efforts in this area may serve as a launching point for community development of a software performance engineering curriculum, challenges in and solutions for providing the necessary infrastructure to universities, and future directions.

Fully automated whole brain segmentation from rat MRI scans with a convolutional neural network

(2024)

Background

Whole brain delineation (WBD) is utilized in neuroimaging analysis for data preprocessing and deriving whole brain image metrics. Current automated WBD techniques for analysis of preclinical brain MRI data show limited accuracy when images present with significant neuropathology and anatomical deformations, such as that resulting from organophosphate intoxication (OPI) and Alzheimer's Disease (AD), and inadequate generalizability.

Methods

A modified 2D U-Net framework was employed for WBD of MRI rodent brains, consisting of 27 convolutional layers, batch normalization, two dropout layers and data augmentation, after training parameter optimization. A total of 265 T2-weighted 7.0 T MRI scans were utilized for the study, including 125 scans of an OPI rat model for neural network training. For testing and validation, 20 OPI rat scans and 120 scans of an AD rat model were utilized. U-Net performance was evaluated using Dice coefficients (DC) and Hausdorff distances (HD) between the U-Net-generated and manually segmented WBDs.

Results

The U-Net achieved a DC (median[range]) of 0.984[0.936-0.990] and HD of 1.69[1.01-6.78] mm for OPI rat model scans, and a DC (mean[range]) of 0.975[0.898-0.991] and HD of 1.49[0.86-3.89] for the AD rat model scans.

Comparison with existing methods

The proposed approach is fully automated and robust across two rat strains and longitudinal brain changes with a computational speed of 8 seconds/scan, overcoming limitations of manual segmentation.

Conclusions

The modified 2D U-Net provided a fully automated, efficient, and generalizable segmentation approach that achieved high accuracy across two disparate rat models of neurological diseases.

Cover page of METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial

METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial

(2024)

Purpose

Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression.

Design

Parallel-group, multicenter, randomized phase II clinical trial.

Participants

Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye.

Methods

We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months.

Main outcome measures

The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit.

Results

Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin.

Conclusions

The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease.

Financial disclosures

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Cover page of A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction

A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction

(2024)

Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively byβcells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of isletβcells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlyingβcell damage in diabetes rely onin vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing-key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel,ex vivoplatform for studying human islet biology in both health and disease.

Cover page of Student Opposition to University Pouring Rights Contracts.

Student Opposition to University Pouring Rights Contracts.

(2024)

INTRODUCTION: The majority of large public universities have exclusive pouring rights contracts with beverage companies that produce and market sugar-sweetened beverages. Pouring rights contracts contain provisions that conflict with recommendations from major public health organizations that institutions reduce sugar-sweetened beverage availability, marketing, and consumption. This study assessed the following among students at 3 public universities: student perception of pouring rights contracts (the extent to which they favored or opposed pouring rights contracts), the association between student socioeconomic characteristics and perception of pouring rights contracts, student estimates of pouring rights contract revenue, and the association between student pouring rights contract revenue estimates and perception of pouring rights contracts. To contextualize results, actual pouring rights contract revenue as a percentage of total revenues was estimated. METHODS: A cross-sectional exploratory study was conducted among a convenience sample of 1,311 undergraduate sugar-sweetened beverages-consuming students recruited from 3 large and diverse public universities in Northern California. On an online questionnaire, undergraduate students indicated the extent to which they favored or opposed pouring rights contracts on a 10-point scale (oppose=1-5, favor=6-10) and provided a numeric estimate of the percentage of total university revenue they thought their universitys pouring rights contract generated. Regression models were used to analyze differences in perception of pouring rights contracts by student socioeconomic characteristics and estimates of university revenues generated by pouring rights contracts. In addition, pouring rights contracts and financial reports were obtained from the 3 universities to estimate actual pouring rights contract revenue as a percentage of total revenues. Survey data were collected between August and November 2018 and analyzed in August 2022. RESULTS: A large majority of students (81%) opposed pouring rights contracts, and the opposition did not significantly differ by student socioeconomic characteristics, including by levels of food security, need-based financial aid, participation in federal food assistance or healthcare programs, parental education, or parental income (all ps>0.14). The median student estimate for pouring rights contract revenue as a percentage of total university revenue was 10%. In contrast, the estimated actual annual revenue generated from the pouring rights contracts ranged from 0.01% to 0.04% at these schools. Revenue estimates were not significantly associated with participants opposition or favoring of pouring rights contracts (p=0.65). CONCLUSIONS: A large majority of students opposed pouring rights contracts, and this opposition was similar regardless of student socioeconomic characteristics or student estimates of pouring rights contract revenues. Students markedly overestimated (by >100-1,000-fold) the percentage of university revenue that came from pouring rights contracts. University administration should consider student views on pouring rights contracts when deciding whether to exit or continue with pouring rights contracts.

Cover page of Leveraging the unique social organization of California mice to study circuit-specific effects of oxytocin on behavior

Leveraging the unique social organization of California mice to study circuit-specific effects of oxytocin on behavior

(2024)

Oxytocin is a versatile neuropeptide that modulates many different forms of social behavior. Recent hypotheses pose that oxytocin enhances the salience of rewarding and aversive social experiences, and the field has been working to identify mechanisms that allow oxytocin to have diverse effects on behavior. Here we review studies conducted on the California mouse (Peromyscus californicus) that shed light on how oxytocin modulates social behavior following stressful experiences. In this species, both males and females exhibit high levels of aggression, which has facilitated the study of how social stress impacts both sexes. We review findings of short- and long-term effects of social stress on the reactivity of oxytocin neurons. We also consider the results of pharmacological studies which show that oxytocin receptors in the bed nucleus of the stria terminalis and nucleus accumbens have distinct but overlapping effects on social approach behaviors. These findings help explain how social stress can have different behavioral effects in males and females, and how oxytocin can have such divergent effects on behavior. Finally, we consider how new technological developments and innovative research programs take advantage of the unique social organization of California mice to address questions that can be difficult to study in conventional rodent model species. These new methods and questions have opened new avenues for studying the neurobiology of social behavior.

Cover page of Effects of Excess Pore Pressure Redistribution in Liquefiable Layers

Effects of Excess Pore Pressure Redistribution in Liquefiable Layers

(2024)

Existing simplified procedures for evaluating soil liquefaction potential or for estimating excess pore pressures during earthquakes are typically based on undrained cyclic tests performed on saturated soil samples under controlled loading and boundary conditions. Under such conditions, the effect of excess pore pressure (ue) dissipation and redistribution to neighboring soil layers cannot be accounted for. Existing simplified procedures treat liquefiable layers as isolated soil layers without any boundary conditions even if dense and loose layers are very thin, permeable, and adjacent to each other. However, redistribution is likely to increase and decrease ue in the neighboring dense and loose layers respectively. Until now, no procedure short of fully coupled numerical analysis is available to estimate the importance of redistribution. This paper presents an approximate analytical procedure for assessing the effects of ue redistribution in (1) soil layers that would have liquefied if they were undrained, and (2) soil layers that would have not liquefied even if undrained. It is found that a layer that is initially assumed liquefied under undrained conditions might not even liquefy accounting for the ue redistribution to neighboring layers. On the other hand, a layer initially assumed to not liquefy can develop significant ue and can even liquefy due to pore pressure migration from the neighboring layers. Thus, accounting for redistributed ue is important for liquefaction consequence assessment quantification, particularly in systems that span the depth of these effects like deep foundations. Migration of u toward the tip of a pile can reduce its capacity, even if the tip is embedded in a dense sand layer. On the other hand, if redistribution can result in the reduction of ue in initially assumed liquefied layers, risks associated with liquefaction might be avoided. A criterion is also developed to evaluate the thicknesses of a layer below which redistribution could prevent liquefaction even if the layer is deemed liquefied according to the existing liquefaction-triggering procedures. Finally, the proposed procedure is illustrated by application to selected shaking events of centrifuge tests involving liquefaction of layered soil profiles. The predictions from the procedure matched the centrifuge test results reasonably.

Cover page of Sex and pubertal variation in reward-related behavior and neural activation in early adolescents

Sex and pubertal variation in reward-related behavior and neural activation in early adolescents

(2024)

This study aimed to characterize the role of sex and pubertal markers in reward motivation behavior and neural processing in early adolescence. We used baseline and two-year follow-up data from the Adolescent Brain and Cognitive DevelopmentSM study (15844 observations; 52% from boys; age 9-13). Pubertal development was measured with parent-reported Pubertal Development Scale, and DHEA, testosterone, and estradiol levels. Reward motivation behavior and neural processing at anticipation and feedback stages were assessed with the Monetary Incentive Delay task. Boys had higher reward motivation than girls, demonstrating greater accuracy difference between reward and neutral trials and higher task earnings. Girls had lower neural activation during reward feedback than boys in the nucleus accumbens, caudate, rostral anterior cingulate, medial orbitofrontal cortex, superior frontal gyrus and posterior cingulate. Pubertal stage and testosterone levels were positively associated with reward motivation behavior, although these associations changed when controlling for age. There were no significant associations between pubertal development and neural activation during reward anticipation and feedback. Sex differences in reward-related processing exist in early adolescence, signaling the need to understand their impact on typical and atypical functioning as it unfolds into adulthood.