Metabolic networks of the human gut microbiota.

The human gut microbiota controls factors that relate to human metabolism with a reach far greater than originally expected. Microbial communities and human (or animal) hosts entertain reciprocal exchanges between various inputs that are largely controlled by the host via its genetic make-up, nutrition and lifestyle. The composition of these microbial communities is fundamental to supply metabolic capabilities beyond those encoded in the host genome, and contributes to hormone and cellular signalling that support the dynamic adaptation to changes in food availability, environment and organismal development. Poor functional exchange between the microbial communities and their human host is associated with dysbiosis, metabolic dysfunction and disease. This review examines the biology of the dynamic relationship between the reciprocal metabolic state of the microbiota-host entity in balance with its environment (i.e. in healthy states), the enzymatic and metabolic changes associated with its imbalance in three well-studied diseases states such as obesity, diabetes and atherosclerosis, and the effects of bariatric surgery and exercise.

In Vivo Glycan Engineering via the Mannosidase I Inhibitor (Kifunensine) Improves Efficacy of Rituximab Manufactured in Nicotiana benthamiana Plants.

N-glycosylation has been shown to affect the pharmacokinetic properties of several classes of biologics, including monoclonal antibodies, blood factors, and lysosomal enzymes. In the last two decades, N-glycan engineering has been employed to achieve a N-glycosylation profile that is either more consistent or aligned with a specific improved activity (i.e., effector function or serum half-life). In particular, attention has focused on engineering processes in vivo or in vitro to alter the structure of the N-glycosylation of the Fc region of anti-cancer monoclonal antibodies in order to increase antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we applied the mannosidase I inhibitor kifunensine to the Nicotiana benthamiana transient expression platform to produce an afucosylated anti-CD20 antibody (rituximab). We determined the optimal concentration of kifunensine used in the infiltration solution, 0.375 µM, which was sufficient to produce exclusively oligomannose glycoforms, at a concentration 14 times lower than previously published levels. The resulting afucosylated rituximab revealed a 14-fold increase in ADCC activity targeting the lymphoma cell line Wil2-S when compared with rituximab produced in the absence of kifunensine. When applied to the cost-effective and scalable N. benthamiana transient expression platform, the use of kifunensine allows simple in-process glycan engineering without the need for transgenic hosts.

Using tele-ultrasound to teach medical students: A randomised control equivalence study.

Objectives: Undergraduate ultrasound education is becoming increasingly important, but its expansion is limited by time, space and the availability of trained faculty. In order to validate an alternative and more accessible teaching model, our aim was to assess whether combining teleguidance and peer-assisted learning to teach ultrasound is as effective as traditional in-person methods. Methods: Peer instructors taught 47 second-year medical students ocular ultrasound via either teleguidance or traditional in-person methods. Proficiency was assessed using a multiple-choice knowledge test and objective structured clinical examination (OSCE). Confidence, overall experience, and experience with a peer instructor were measured using a 5-point Likert scale. Two one-sided t-tests were used to measure equivalency between the two groups. The null hypothesis that the two groups were not different was rejected when P < 0.05. Results: The teleguidance group performed as well as the traditional in-person group in terms of knowledge change, confidence change, OSCE time and OSCE score (p = 0.011, p = 0.006, p = 0.005 and  = 0.004, respectively, indicating the two groups are statistically equivalent). The teleguidance group rated the experience highly overall (4.06/5), but less than the traditional group (4.47/5; P = 0.448, indicating statistical difference). Peer instruction was rated 4.35/5 overall. Conclusion: Peer-instructed teleguidance was equivalent to in-person instruction with respect to knowledge change, confidence gain and OSCE performance in basic ocular ultrasound.

Excitation-inhibition imbalance disrupts visual familiarity in amyloid and non-pathology conditions.

Neuronal hyperactivity induces memory deficits in Alzheimer's disease. However, how hyperactivity disrupts memory is unclear. Using in vivo synaptic imaging in the mouse visual cortex, we show that structural excitatory-inhibitory synapse imbalance in the apical dendrites favors hyperactivity in early amyloidosis. Consistent with this, natural images elicit neuronal hyperactivity in these mice. Compensatory changes that maintain activity homeostasis disrupt functional connectivity and increase population sparseness such that a small fraction of neurons dominates population activity. These properties reduce the selectivity of neural response to natural images and render visual recognition memory vulnerable to interference. Deprivation of non-specific visual experiences improves the neural representation and behavioral expression of visual familiarity. In contrast, in non-pathological conditions, deprivation of non-specific visual experiences induces disinhibition, increases excitability, and disrupts visual familiarity. We show that disrupted familiarity occurs when the fraction of high-responsive neurons and the persistence of neural representation of a memory-associated stimulus are not constrained.

Noninvasive Fibrosis Screening in Fatty Liver Disease Among Vulnerable Populations: Impact of Diabetes and Obesity on FIB-4 Score Accuracy.

OBJECTIVE: Fatty liver disease (FLD) is prevalent in diabetes, and both disproportionately affect vulnerable populations. The FIB-4 index is recommended to screen for advanced liver fibrosis. Limited data have suggested that diabetes may impact FIB-4. RESEARCH DESIGN AND METHODS: We evaluated FIB-4 accuracy for advanced fibrosis compared with liver biopsy in the presence of diabetes and obesity. RESULTS: Among 363 FLD patients receiving care in San Francisco's safety net health care system from August 2009 to February 2020, characteristics were as follows: median age 51 years, 46% male, 59% Hispanic, 68% obese, 33% with diabetes, and 31% with advanced fibrosis on histology. Overall, the c-statistic for FIB-4 was 0.79, but was worse in patients with diabetes, 0.68, than without, 0.85 (P = 0.003). Accuracy also varied by weight, at 0.65, 0.85, and 0.75 for normal weight, overweight, and obese, respectively, although not significantly (P = 0.24). CONCLUSIONS: The findings highlight limitations of FIB-4 in screening for advanced liver fibrosis, particularly in individuals with diabetes.

Racial/ethnic differences in fibrosis prevalence and progression in biopsy-proven steatosis: A focus on the Asian American population.

Fatty liver disease (FLD) is a leading cause of chronic liver disease (CLD) globally, and vulnerable populations are disproportionately affected. Prior studies have suggested racial/ethnic differences in FLD prevalence and severity; however, these studies often excluded Asian Americans. This study aims to evaluate racial/ethnic differences in the prevalence of, and predictors associated with steatohepatitis, advanced fibrosis, and fibrosis progression over time within a diverse population. Using descriptive analyses and multivariable modeling, we performed a longitudinal evaluation of 648 patients with histologic evidence of FLD (steatosis or steatohepatitis) from August 2009 to February 2020 within San Francisco's safety-net health care system. Overall demographics were median age of 53 years, 54% male, and 38% Asian (40% Hispanic, 14% White). On histology, 61% had steatohepatitis and 30% had advanced fibrosis (≥F3). The comparison between steatosis and steatohepatitis groups showed differences in sex, race/ethnicity, metabolic risk factors, and co-existing CLD (predominantly viral hepatitis); patients with steatosis were more likely to be Asian (50%), and those with steatohepatitis were more likely to be Hispanic (51%). On multivariable modeling, while Asian race (vs. non-Asian) was not associated with steatohepatitis or advanced fibrosis when models included all relevant clinical predictors, Asian race was associated with higher relative risk of fibrosis progression as defined by change in Fibrosis-4 category over time (relative risk ratio = 1.9; p = 0.047). Conclusion: In this vulnerable population with a large proportion of Asian Americans, Asian race was associated with progression of fibrosis. Given the relative paucity of data in this high-risk group, future studies should confirm these findings.

Dnmt3a is an epigenetic mediator of adipose insulin resistance.

Insulin resistance results from an intricate interaction between genetic make-up and environment, and thus may be orchestrated by epigenetic mechanisms like DNA methylation. Here, we demonstrate that DNA methyltransferase 3a (Dnmt3a) is both necessary and sufficient to mediate insulin resistance in cultured mouse and human adipocytes. Furthermore, adipose-specific Dnmt3a knock-out mice are protected from diet-induced insulin resistance and glucose intolerance without accompanying changes in adiposity. Unbiased gene profiling studies revealed Fgf21 as a key negatively regulated Dnmt3a target gene in adipocytes with concordant changes in DNA methylation at the Fgf21 promoter region. Consistent with this, Fgf21 can rescue Dnmt3a-mediated insulin resistance, and DNA methylation at the FGF21 locus was elevated in human subjects with diabetes and correlated negatively with expression of FGF21 in human adipose tissue. Taken together, our data demonstrate that adipose Dnmt3a is a novel epigenetic mediator of insulin resistance in vitro and in vivo.