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Synthetic probiotic for a human metabolic disease is taken through a drug development pathway to enable translation into clinic trials. Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pah enu2/enu2 PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake. In healthy Cynomolgus monkeys, we found that SYNB1618 inhibited increases in serum Phe after an oral Phe dietary challenge. In mice and primates, Phe was converted to trans -cinnamate by SYNB1618, quantitatively metabolized by the host to hippurate and excreted in the urine, acting as a predictive biomarker for strain activity. SYNB1618 was detectable in murine or primate feces after a single oral dose, permitting the evaluation of pharmacodynamic properties. Our results define a strategy for translation of live bacterial therapeutics to treat metabolic disorders.

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine. Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in murine models.

Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non‐human primates, demonstrating the strain's ability to consume oxalate in vivo . A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH. SYNOPSIS SYNB8802 is an engineered probiotic designed to metabolize oxalate in patients with enteric hyperoxaluria. The strain shows significant oxalate degradation in vitro and in vivo , and in silico modeling predicts that it can lower urinary oxalate in patients. Enteric hyperoxaluria is a metabolic disorder where oxalate overabsorption can lead to chronic kidney stones and ultimately kidney failure. SYNB8802 is an engineered probiotic, derived from Escherichia coli Nissle capable of degrading oxalate. SYNB8802 lowers urinary oxalate, a disease biomarker, as shown in preclinical data from mice and non‐human primates. In silico modeling predicts that SYNB8802 lowers urinary oxalate up to 71% in patients. Graphical Abstract SYNB8802 is an engineered probiotic designed to metabolize oxalate in patients with enteric hyperoxaluria. The strain shows significant oxalate degradation in vitro and in vivo , and in silico modeling predicts that it can lower urinary oxalate in patients.

Previous in-vivo magnetic resonance imaging (MRI)-based studies of age-related differences in the human brainstem have focused on volumetric morphometry. These investigations have provided pivotal insights into regional brainstem atrophy but have not addressed microstructural age differences. However, growing evidence indicates the sensitivity of quantitative MRI to microstructural tissue changes in the brain. These studies have largely focused on the cerebrum, with very few MR investigations addressing age-dependent differences in the brainstem, in spite of its central role in the regulation of vital functions. Several studies indicate early brainstem alterations in a myriad of neurodegenerative diseases and dementias. The paucity of MR-focused investigations is likely due in part to the challenges imposed by the small structural scale of the brainstem itself as well as of substructures within, requiring accurate high spatial resolution imaging studies. In this work, we applied our recently developed approach to high-resolution myelin water fraction (MWF) mapping, a proxy for myelin content, to investigate myelin differences with normal aging within the brainstem. In this cross-sectional investigation, we studied a large cohort (n = 125) of cognitively unimpaired participants spanning a wide age range (21–94 years) and found a decrease in myelination with age in most brainstem regions studied, with several regions exhibiting a quadratic association between myelin and age. We believe that this study is the first investigation of MWF differences with normative aging in the adult brainstem. Further, our results provide reference MWF values. •We investigated age-differences in MWF of the human brainstem.•We found a linear association between MWF and age in several brainstem structures.•We found a quadratic association between MWF and age in various brainstem structures.•We provided MWF reference values.

Background The Locus Coeruleus (LC) is a critical brain region affected by neurodegenerative diseases and aging. Despite its importance, in-vivo investigations of age-related LC degeneration and association with cognitive decline have been limited. Method We employed magnetic resonance relaxometry, namely the Bayesian Monte-Carlo analysis of multicomponent driven equilibrium single pulse observation of T 1 and T 2 (BMC-mcDESPOT) MRI method, to estimate microstructural integrity represented by longitudinal (R 1 ) and transverse (R 2 ) relaxation rates, as well as Myelin Water Fraction (MWF) in the LC of a diverse cohort of 120 cognitively unimpaired individuals aged 22 to 94 years. BMC-mcDESPOT offers high spatial resolution and is effective for mapping detailed microstructural changes within the LC. We examined age-related differences in LC microstructure, their associations with cognitive changes, and the spatial variation of these microstructural changes within the LC, exploring their distinctive contributions to cognitive decline. Results LC-R 2 values declined significantly with age, particularly in the rostral-middle regions. LC-R 1 and LC-MWF values showed significant positive correlations with cross-sectional memory scores. Longitudinally, the rostra-middle LC-R 2 values showed an age-moderated effect, with lower values predicting steeper memory decline at advanced ages. Conclusions Quantitative MR relaxometry reveals that LC microstructural integrity declines with age and is predictive of cognitive decline, particularly in memory. Our MR relaxometry biomarkers, especially in the rostral LC, serve as sensitive imaging biomarkers of early structural alterations and cognitive declines in aging.

Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy ( 31 P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34–70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression ( rho ρ = − 0.69, p  = 0.018, and Cohen’s d = − 1.104), anxiety (ρ = − 0.61, p  = .046, d = − 0.677), and overall mental health (ρ = 0.74, p  = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p  = 0.029), and coping-self efficacy (ρ = 0.63, p  = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.

Background Age‐related white matter (WM) deterioration has been associated with several neurodegenerative diseases, including Alzheimer’s disease. Studies suggest that cardiorespiratory fitness (CRF) is important in preserving WM structure and function. However, clinical investigations of the relationship between myelin integrity and CRF are lacking. In this study, we evaluated the association between CRF, assessed by the maximum rate of oxygen consumption (VO2max), and cerebral myelin content, defined by myelin water fraction (MWF), throughout the adult lifespan. Understanding the mechanisms of WM degeneration is crucial for developing targeted interventions to maintain cognitive health into late life. Method After excluding subjects with cognitive impairments or unexploitable MRI data, a total of 110 cognitively unimpaired participants, ranging in age from 22 to 94 years, were drawn from the BLSA and GESTALT studies. Each participant underwent our BMC‐mcDESPOT MRI protocol for whole brain MWF mapping. VO2max was assessed using graded maximal treadmill test as per our established protocol. Fourteen WM ROIs were defined from the MNI structural atlas. For each ROI, a linear regression model adjusted for relevant covariates (Table 1) was used to determine whether 1) VO2max is significantly correlated with MWF, and 2) the strength of the correlation between VO2max and MWF depends on age (age×VO2max interaction). Continuous variables were z‐scored. Result Higher VO2max was significantly associated with higher MWF (Figure 1). This association was strongest in brain regions susceptible to early degeneration (Table 1), including the frontal lobes (β=0.28, p=0.011) and white matter tracts, such as the internal capsule (β=0.27, p=0.025) and corona radiata (β=0.27, p=0.016). Further, the interaction between age and VO2max exhibited i) a steeper positive slope in the older age group, suggesting that the effect of VO2max on MWF is stronger at older ages, and ii) a negative slope in the lower VO2max group, indicating that lower VO2max levels are associated with more rapid demyelination with advancing age (Figure 2 & Table 1). Conclusion These original findings provide the first evidence that high CRF is important for the preservation of myelin integrity and slowing of age‐related neurodegeneration, laying the groundwork for further investigations including longitudinal and interventional studies.

[...]the Navy was interested in more than just online courses since \"The education environment of our sailors includes frequent deployments, infrequent or intermittent Internet connectivity, and a mobile lifestyle,\" said the commander. [...]not only is the number of distance-learning courses offered important, but also a variety of distance-learning formats\" (Carr, 2000, p. 60). The distance learning courses are offered by a consortium of 10 colleges that have service-member opportunity agreements to ensure that the credits are transferable. Because NCPACE tuition is covered by the Navy, sailors pay only for textbooks and materials.

The AAA Northern Region girls' semifinals are tonight at Patriot Center; the boys play Friday. The AAA Northwestern Region boys' and girls' semifinals, as well as the AA Region II boys' semifinals, are also tonight. All semifinal winners qualify for the AAA state tournament quarterfinals. Troupe, a 6-foot post player, will be the Majors' only senior on the court. Fellow senior Dalayna Tillman broke a leg during a Christmas tournament in December and has not played since. In Tuesday's quarterfinal, Troupe scored 27 points in the victory over Hayfield and Monday she scored 25 in an opening-round victory against Westfield. The Westfield boys' basketball team had its ups and downs, from a 10-1 start to a fifth-place finish in the AAA Concorde District, and then a district tournament championship and a trip to Friday's Virginia AAA Northern Region semifinals. But all along the Bulldogs (19-7) felt they had a team that could be one of the Northern Region's best.

Fire is fundamental to the natural dynamics of the North American boreal forest. It is therefore often suggested that the impacts of anthropogenic disturbances (eg logging) on a managed landscape are attenuated if the patterns and processes created by these events resemble those of natural disturbances (eg fire). To provide forest management guidelines, we investigate the long‐term variability in the mean fire interval (MFI) of a boreal landscape in eastern North America, as reconstructed from lacustrine (lake‐associated) sedimentary charcoal. We translate the natural variability in MFI into a range of landscape age structures, using a simple modeling approach. Although using the array of possible forest age structures provides managers with some flexibility, an assessment of the current state of the landscape suggests that logging has already caused a shift in the age‐class distribution toward a stronger representation of young stands with a concurrent decrease in old‐growth stands. Logging is indeed quickly forcing the studied landscape outside of its long‐term natural range of variability, implying that substantial changes in management practices are required, if we collectively decide to maintain these fundamental attributes of the boreal forest.