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The apolipoprotein ε4 allele (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). APOE4 carriers develop systemic metabolic dysfunction decades before showing AD symptoms. Accumulating evidence shows that the metabolic dysfunction accelerates AD development, including exacerbated amyloid-beta (Aβ) retention, neuroinflammation and cognitive decline. Therefore, preserving metabolic function early on may be critical to reducing the risk for AD. Here, we show that inulin increases beneficial microbiota and decreases harmful microbiota in the feces of young, asymptomatic APOE4 transgenic (E4FAD) mice and enhances metabolism in the cecum, periphery and brain, as demonstrated by increases in the levels of SCFAs, tryptophan-derived metabolites, bile acids, glycolytic metabolites and scyllo-inositol. We show that inulin also reduces inflammatory gene expression in the hippocampus. This knowledge can be utilized to design early precision nutrition intervention strategies that use a prebiotic diet to enhance systemic metabolism and may be useful for reducing AD risk in asymptomatic APOE4 carriers.

Advancing age is the top risk factor for the development of neurodegenerative disorders, including Alzheimer's disease (AD). However, the contribution of aging processes to AD etiology remains unclear. Emerging evidence shows that reduced brain metabolic and vascular functions occur decades before the onset of cognitive impairments, and these reductions are highly associated with low-grade, chronic inflammation developed in the brain over time. Interestingly, recent findings suggest that the gut microbiota may also play a critical role in modulating immune responses in the brain via the brain-gut axis. In this study, our goal was to identify associations between deleterious changes in brain metabolism, cerebral blood flow (CBF), gut microbiome and cognition in aging, and potential implications for AD development. We conducted our study with a group of young mice (5-6 months of age) and compared those to old mice (18-20 months of age) by utilizing metabolic profiling, neuroimaging, gut microbiome analysis, behavioral assessments and biochemical assays. We found that compared to young mice, old mice had significantly increased levels of numerous amino acids and fatty acids that are highly associated with inflammation and AD biomarkers. In the gut microbiome analyses, we found that old mice had increased / ratio and alpha diversity. We also found impaired blood-brain barrier (BBB) function and reduced CBF as well as compromised learning and memory and increased anxiety, clinical symptoms often seen in AD patients, in old mice. Our study suggests that the aging process involves deleterious changes in brain metabolic, vascular and cognitive functions, and gut microbiome structure and diversity, all which may lead to inflammation and thus increase the risk for AD. Future studies conducting comprehensive and integrative characterization of brain aging, including crosstalk with peripheral systems and factors, will be necessary to define the mechanisms underlying the shift from normal aging to pathological processes in the etiology of AD.

Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome. The purpose of the study was to identify if ketogenic diet (KD) intervention would alter gut microbiome and enhance neurovascular functions, and thus reduce risk for neurodegeneration in young healthy mice (12–14 weeks old). Here we show that with 16 weeks of KD, mice had significant increases in CBF and P-glycoprotein transports on BBB to facilitate clearance of amyloid-beta, a hallmark of Alzheimer’s disease (AD). These neurovascular enhancements were associated with reduced mechanistic target of rapamycin (mTOR) and increased endothelial nitric oxide synthase (eNOS) protein expressions. KD also increased the relative abundance of putatively beneficial gut microbiota ( Akkermansia muciniphila and Lactobacillus ), and reduced that of putatively pro-inflammatory taxa ( Desulfovibrio and Turicibacter ). We also observed that KD reduced blood glucose levels and body weight, and increased blood ketone levels, which might be associated with gut microbiome alteration. Our findings suggest that KD intervention started in the early stage may enhance brain vascular function, increase beneficial gut microbiota, improve metabolic profile, and reduce risk for AD.

The mechanistic target of rapamycin (mTOR) is a nutrient sensor of eukaryotic cells. Inhibition of mechanistic mTOR signaling can increase life and health span in various species via interventions that include rapamycin and caloric restriction (CR). In the central nervous system, mTOR inhibition demonstrates neuroprotective patterns in aging and Alzheimer's disease (AD) by preserving mitochondrial function and reducing amyloid beta retention. However, the effects of mTOR inhibition for brain physiology remain largely unknown. Here, we review recent findings of metabolic and vascular measures using non-invasive, multimodal neuroimaging methods in rodent models for brain aging and AD. Specifically, we focus on pharmacological treatment (e.g., rapamycin) for restoring brain functions in animals modeling human AD; nutritional interventions (e.g., CR and ketogenic diet) for enhancing brain vascular and metabolic functions in rodents at young age (5-6 months of age) and preserving those functions in aging (18-20 months of age). Various magnetic resonance (MR) methods [i.e., imaging (MRI), angiography (MRA), and spectroscopy (MRS)], confocal microscopic imaging, and positron emission tomography (PET) provided metabolic and vascular measures. We also discuss the translational potential of mTOR interventions. Since PET and various MR neuroimaging methods, as well as the different interventions (e.g., rapamycin, CR, and ketogenic diet) are also available for humans, these findings may have tremendous implications in future clinical trials of neurological disorders in aging populations.

Understanding and tailoring the physical behaviour of halide perovskites under practical environments is critical for designing efficient and durable optoelectronic devices. Here, we report that continuous light illumination leads to >1% contraction in the out-of-plane direction in two-dimensional hybrid perovskites, which is reversible and strongly dependent on the specific superlattice packing. X-ray photoelectron spectroscopy measurements show that constant light illumination results in the accumulation of positive charges in the terminal iodine atoms, thereby enhancing the bonding character of inter-slab I–I interactions across the organic barrier and activating out-of-plane contraction. Correlated charge transport, structural and photovoltaic measurements confirm that the onset of the light-induced contraction is synchronized to a threefold increase in carrier mobility and conductivity, which is consistent with an increase in the electronic band dispersion predicted by first-principles calculations. Flux-dependent space-charge-limited current measurement reveals that light-induced interlayer contraction activates interlayer charge transport. The enhanced charge transport boosts the photovoltaic efficiency of two-dimensional perovskite solar cells up to 18.3% by increasing the device’s fill factor and open-circuit voltage. Light-induced contraction in the out-of-plane direction in two-dimensional (2D) hybrid perovskites enables the realization of high-efficiency 2D perovskite solar cells.

Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior.

The study highlights that electron paramagnetic resonance (EPR) spectroscopy is sufficiently sensitive to detect small differences in radiation resistance among Borrelia burgdorferi strains based on their population of Mn 2+ -metabolite complexes (H-Mn). B. burgdorferi appears to have evolved a system not to protect from irradiation, but presumably to protect from oxidative stress when cyclically transmitted from tick to mammalian host and back. These data also suggest a path forward in the development of novel vaccines against spirochete infections, including Lyme disease, through preparation involving the synthetic Mn 2+ -decapeptide-phosphate antioxidant complex MDP to provide B. burgdorferi epitope protection during sterilizing gamma-irradiation that eliminates growth. Given the current lack of effective whole-cell vaccines for Lyme disease, this research identifies a potential strategy for developing alternative radiation-inactivated, yet highly effective vaccines.

The taxonomy of giraffe ( Giraffa spp.) has a long and complex history, with scientists debating merits of various classification schemes. Currently, the International Union for the Conservation of Nature (IUCN) recognises giraffe as a single species ( G. camelopardalis ), based primarily on analyses of pelage patterns and geographic distribution carried out ~ 60 years ago. However, recent scientific findings on distribution and pelage pattern, along with detailed genomic analyses, have revealed inconsistencies with the existing classification, emphasizing the need for a reassessment. We conducted a systematic review of the taxonomic history of giraffe and evaluated the various classification schemes applied to the genus Giraffa . We describe these and summarise the distinguishing characteristics used for taxonomic assessments to lump or split different giraffe species and subspecies. Recent research aligns with taxonomic principles that support the hypothesis that there are four giraffe species, each of which is genetically distinct, with clear delineation between different monophyletic clades that are indicative of a long history of reproductive isolation in the wild. Based on genomic evidence supporting four reproductively isolated lineages that have been separated for hundreds of thousands of years, we urge the use of this designation in international treaties and the IUCN. We place the findings from our review in the context of the threats facing giraffe populations across their distributional range and highlight the need for incorporating up-to-date and more comprehensive data to inform conservation management of these threatened species.

We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.