A Common Embryonic Origin of Stem Cells Drives Developmental and Adult Neurogenesis.

New neurons arise from quiescent adult neural progenitors throughout life in specific regions of the mammalian brain. Little is known about the embryonic origin and establishment of adult neural progenitors. Here, we show that Hopx+ precursors in the mouse dentate neuroepithelium at embryonic day 11.5 give rise to proliferative Hopx+ neural progenitors in the primitive dentate region, and they, in turn, generate granule neurons, but not other neurons, throughout development and then transition into Hopx+ quiescent radial glial-like neural progenitors during an early postnatal period. RNA-seq and ATAC-seq analyses of Hopx+ embryonic, early postnatal, and adult dentate neural progenitors further reveal common molecular and epigenetic signatures and developmental dynamics. Together, our findings support a "continuous" model wherein a common neural progenitor population exclusively contributes to dentate neurogenesis throughout development and adulthood. Adult dentate neurogenesis may therefore represent a lifelong extension of development that maintains heightened plasticity in the mammalian hippocampus.

Microbiome-informed study of the mechanistic basis of methane inhibition by Asparagopsis taxiformis in dairy cattle.

Copious amounts of methane, a major constituent of greenhouse gases currently driving climate change, are emitted by livestock, and efficient methods that curb such emissions are urgently needed to reduce global warming. When fed to cows, the red seaweed Asparagopsis taxiformis (AT) can reduce enteric methane emissions by up to 80%, but the achieved results can vary widely. Livestock produce methane as a byproduct of methanogenesis, which occurs during the breakdown of feed by microbes in the rumen. The ruminant microbiome is a diverse ecosystem comprising bacteria, protozoa, fungi, and archaea, and methanogenic archaea work synergistically with bacteria to produce methane. Here, we find that an effective reduction in methane emission by high-dose AT (0.5% dry matter intake) was associated with a reduction in methanol-utilizing Methanosphaera within the rumen, suggesting that they may play a greater role in methane formation than previously thought. However, a later spike in Methanosphaera suggested an acquired resistance, possibly via the reductive dehalogenation of bromoform. While we found that AT inhibition of methanogenesis indirectly impacted ruminal bacteria and fermentation pathways due to an increase in spared H2, we also found that an increase in butyrate synthesis was due to a direct effect of AT on butyrate-producing bacteria such as Butyrivibrio, Moryella, and Eubacterium. Together, our findings provide several novel insights into the impact of AT on both methane emissions and the microbiome, thereby elucidating additional pathways that may need to be targeted to maintain its inhibitory effects while preserving microbiome health and animal productivity. IMPORTANCE: Livestock emits copious quantities of methane, a major constituent of the greenhouse gases currently driving climate change. Methanogens within the bovine rumen produce methane during the breakdown of feed. While the red seaweed Asparagopsis taxiformis (AT) can significantly reduce methane emissions when fed to cows, its effects appear short-lived. This study revealed that the effective reduction of methane emissions by AT was accompanied by the near-total elimination of methane-generating Methanosphaera. However, Methanosphaera populations subsequently rebounded due to their ability to inactivate bromoform, a major inhibitor of methane formation found in AT. This study presents novel findings on the contribution of Methanosphaera to ruminal methanogenesis, the mode of action of AT, and the possibility for complementing different strategies to effectively curb methane emissions.

Process intensification for lentiviral vector manufacturing using tangential flow depth filtration.

For gene therapies to become more accessible and affordable treatment options, process intensification is one possible strategy to increase the number of doses generated per batch of viral vector. Process intensification for lentiviral vector manufacturing can be achieved by enabling perfusion in the production bioreactor when applied in tandem with a stable producer cell line, allowing for significant expansion of cells and production of lentiviral vectors without the need for transfer plasmids. Tangential flow depth filtration was used to achieve an intensified lentiviral vector production by enabling perfusion to expand cell density and allow for continuous separation of lentiviral vectors from producer cells. Hollow-fiber depth filters made of polypropylene with 2- to 4-µm channels demonstrated high filter capacity, extended functional life, and efficient separation of lentiviral vectors from producer cells and debris when used for this intensified process. We anticipate that process intensification with tangential flow depth filtration at 200-L scale from a suspension culture can produce on the order of magnitude of 10,000 doses per batch of lentiviral vectors required for CAR T or TCR cell and gene therapy that would require approximately 2 × 109 transducing units per dose.