Biology subjects

Brown, N. E.

Publications and source records attributed to Brown, N. E..

3 recordsLinked to original sources

bioRxiv2025

Engineering Large-Scale and Innervated Functional Human Gut for Transplantation

A confined culture system (CCS) establishes methods to generate complex functional human gastrointestinal tissues. This approach yields large-scale innervated small intestinal, colonic and gastric organoids with an elongated tubular shape for both in vitro and in vivo studies. Transcriptomic and electrophysiological data demonstrate the co-development of a functional de novo enteric nervous system, which is absent from conventional organoids. When compared to traditional methods, CCS derived small intestinal, colonic and gastric organoids reached maturation supporting transplantation in half of the time, resulting in enhanced engraftment rates and sizes. Murine luminal content exposure within CCS organoids in vivo further augmented function, supporting the potential translational benefits required to model complex intestinal diseases. In summary, the CCS methodology simplifies current protocols while adding complexity and expediting the generation of clinically relevant functional gut tissues.

bioengineering↗

bioRxiv2023

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion.

The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that ATR is dispensable for the viability of G0-arrested naive B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently in early S phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that suppress origin firing, such as downregulation of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.

genetics↗

bioRxiv2022

Abstinence-dependent effects of long-access cocaine self-administration on nucleus accumbens astrocytes are observed in male, but not female rats

Accumulating evidence indicates significant consequences for astrocytes associated with drug abuse. For example, reductions in structural features and synaptic colocalization of male rat nucleus accumbens (NAc) astrocytes are observed following short-access (ShA, 2 hours/day) self-administration and extinction from cocaine, methamphetamine, and heroin. However, it is unknown whether these observations extend to other rodent models of drug abuse, how enduring these effects may be, and whether similar effects are observed in female rats. Here we assess the effects of long-access (LgA, 6 hours/day) cocaine self-administration and abstinence on NAc astrocytes separately in male and female rats, a commonly used behavioral approach to investigate the incubation of cocaine craving. NAc astrocytes from male rats exhibit extensive ([~]40%) reductions in surface area, volume, and postsynaptic colocalization 45 days, but not 24 hours after the last self-administration session. In contrast, no effect of self-administration was observed in astrocytes from female rats. Moreover, no effect of LgA self-administration and abstinence was observed on NAc GLT-1 expression in female rats, an effect that has been well described in males. The results indicate striking and sexually dimorphic effects of abstinence subsequent to LgA self-administration on astrocytes. Taken together, these results indicate a pivotal role of prolonged abstinence in the effects of cocaine self-administration on NAc astrocytes, and extend a growing body of evidence regarding sex differences in the cellular consequences of drug self-administration in the brain.

neuroscience↗