Publications by authors named "Alice M Li"

6 Publications

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Intravital Imaging of Neocortical Heterotopia Reveals Aberrant Axonal Pathfinding and Myelination around Ectopic Neurons.

Cereb Cortex 2021 Apr 20. Epub 2021 Apr 20.

Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USA.

Neocortical heterotopia consist of ectopic neuronal clusters that are frequently found in individuals with cognitive disability and epilepsy. However, their pathogenesis remains poorly understood due in part to a lack of tractable animal models. We have developed an inducible model of focal cortical heterotopia that enables their precise spatiotemporal control and high-resolution optical imaging in live mice. Here, we report that heterotopia are associated with striking patterns of circumferentially projecting axons and increased myelination around neuronal clusters. Despite their aberrant axonal patterns, in vivo calcium imaging revealed that heterotopic neurons remain functionally connected to other brain regions, highlighting their potential to influence global neural networks. These aberrant patterns only form when heterotopia are induced during a critical embryonic temporal window, but not in early postnatal development. Our model provides a new way to investigate heterotopia formation in vivo and reveals features suggesting the existence of developmentally modulated, neuron-derived axon guidance and myelination factors.
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http://dx.doi.org/10.1093/cercor/bhab090DOI Listing
April 2021

Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain.

Nat Neurosci 2018 05 19;21(5):683-695. Epub 2018 Mar 19.

Department of Neurology, Yale School of Medicine, New Haven, CT, USA.

Axonal myelin increases neural processing speed and efficiency. It is unknown whether patterns of myelin distribution are fixed or whether myelinating oligodendrocytes are continually generated in adulthood and maintain the capacity for structural remodeling. Using high-resolution, intravital label-free and fluorescence optical imaging in mouse cortex, we demonstrate lifelong oligodendrocyte generation occurring in parallel with structural plasticity of individual myelin internodes. Continuous internode formation occurred on both partially myelinated and unmyelinated axons, and the total myelin coverage along individual axons progressed up to two years of age. After peak myelination, gradual oligodendrocyte death and myelin degeneration in aging were associated with pronounced internode loss and myelin debris accumulation within microglia. Thus, cortical myelin remodeling is protracted throughout life, potentially playing critical roles in neuronal network homeostasis. The gradual loss of internodes and myelin degeneration in aging could contribute significantly to brain pathogenesis.
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http://dx.doi.org/10.1038/s41593-018-0120-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920745PMC
May 2018

Ecological determinants of health: food and environment on human health.

Authors:
Alice M L Li

Environ Sci Pollut Res Int 2017 Apr 10;24(10):9002-9015. Epub 2015 Nov 10.

College of Life Sciences and Technology, HKU SPACE, Hong Kong SAR, People's Republic of China.

Human health and diseases are determined by many complex factors. Health threats from the human-animal-ecosystems interface (HAEI) and zoonotic diseases (zoonoses) impose an increasing risk continuously to public health, from those emerging pathogens transmitted through contact with animals, food, water and contaminated environments. Immense challenges forced on the ecological perspectives on food and the eco-environments, including aquaculture, agriculture and the entire food systems. Impacts of food and eco-environments on human health will be examined amongst the importance of human interventions for intended purposes in lowering the adverse effects on the biodiversity. The complexity of relevant conditions defined as factors contributing to the ecological determinants of health will be illuminated from different perspectives based on concepts, citations, examples and models, in conjunction with harmful consequential effects of human-induced disturbances to our environments and food systems, together with the burdens from ecosystem disruption, environmental hazards and loss of ecosystem functions. The eco-health literacy should be further promoting under the "One Health" vision, with "One World" concept under Ecological Public Health Model for sustaining our environments and the planet earth for all beings, which is coincidentally echoing Confucian's theory for the environmental ethics of ecological harmony.
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http://dx.doi.org/10.1007/s11356-015-5707-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089083PMC
April 2017

High-copy bacterial plasmids diffuse in the nucleoid-free space, replicate stochastically and are randomly partitioned at cell division.

Nucleic Acids Res 2014 Jan 16;42(2):1042-51. Epub 2013 Oct 16.

Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK, Department of Biology, McGill University, Montreal, Quebec H3G 0B1, Canada and Department of Biological Science, Center for Applied Biotechnology Studies, College of Natural Science and Mathematics, California State University Fullerton, Fullerton, CA 92834-6850, USA.

Bacterial plasmids play important roles in the metabolism, pathogenesis and bacterial evolution and are highly versatile biotechnological tools. Stable inheritance of plasmids depends on their autonomous replication and efficient partition to daughter cells at cell division. Active partition systems have not been identified for high-copy number plasmids, and it has been generally believed that they are partitioned randomly at cell division. Nevertheless, direct evidence for the cellular location of replicating and nonreplicating plasmids, and the partition mechanism has been lacking. We used as model pJHCMW1, a plasmid isolated from Klebsiella pneumoniae that includes two β-lactamase and two aminoglycoside resistance genes. Here we report that individual ColE1-type plasmid molecules are mobile and tend to be excluded from the nucleoid, mainly localizing at the cell poles but occasionally moving between poles along the long axis of the cell. As a consequence, at the moment of cell division, most plasmid molecules are located at the poles, resulting in efficient random partition to the daughter cells. Complete replication of individual molecules occurred stochastically and independently in the nucleoid-free space throughout the cell cycle, with a constant probability of initiation per plasmid.
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http://dx.doi.org/10.1093/nar/gkt918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902917PMC
January 2014

Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior.

Proc Natl Acad Sci U S A 2013 Feb 11;110(9):3573-8. Epub 2013 Feb 11.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.

Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.
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http://dx.doi.org/10.1073/pnas.1219731110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587265PMC
February 2013

A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin, combines superb potency and lipophilicity with low toxicity.

Free Radic Biol Med 2012 May 13;52(9):1828-34. Epub 2012 Feb 13.

Department of Radiation Oncology, Duke University Medical Center, NC 27710, USA.

The Mn porphyrins of k(cat)(O(2)(.-)) as high as that of a superoxide dismutase enzyme and of optimized lipophilicity have already been synthesized. Their exceptional in vivo potency is at least in part due to their ability to mimic the site and location of mitochondrial superoxide dismutase, MnSOD. MnTnHex-2-PyP(5+) is the most studied among lipophilic Mn porphyrins. It is of remarkable efficacy in animal models of oxidative stress injuries and particularly in central nervous system diseases. However, when used at high single and multiple doses it becomes toxic. The toxicity of MnTnHex-2-PyP(5+) has been in part attributed to its micellar properties, i.e., the presence of polar cationic nitrogens and hydrophobic alkyl chains. The replacement of a CH(2) group by an oxygen atom in each of the four alkyl chains was meant to disrupt the porphyrin micellar character. When such modification occurs at the end of long alkyl chains, the oxygens become heavily solvated, which leads to a significant drop in the lipophilicity of porphyrin. However, when the oxygen atoms are buried deeper within the long heptyl chains, their excessive solvation is precluded and the lipophilicity preserved. The presence of oxygens and the high lipophilicity bestow the exceptional chemical and physical properties to Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP(5+). The high SOD-like activity is preserved and even enhanced: log k(cat)(O(2)(.-))=7.83 vs 7.48 and 7.65 for MnTnHex-2-PyP(5+) and MnTnHep-2-PyP(5+), respectively. MnTnBuOE-2-PyP(5+) was tested in an O(2)(.-) -specific in vivo assay, aerobic growth of SOD-deficient yeast, Saccharomyces cerevisiae, where it was fully protective in the range of 5-30 μM. MnTnHep-2-PyP(5+) was already toxic at 5 μM, and MnTnHex-2-PyP(5+) became toxic at 30 μM. In a mouse toxicity study, MnTnBuOE-2-PyP(5+) was several-fold less toxic than either MnTnHex-2-PyP(5+) or MnTnHep-2-PyP(5+).
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http://dx.doi.org/10.1016/j.freeradbiomed.2012.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353805PMC
May 2012