PubMed Health⌕ Search

Biomedical subjects

Zhiping Liu

Publications and source records attributed to Zhiping Liu.

14 recordsLinked to original sources

soFusion: facilitating tissue structure identification via spatial multi-omics data fusion.

The rapid advancement of spatial multi-omics technologies has opened new avenues for dissecting tissue architecture with unprecedented resolution. However, inherent disparities across omics modalities, such as differences in biological hierarchy and resolution, pose significant challenges for integrative analysis. To address this, we present soFusion, a method for representation learning on spatial multi-omics data that enables automated identification of tissue compartmentalization. soFusion employs a graph convolutional network (GCN) to extract latent embeddings from spatial omics profiles. To simultaneously capture both cross-modality relationships and modality-specific features, we introduce a novel strategy for intra- and inter-omics feature learning. Moreover, modality-specific decoders are designed to preserve the unique information embedded in each omics type. We evaluated soFusion on multiple datasets including gene expression, protein expression, and epigenetic features. Across all benchmarks, soFusion consistently outperformed existing methods in delineating anatomical structures and identifying spatial domains with improved continuity and reduced noise. Collectively, soFusion offers an effective solution for spatial multi-omics integration, substantially enhancing the robustness of spatial domain identification.

Humans↗

Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death.

The mechanisms of human mutant superoxide dismutase-1 (mSOD1) toxicity to motor neurons (MNs) are unresolved. We show that MNs in G93A-mSOD1 transgenic mice undergo slow degeneration lacking similarity to apoptosis structurally and biochemically. It is characterized by somal and mitochondrial swelling and formation of DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. p53 and p73 are activated in degenerating MNs, but without nuclear import. The MN death is independent of activation of caspases-1, -3, and -8 or apoptosis-inducing factor within MNs, with a blockade of apoptosis possibly mediated by Aven up-regulation. MN swelling is associated with compromised Na,K-ATPase activity and aggregation. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of superoxide, nitric oxide, and peroxynitrite than MNs in control mice. Nitrated and aggregated cytochrome c oxidase subunit-I and alpha-synuclein as well as nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible nitric oxide synthase (iNOS)-like immunoreactivity, and iNOS gene deletion extends significantly the life span of G93A-mSOD1 mice. Prior to MN loss, spinal interneurons degenerate. These results identify novel mechanisms for mitochondriopathy and MN degeneration in amyotrophic lateral sclerosis (ALS) mice involving blockade of apoptosis, accumulation of MN mitochondria with enhanced toxic potential from distal terminals, NOS localization in MN mitochondria and peroxynitrite damage, and early degeneration of alpha-synuclein(+) interneurons. The data support roles for oxidative stress, protein nitration and aggregation, and excitotoxicity as participants in the process of MN degeneration caused by mSOD1.

Age Factors↗

Helicobacter bilis triggers persistent immune reactivity to antigens derived from the commensal bacteria in gnotobiotic C3H/HeN mice.

BACKGROUND: Infection with Helicobacter species has been associated with the development of mucosal inflammation and inflammatory bowel disease (IBD) in several mouse models. However, consensus regarding the role of Helicobacter as a model organism to study microbial-induced IBD is confounded by the presence of a complex colonic microbiota. AIM: To investigate the kinetics and inflammatory effects of immune system activation to commensal bacteria following H bilis colonisation in gnotobiotic mice. METHODS: C3H/HeN mice harbouring an altered Schaedler flora (ASF) were selectively colonised with H bilis and host responses were investigated over a 10-week period. Control mice were colonised only with the defined flora (DF). Tissues were analysed for gross/histopathological lesions, and bacterial antigen-specific antibody and T-cell responses. RESULTS: Gnotobiotic mice colonised with H bilis developed mild macroscopic and microscopic lesions of typhlocolitis beginning 3 weeks postinfection. ASF-specific IgG responses were demonstrable within 3 weeks, persisted throughout the 10-week study, and presented as a mixed IgG1:IgG2a profile. Lymphocytes recovered from the mesenteric lymph node of H bilis-colonised mice produced increased levels of interferon gamma, tumour necrosis factor alpha (TNFalpha), interleukin 6 (IL6) and IL12 in response to stimulation with commensal- or H bilis-specific bacterial lysates. In contrast, DF mice not colonised with H bilis did not develop immune responses to their resident flora and remained disease free. CONCLUSIONS: Colonisation of gnotobiotic C3H/HeN mice with H bilis perturbs the host's response to its resident flora and induces progressive immune reactivity to commensal bacteria that contributes to the development of immune-mediated intestinal inflammation.

Animals↗

The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain.

Amyotrophic lateral sclerosis (ALS) is a fatal adult human disease caused by motor neuron degeneration. Stem cell therapy might be a treatment for ALS. The adult mammalian forebrain has neural stem cells (NSCs) and neural progenitor cells (NPCs) in the anterior subventricular zone (SVZa), rostral migratory stream (RMS), olfactory bulb (OB) core, and dentate gyrus (DG). These cells could be used to rescue or replace degenerating upper and lower motor neurons through endogenous recruitment or autologous/allogenic transplantation. We evaluated the competency of forebrain NSCs and NPCs in transgenic (tg) mice harboring human mutant superoxide dismutase-1 (mSOD1), a model of ALS. Tg human wild-type SOD1 (wtSOD1) mice and non-tg mice were controls. Bromodeoxyuridine (BrdU) labeling of cells, a marker for cell proliferation and other events, was reduced in a niche-specific pattern in presymptomatic and symptomatic mice, with the SVZa having greater reductions than the RMS, OB, and DG. Different NSC and NPC complements were evaluated by localizing nestin, neural cell adhesion molecule, distalless-2 transcription factor, vimentin, and glial fibrillary acidic protein. In symptomatic mice, NSC markers were reduced, whereas NPC markers were unchanged or elevated. Neurogenesis was preserved in symptomatic mSOD1 mice. NSC/NPC competence assessment in vitro revealed that mSOD1 SVZa cells had the ability to proliferate and form neurospheres but had an impaired response to mitogen stimulation. We conclude that adult mSOD1 ALS mice have abnormalities in forebrain NSCs, but the essential features of NSC/NPCs remained in presymptomatic and symptomatic mice.

Amyotrophic Lateral Sclerosis↗

Induction of differential immune reactivity to members of the flora of gnotobiotic mice following colonization with Helicobacter bilis or Brachyspira hyodysenteriae.

Aberrant host immune responses to bacterial components of the resident microflora may initiate and perpetuate gastrointestinal inflammation. To investigate how microbial perturbation promotes host immunological responsiveness to commensal bacteria and contributes to the development of typhlocolitis, we selectively colonized defined (altered Schaedler) flora C3H mice with either Helicobacter bilis or Brachyspira hyodysenteriae. Following selective colonization, tissues were analyzed for gross/histopathologic lesions and bacterial antigen-specific B- and T-cell responses. Gnotobiotic mice colonized with H. bilis or B. hyodysenteriae developed typhlocolitis of varying severity, with the most severe gross and histopathogical lesions observed in B. hyodysenteriae-colonized mice. Antigen-specific IgG1 and IgG2a responses to the resident microflora were increased in both H. bilis-and B. hyodysenteriae-colonized mice. The greater antibody responses were associated with less severe cecal inflammation in H. bilis-colonized mice. Altered Schaedler flora (ASF)-stimulated mesenteric lymphocytes from B. hyodysenteriae-colonized mice produced higher levels of interferon-gamma and interleukin (IL)-4 than did lymphocytes from H. bilis-colonized mice. However, ASF-stimulated mesenteric and splenic lymphocytes from both H. bilis and B. hyodysenteriae-colonized mice secreted higher amounts of IL-10 compared to similarly stimulated lymphocytes recovered from control mice. These results indicate that microbial perturbation may induce differential immune responses to nonpathogenic resident bacteria that can lead to intestinal inflammation.

Animals↗

A novel united-atom force field for imidazolium-based ionic liquids.

A novel united-atom (UA) force field is proposed from our previously developed all-atom (AA) force field for the imidazolium-based ionic liquids by the introduction of a coarse-grained method. The Lennard-Jones parameters for CH(2) and CH(3) in alkyls are fitted to match the AA force field, and the partial atomic charges are re-fitted by the one conformation two-step RESP method. The force field is verified by molecular dynamics simulations of pure ionic liquids and the mixture of [bmim][BF(4)] and acetonitrile. The densities, self-diffusion coefficients, vaporization enthalpies, cohesive energy densities, and microscopic structures of both the pure components and mixtures are simulated. The simulated results from the UA force field agree well with those from the AA force field. In addition, the predictive capability of the UA force field for the liquid densities of [C(n)mim][PF(6)] is tested. The UA force field proposed in this work provides a useful tool with good accuracy and much less computational intensity for future molecular design of ionic liquids.

Alkylation↗

Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation.

The mechanisms of injury- and disease-related degeneration of motor neurons (MNs) need clarification. Unilateral avulsion of the sciatic nerve in the mouse induces apoptosis of spinal MNs that is p53 and Bax dependent. We tested the hypothesis that MN apoptosis is Fas death receptor dependent and triggered by nitric oxide (NO)- and superoxide-mediated damage to DNA. MNs in mice lacking functional Fas receptor and Fas ligand were protected from apoptosis. Fas protein levels and cleaved caspase-8 increased in MNs after injury. Fas upregulation was p53 dependent. MNs in mice deficient in neuronal NO synthase (nNOS) and inducible NOS (iNOS) resisted apoptosis. After injury, MNs increased nNOS protein but decreased iNOS protein; however, iNOS contributed more than nNOS to basal and injury-induced levels of NADPH diaphorase activity in MNs. NO and peroxynitrite (ONOO-) fluorescence increased in injured MNs, as did nitrotyrosine staining of MNs. DNA damage, assessed as 8-hydroxy-2-deoxyguanosine and single-stranded DNA, accumulated within injured MNs and was attenuated by nNOS and iNOS deficiency. nNOS deficiency increased DNA repair protein oxoguanine DNA-glycosylase, whereas iNOS deficiency blocked diaphorase activity. MN apoptosis was blocked by the antioxidant Trolox and by overexpression of wild-type human superoxide dismutase-1 (SOD1). In contrast, injured MNs in mice harboring mutant human SOD1 had upregulated Fas and iNOS, escalated DNA damage, and accelerated and increased MN degeneration and underwent necrosis instead of apoptosis. Thus, adult spinal MN apoptosis is mediated by upstream NO and ONOO- genotoxicity and downstream p53 and Fas activation and is shifted to necrosis by mutant SOD1.

Amino Acid Substitution↗

Molecular dynamics simulation of room-temperature ionic liquid mixture of [bmim][BF4] and acetonitrile by a refined force field.

1-Butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]) is one of the promising room-temperature ionic liquids. To test the refined force field for [bmim][BF4] proposed in our previously work (J. Phys. Chem. B, 2004, 108, 12978-12989), thermodynamic properties of mixtures of [bmim][BF4](1)+ acetonitrile (2) are presented by using molecular dynamics over the whole concentration range. The calculated densities are in good agreement with the experimental data with deviations less than 2%, indicating the force field is applicable to the mixtures. In addition, the diffusion constants, viscosities, heats of vaporization, cohesive energy densities and excess properties of the mixtures are reported. The microscopic structures are discussed in detail, corresponding to the thermodynamic properties.

Acetonitriles↗

Direct, complex effects of estrogens on basal forebrain cholinergic neurons.

Although controversial, estrogens remain one of the few agents purported to influence the incidence of Alzheimer's disease and one of their postulated mechanisms of action is their effects on basal forebrain cholinergic neurons. However, it is unclear whether the responses of cholinergic neurons to estrogens are direct or mediated via the retrograde influences of neurotrophins, known to be induced by estrogens in the hippocampus and neocortex. In the present study, we explore the issue of the primary site of action of estrogens by studying the regulation of expression of genes that characterize mature cholinergic neurons, i.e., choline acetyltransferase, trkA, and p75(NTR) in the medial septum and the nucleus basalis complex. In parallel, we study the hippocampal expression of NGF, BDNF, and NT-3, i.e., neurotrophins with known trophic roles on cholinergic neurons. Gene expression is studied by RT-PCR in ovariectomized female rats with and without estrogen supplementation within the physiological estradiol range and in rats with complete fimbria-fornix transactions treated with estrogen or vehicle. To clarify mechanisms of estrogen transduction in cholinergic neurons, we study the effects of estrogen treatment on fimbria-fornix-lesioned mice with genetic ablations of ER subtypes alpha and beta. The results of the present study suggest that, while estrogens do regulate BDNF expression in the hippocampus and neocortex, they also exert stimulatory non-trophic effects on basal forebrain cholinergic neurons, primarily on ChAT expression. Cholinergic neurons retain their ability to respond to estrogens after their complete separation from the hippocampus. The elimination of ERalpha alters significantly the phenotypic responsiveness of cholinergic neurons to estrogens, whereas elimination of ERbeta appears to have no effect. Our findings support the idea that estrogens directly enhance cholinergic neuron function and that ERalpha plays a significant role in transducing these regulatory effects.

Alzheimer Disease↗

Pluripotent fates and tissue regenerative potential of adult olfactory bulb neural stem and progenitor cells.

Neural stem cells and progenitor cells reside in the adult olfactory bulb (OB) core of mouse, rat, and human. Adult rodent OB core cells have the capacities for self-renewal and multipotency and form neurospheres. The differentiation fates of these neurosphere-forming cells were studied in vitro and in vivo. Adult OB neurospheres were comprised of stem cells and neuronal and glial progenitor cells. OB neurospheres in co-culture with primary embryonic striatal neurons and cortical neurons generated cells with morphological and neurochemical phenotypes of striatal and cortical neurons, respectively. Transplanted OB cells, delivered as dissociated cells or as intact neurospheres, dispersed, survived for long-term, extended neurites, migrated, expressed neuronal or glial markers, and formed synapses with host neurons when placed into the environment of the nonlesioned and lesioned central nervous system (CNS). Grafted cells in the CNS also showed angiogenic capacity by forming blood vessels. In a model of spinal motor neuron degeneration, adult OB neurosphere cells transplanted into lesioned spinal cord adopted phenotypes of motor neurons and had a robust potential to become oligodendrocytes. OB core cells in co-culture with skeletal myoblasts generated skeletal muscle cells. Chimeric skeletal muscle was formed when mouse OB neurospheres were transplanted into rat skeletal muscle. Within skeletal muscle, adult OB neurosphere cells became myogenic progenitor cells to form myotubes de novo. We conclude that the adult mammalian OB is a source of pluripotent neural stem cells and progenitor cells that have the potential to become, in a context-dependent manner, specific types of cells for regeneration of tissues in brain, spinal cord, and muscle.

Animals↗

Olfactory bulb core is a rich source of neural progenitor and stem cells in adult rodent and human.

The olfactory bulb (OB) core is an extension of the rostral migratory stream and thus is a potential source of neural progenitor and neural stem cells. We characterized in vivo and in vitro neuronal progenitor and neural stem cells in the adult OB core. In mouse and rat, bromodeoxyuridine (BrdU) labeling showed that the OB core accumulates newly replicated cells. Nestin, a neuroepithelial stem cell marker, was enriched in the OB core. BrdU-positive cells were immunolabeled for nestin and TUC4, a marker for early postmitotic neurons. The distributions of cells labeled for BrdU, TUC4, and nestin were similarly concentrated in the OB core. Nestin- and TUC4-positive cells were also found in the OB of young and aged humans. Isolated and cultured OB core cells from adult rat and mouse had the capacity to generate numerous neurospheres. Adult OB core neurospheres were cryopreserved and subsequently cultured. Single cell clonal analysis of neurospheres revealed the capacity for self-renewal and multipotency. Cultured adult OB core cells differentiated into neurons, astrocytes, and oligodendrocytes. Some neurons expressed choline acetlytransferase, substance P, and glutamic acid decarboxylase. Basic fibroblast growth factor potentiated the self-renewal of cells and beta-nerve growth factor stimulated differentiation. OB-derived neural stem cells in coculture with skeletal muscle cells were induced to become neurons expressing choline acetyltransferase and substance P and formed neuromuscular synaptic junctions on myocytes displaying acetylcholinesterase-positive motor end plates. Cocultured OB-derived neural stem cells with myoblast cells also generated nonneural cell progeny. We conclude that the adult mammalian OB core is a reservoir of neural progenitor cells and pluripotent neural stem cells.

Adult↗

Early events of target deprivation/axotomy-induced neuronal apoptosis in vivo: oxidative stress, DNA damage, p53 phosphorylation and subcellular redistribution of death proteins.

The mechanisms of injury- and disease-associated apoptosis of neurons within the CNS are not understood. We used a model of cortical injury in rat and mouse to induce retrograde neuronal apoptosis in thalamus. In this animal model, unilateral ablation of the occipital cortex induces apoptosis of corticopetal projection neurons in the dorsal lateral geniculate nucleus (LGN), by 7 days post-lesion, that is p53 modulated and Bax dependent. We tested the hypothesis that this degenerative process is initiated by oxidative stress and early formation of DNA damage and is accompanied by changes in the levels of pro-apoptotic mediators of cell death. Immunoblotting revealed that the protein profiles of Bax, Bak and Bad were different during the progression of neuronal apoptosis in the LGN. Bax underwent a subcellular redistribution by 1 day post-lesion, while Bak increased later. Bad showed an early sustained increase. Cleaved caspase-3 was elevated maximally at 5 and 6 days. Active caspase-3 underwent a subcellular translocation to the nucleus. A dramatic phosphorylation of p53 was detected at 4 days post-lesion. DNA damage was assessed immunocytochemically as hydroxyl radical adducts (8-hydroxy-2-deoxyguanosine) and single-stranded DNA. Both forms of DNA damage accumulated early in target-deprived LGN neurons. Transgenic overexpression of superoxide dismutase-1 provided significant protection against the apoptosis but antioxidant pharmacotreatments with trolox and ascorbate were ineffective. We conclude that overlapping and sequential signaling pathways are involved in the apoptosis of adult brain neurons and that DNA damage generated by superoxide derivatives is an upstream mechanism for p53-regulated, Bax-dependent apoptosis of target-deprived neurons.

Animals↗

Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and Bax-dependent.

The mechanisms of injury-induced apoptosis of neurons within the spinal cord are not understood. We used a model of peripheral nerve-spinal cord injury in the rat and mouse to induce motor neuron degeneration. In this animal model, unilateral avulsion of the sciatic nerve causes apoptosis of motor neurons. We tested the hypothesis that p53 and Bax regulate this neuronal apoptosis, and that DNA damage is an early upstream signal. Adult mice and rats received unilateral avulsions causing lumbar motor neurons to achieve endstage apoptosis at 7-14 days postlesion. This motor neuron apoptosis is blocked in bax(-/-) and p53(-/-) mice. Single-cell gel electrophoresis (comet assay), immunocytochemistry, and quantitative immunogold electron microscopy were used to measure molecular changes in motor neurons during the progression of apoptosis. Injured motor neurons accumulate single-strand breaks in DNA by 5 days. p53 accumulates in nuclei of motor neurons destined to undergo apoptosis. p53 is functionally activated by 4-5 days postlesion, as revealed by immunodetection of phosphorylated p53. Preapoptotically, Bax translocates to mitochondria, cytochrome c accumulates in the cytoplasm, and caspase-3 is activated. These results demonstrate that motor neuron apoptosis in the adult spinal cord is controlled by upstream mechanisms involving DNA damage and activation of p53 and downstream mechanisms involving upregulated Bax and cytochrome c and their translocation, accumulation of mitochondria, and activation of caspase-3. We conclude that adult motor neuron death after nerve avulsion is DNA damage-induced, p53- and Bax-dependent apoptosis.

Animals↗

DNA damage profiling in motor neurons: a single-cell analysis by comet assay.

We developed a method to measure DNA damage in single motor neurons (MN). A cell fraction enriched in viable alpha-motor neurons was isolated from adult rat spinal cord. This cell preparation was used to measure the vulnerability of the MN genome to different reactive oxygen species (ROS). MN were exposed in vitro to hydrogen peroxide, nitric oxide and peroxynitrite. Specific types of DNA lesions (e.g., abasic sites, single-strand breaks, and double-strand breaks) were measured using single-cell gel electrophoresis (comet assay). The MN genome was very susceptible to attack by ROS. Different ROS induced different DNA damage profiles in MN. MN were also isolated from adult rats with sciatic nerve avulsions to show that DNA damage emerges early during their degeneration in vivo. This study demonstrates that the comet assay is a feasible method for profiling DNA lesions in the genome of single MN. Viable mature MN can be isolated and used for in vitro models of MN genotoxicity and can be isolated from in vivo models of MN degeneration for profiling DNA damage on a single-cell basis.

Animals↗