The latest medical research on Molecular Genetic Pathology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about molecular genetic pathology gathered by our medical AI research bot.

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Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains.

Molecular Neurodegeneration

The role of viral infection in Alzheimer Disease (AD) pathogenesis is an area of great interest in recent years. Several studies have suggested an association between the human roseoloviruses, HHV-6 and HHV-7, and AD. Amyloid-β (Aβ) plaques are a hallmark neuropathological finding of AD and were recently proposed to have an antimicrobial function in response to infection. Identifying a causative and mechanistic role of human roseoloviruses in AD has been confounded by limitations in performing in vivo studies. Recent -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Murine roseolovirus (MRV) is a natural murine pathogen that is highly-related to the human roseoloviruses, providing an opportunity to perform well-controlled studies of the impact of roseolovirus on Aβ deposition.

We utilized the 5XFAD mouse model to test whether MRV induces Aβ deposition in vivo. We also evaluated viral load and neuropathogenesis of MRV infection. To evaluate Aβ interaction with MRV, we performed electron microscopy. RNA-sequencing of a cohort of AD brains compared to control was used to investigate the association between human roseolovirus and AD.

We found that 5XFAD mice were susceptible to MRV infection and developed neuroinflammation. Moreover, we demonstrated that Aβ interacts with viral particles in vitro and, subsequent to this interaction, can disrupt infection. Despite this, neither peripheral nor brain infection with MRV increased or accelerated Aβ plaque formation. Moreover, -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Our RNA-sequencing analysis of a cohort of AD brains compared to controls did not show an association between roseolovirus infection and AD.

Although MRV does infect the brain and cause transient neuroinflammation, our data do not support a role for murine or human roseoloviruses in the development of Aβ plaque formation and AD.

Dynamic changes of CSF sPDGFRβ during ageing and AD progression and associations with CSF ATN biomarkers.

Molecular Neurodegeneration

Loss of brain capillary pericyte is involved in the pathologies and cognitive deficits in Alzheimer's disease (AD). The role of pericyte in early stage of AD pathogenesis remains unclear.

We investigated the dynamic changes of soluble platelet-derived growth factor receptor β (sPDGFRβ) in cerebrospinal fluid (CSF), a marker of brain pericyte injury, in transition from normal ageing to early AD in a cognitively unimpaired population aged 20 to 90 years. Association between sPDGFRβ and ATN biomarkers were analyzed.

In lifetime, CSF sPDGFRβ continually increased since age of 20 years, followed by the increases of phosphorylated tau-181 (P-tau181) and total tau (T-tau) at the age of 22.2 years and 31.7 years, respectively; CSF Aβ42 began to decline since the age of 39.6 years, indicating Aβ deposition. The natural trajectories of biomarkers suggest that pericyte injury is an early event during transition from normal status to AD, even earlier than Aβ deposition. In AD spectrum, CSF sPDGFRβ was elevated in preclinical stage 2 and participants with suspected non-AD pathophysiologies. Additionally, CSF sPDGFRβ was positively associated with P-tau181 and T-tau independently of Aβ42, and significantly strengthened the effects of Aβ42 on P-tau181, suggesting that pericyte injury accelerates Aβ-mediated tau hyperphosphorylation.

Our results suggest that pericyte injury contributes to AD progression in the early stage in an Aβ-independent pathway. Recovery of pericyte function would be a target for prevention and early intervention of AD.

Phenotypic, trophic, and regenerative properties of mesenchymal stem cells from different osseous tissues.

Cell and Tissue Research

Mesenchymal stem cells (MSCs) have broad-based therapeutic potential in regenerative medicine. However, a major barrier to their clinical utility i...

Engineering strategies towards overcoming bleeding and glial scar formation around neural probes.

Cell and Tissue Research

Neural probes are sophisticated electrophysiological tools used for intra-cortical recording and stimulation. These microelectrode arrays, designed...

Epithelial-mesenchymal transition process during embryo implantation.

Cell and Tissue Research

The epithelial to mesenchymal transition (EMT) in endometrial epithelial and trophectoderm cells is essential for the progression of embryo implant...

Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells.

Molecular Neurodegeneration

Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy.

We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy.

We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment.

This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases.

A novel H129-based anterograde monosynaptic tracer exhibits features of strong labeling intensity, high tracing efficiency, and reduced retrograde labeling.

Molecular Neurodegeneration

Viral tracers are important tools for mapping brain connectomes. The feature of predominant anterograde transneuronal transmission offers herpes simplex virus-1 (HSV-1) strain H129 (HSV1-H129) as a promising candidate to be developed as anterograde viral tracers. In our earlier studies, we developed H129-derived anterograde polysynaptic tracers and TK deficient (H129-dTK) monosynaptic tracers. However, their broad application is limited by some intrinsic drawbacks of the H129-dTK tracers, such as low labeling intensity due to TK deficiency and potential retrograde labeling caused by axon terminal invasion. The glycoprotein K (gK) of HSV-1 plays important roles in virus entry, egress, and virus-induced cell fusion. Its deficiency severely disables virus egress and spread, while only slightly limits viral genome replication and expression of viral proteins. Therefore, we created a novel H129-derived anterograde monosynaptic tracer (H129-dgK) by targeting gK, which overcomes the limitations of H129-dTK.

Using our established platform and pipeline for developing viral tracers, we generated a novel tracer by deleting the gK gene from the H129-G4. The gK-deleted virus (H129-dgK-G4) was reconstituted and propagated in the Vero cell expressing wildtype H129 gK (gKwt) or the mutant gK (gKmut, A40V, C82S, M223I, L224V, V309M), respectively. Then the obtained viral tracers of gKmut pseudotyped and gKwt coated H129-dgK-G4 were tested in vitro and in vivo to characterize their tracing properties.

H129-dgK-G4 expresses high levels of fluorescent proteins, eliminating the requirement of immunostaining for imaging detection. Compared to the TK deficient monosynaptic tracer H129-dTK-G4, H129-dgK-G4 labeled neurons with 1.76-fold stronger fluorescence intensity, and visualized 2.00-fold more postsynaptic neurons in the downstream brain regions. gKmut pseudotyping leads to a 77% decrease in retrograde labeling by reducing axon terminal invasion, and thus dramatically improves the anterograde-specific tracing of H129-dgK-G4. In addition, assisted by the AAV helper trans-complementarily expressing gKwt, H129-dgK-G4 allows for mapping monosynaptic connections and quantifying the circuit connectivity difference in the Alzheimer's disease and control mouse brains.

gKmut pseudotyped H129-dgK-G4, a novel anterograde monosynaptic tracer, overcomes the limitations of H129-dTK tracers, and demonstrates desirable features of strong labeling intensity, high tracing efficiency, and improved anterograde specificity.

Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain.

Molecular Neurodegeneration

Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson's disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses.

Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers.

α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis.

Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.

Oxygen supplementation to limit hypoxia-induced muscle atrophy in C2C12 myotubes: comparison with amino acid supplement and electrical stimulation.

Cell and Tissue Research

In skeletal muscle, chronic oxygen depletion induces a disturbance leading to muscle atrophy. Mechanical stress (physical exercise) and nutritional...

Stem cell transplantation as a progressing treatment for retinitis pigmentosa.

Cell and Tissue Research

Retinal degenerative diseases such as retinitis pigmentosa (RP) are of the major causes of vision loss in developed countries. Despite the unclear ...

The landscape of human tissue and cell type specific expression and co-regulation of senescence genes.

Molecular Neurodegeneration

Cellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems. However, the prevalence of senescent cells in healthy human tissues and the global SnG expression signature in different cell types are poorly understood.

This study performed an integrative gene network analysis of bulk and single-cell RNA-seq data in non-diseased human tissues to investigate SnG co-expression signatures and their cell-type specificity.

Through a comprehensive transcriptomic network analysis of 50 human tissues in the Genotype-Tissue Expression Project (GTEx) cohort, we identified SnG-enriched gene modules, characterized SnG co-expression patterns, and constructed aggregated SnG networks across primary tissues of the human body. Our network approaches identified 51 SnGs highly conserved across the human tissues, including CDKN1A (p21)-centered regulators that control cell cycle progression and the senescence-associated secretory phenotype (SASP). The SnG-enriched modules showed remarkable cell-type specificity, especially in fibroblasts, endothelial cells, and immune cells. Further analyses of single-cell RNA-seq and spatial transcriptomic data independently validated the cell-type specific SnG signatures predicted by the network analysis.

This study systematically revealed the co-regulated organizations and cell type specificity of SnGs in major human tissues, which can serve as a blueprint for future studies to map senescent cells and their cellular interactions in human tissues.

Sleep and circadian rhythms in Parkinson's disease and preclinical models.

Molecular Neurodegeneration

The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human d...