Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.

We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations included severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband's low levels of citrulline and lactic acidosis provoked by administration of Depakoke were evocative of a mitochondrial etiology.

The Location of Biofilms on Chronic Prosthetic Joint Infections and the Ramifications for Clinical Practice.

Revision surgery is paramount to cure chronic prosthetic joint infections because these infections are associated with biofilms on prosthetics that conventional antibiotics cannot eradicate. However, there is a paucity of research on where in vivo biofilms are located on infected prosthetics. Consequently, the objective of this pilot study was to address this gap in knowledge by staining 5 chronically infected prosthetics, that were removed at the time of revision surgery, with methylene blue.

Outcomes of hypothalamic oxytocin neuron-driven cardioprotection after acute myocardial infarction.

Altered autonomic balance is a hallmark of numerous cardiovascular diseases, including myocardial infarction (MI). Although device-based vagal stimulation is cardioprotective during chronic disease, a non-invasive approach to selectively stimulate the cardiac parasympathetic system immediately after an infarction does not exist and is desperately needed. Cardiac vagal neurons (CVNs) in the brainstem receive powerful excitation from a population of neurons in the paraventricular nucleus (PVN) of the hypothalamus that co-release oxytocin (OXT) and glutamate to excite CVNs.

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity.

Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity.

Ebola Virus NP Binding to Host Protein Phosphatase-1 Regulates Capsid Formation.

The Ebola virus (EBOV) transcriptional regulation involves host protein phosphatases PP1 and PP2A, which dephosphorylate the transcriptional cofactor of EBOV polymerase VP30. The 1E7-03 compound, which targets PP1, induces VP30 phosphorylation and inhibits EBOV infection. This study aimed to investigate the role of PP1 in EBOV replication.

Prostate cancer cell-platelet bidirectional signaling promotes calcium mobilization, invasion and apoptotic resistance via distinct receptor-ligand pairs.

Platelets play a crucial role in cancer and thrombosis. However, the receptor-ligand repertoire mediating prostate cancer (PCa) cell-platelet interactions and ensuing consequences have not been fully elucidated. Microvilli emanating from the plasma membrane of PCa cell lines (RC77 T/E, MDA PCa 2b) directly contacted individual platelets and platelet aggregates.

Retroviral infection of human neurospheres and use of stem Cell EVs to repair cellular damage.

HIV-1 remains an incurable infection that is associated with substantial economic and epidemiologic impacts. HIV-associated neurocognitive disorders (HAND) are commonly linked with HIV-1 infection; despite the development of combination antiretroviral therapy (cART), HAND is still reported to affect at least 50% of HIV-1 infected individuals. It is believed that the over-amplification of inflammatory pathways, along with release of toxic viral proteins from infected cells, are primarily responsible for the neurological damage that is observed in HAND; however, the underlying mechanisms are not well-defined.

Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.

In this study, we aimed to establish the mitochondrial etiology of the proband's progressive neurodegenerative disease suggestive of an atypical Leigh syndrome, by determining the proband's pathogenic variants. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, spinal cord along with rhombencephalic atrophy, and optic nerve atrophy. Single voxel H MRS performed concurrently over the left cerebral deep gray nuclei showed a small lactate peak, increased glutamate and citrate elevation, elevating suspicion of a mitochondrial etiology.

Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC). The extracellular matrix (ECM) contributes to immune exclusion. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes.

Influence of administration of mesenchymal stromal cell on pediatric oxygenator performance and inflammatory response.

Objective: Mesenchymal stromal cells have important immunomodulatory and neuroprotective properties. The aim of this study was to evaluate the feasibility of mesenchymal stromal cell administration into a cardiopulmonary bypass (CPB) circuit, including a pediatric oxygenator, and to assess the immunomodulatory response of the circulating blood prime.

Methods: A bypass circuit with a pediatric oxygenator, including integral filter was primed with bank whole blood.

Molecular genetic and mitochondrial metabolic analyses confirm the suspected mitochondrial etiology in a pediatric patient with an atypical form of alternating hemiplegia of childhood.

Alternative hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder with an extensive phenotypic variability, resulting in a challenging clinical diagnosis. About 75% of AHC cases are caused by pathogenic variants mapping in the , or gene, leaving many AHC patients clinically and genetically undiagnosed. In this study, we report the case of a 9-year old proband clinically diagnosed with an atypical form of AHC presenting a suspected mitochondrial etiology and an obscure genetic diagnosis.

Single-Cell Metabolic Profiling: Metabolite Formulas from Isotopic Fine Structures in Heterogeneous Plant Cell Populations.

Characterization of the metabolic heterogeneity in cell populations requires the analysis of single cells. Most current methods in single-cell analysis rely on cell manipulation, potentially altering the abundance of metabolites in individual cells. A small sample volume and the chemical diversity of metabolites are additional challenges in single-cell metabolomics.

Mass Spectrometry Imaging of Lipids in Human Skin Disease Model Hidradenitis Suppurativa by Laser Desorption Ionization from Silicon Nanopost Arrays.

Neutral lipids have been implicated in a host of potentially debilitating human diseases, such as heart disease, type-2 diabetes, and metabolic syndrome. Matrix-assisted laser desorption ionization (MALDI), the method-of-choice for mass spectrometry imaging (MSI), has led to remarkable success in imaging several lipid classes from biological tissue sections. However, due to ion suppression by phospholipids, MALDI has limited ability to efficiently ionize and image neutral lipids, such as triglycerides (TGs).

The nuclear background influences the penetrance of the near-homoplasmic m.1630 A > G MELAS variant in a symptomatic proband and asymptomatic mother.

In this study, we report the metabolic consequences of the m.1630 A > G variant in fibroblasts from the symptomatic proband affected with the mitochondrial encephalomyopathy lactic acidosis and stroke-like episode Syndrome and her asymptomatic mother. By long-range PCR followed by massively parallel sequencing of the mitochondrial genome, we accurately measured heteroplasmy in fibroblasts from the proband (89.

Novel metabolic signatures of compound heterozygous variants in a case of early-onset of epileptic encephalopathy.

Our study reports the case of a patient with early onset of epileptic encephalopathy harboring compound heterozygous variants. We provide the first evidence that these variants impair mitochondrial energy metabolism. Our results shed light on their pathogenic molecular mechanism and clinical implications for brain development and disease progression.

TGF-β Sustains Tumor Progression through Biochemical and Mechanical Signal Transduction.

Transforming growth factor β (TGF-β) signaling transduces immunosuppressive biochemical and mechanical signals in the tumor microenvironment. In addition to canonical SMAD transcription factor signaling, TGF-β can promote tumor growth and survival by inhibiting proinflammatory signaling and extracellular matrix (ECM) remodeling. In this article, we review how TGF-β activated kinase 1 (TAK1) activation lies at the intersection of proinflammatory signaling by immune receptors and anti-inflammatory signaling by TGF-β receptors.

The m.11778 A > G variant associated with the coexistence of Leber's hereditary optic neuropathy and multiple sclerosis-like illness dysregulates the metabolic interplay between mitochondrial oxidative phosphorylation and glycolysis.

Little is known about the molecular mechanism of the rare coexistence of Leber's Hereditary Optic Neuropathy (LHON) and multiple sclerosis (MS), also known as the Harding's syndrome. In this study, we provide novel evidence that the m.11778A > G variant causes a defective metabolic interplay between mitochondrial oxidative phosphorylation and glycolysis.

Novel insights into the functional metabolic impact of an apparent de novo m.8993T>G variant in the MT-ATP6 gene associated with maternally inherited form of Leigh Syndrome.

In this study, we report a novel perpective of metabolic consequences for the m.8993T>G variant using fibroblasts from a proband with clinical symptoms compatible with Maternally Inherited Leigh Syndrome (MILS). Definitive diagnosis was corroborated by mitochondrial DNA testing for the pathogenic variant m.

Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells.

During neural development, epigenetic modulation of chromatin acetylation is part of a dynamic, sequential and critical process to steer the fate of multipotent neural progenitors toward a specific lineage. Pan-HDAC inhibitors (HDCis) trigger neuronal differentiation by generating an "acetylation" signature and promoting the expression of neurogenic bHLH transcription factors. Our studies and others have revealed a link between neuronal differentiation and increase of mitochondrial mass.

Lipoprotein X Causes Renal Disease in LCAT Deficiency.

Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice.

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury.

Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B(-/-) heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling.

Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses.

A central paradigm within virology is that each viral particle largely behaves as an independent infectious unit. Here, we demonstrate that clusters of enteroviral particles are packaged within phosphatidylserine (PS) lipid-enriched vesicles that are non-lytically released from cells and provide greater infection efficiency than free single viral particles. We show that vesicular PS lipids are co-factors to the relevant enterovirus receptors in mediating subsequent infectivity and transmission, in particular to primary human macrophages.

Imaging flow cytometry for automated detection of hypoxia-induced erythrocyte shape change in sickle cell disease.

In preclinical and early phase pharmacologic trials in sickle cell disease, the percentage of sickled erythrocytes after deoxygenation, an ex vivo functional sickling assay, has been used as a measure of a patient's disease outcome. We developed a new sickle imaging flow cytometry assay (SIFCA) and investigated its application. To perform the SIFCA, peripheral blood was diluted, deoxygenated (2% oxygen) for 2 hr, fixed, and analyzed using imaging flow cytometry.