Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the ...pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo‐planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta‐analysis, using standardized means and a random‐effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta‐analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.
Mitochondrial health plays a crucial role in human brain development and diseases. However, the evaluation of mitochondrial health in the brain is not incorporated into clinical practice due to ...ethical and logistical concerns. As a result, the development of targeted mitochondrial therapeutics remains a significant challenge due to the lack of appropriate patient-derived brain tissues. To address these unmet needs, we developed cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) derived from human peripheral blood mononuclear cells (PBMCs) and monitored mitochondrial health from the primary, reprogrammed and differentiated stages. Our results show preserved mitochondrial genetics, function and treatment responses across PBMCs to iPSCs to COs, and measurable neuronal activity in the COs. We expect our approach will serve as a model for more widespread evaluation of mitochondrial health relevant to a wide range of human diseases using readily accessible patient peripheral (PBMCs) and stem-cell derived brain tissue samples.
Highlights • Maternal infection is linked to increased risk of psychiatric disorders. • Maternal immune activation changes cytokine levels and brain morphology. • Altered cytokine levels are found in ...subjects with psychiatric disorders.
On March 11, 2020, the World Health Organization declared the outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) as a global pandemic. At the center of SARS-CoV-2 is ...the activation of inflammatory markers; remarkably, interleukin 6 and C-reactive protein seem to be consistently elevated in patients with SARS-CoV-2. Here, we showed that increased systemic C-reactive protein and interleukin 6 are common biomarkers of both severe COVID-19 and DSM-5–defined disorders. However, it is not known whether patients with psychiatric disorders with preexisting increased interleukin 6 and C-reactive protein are more vulnerable to severe complications of COVID-19 because of the additive inflammatory processes.
BackgroundAdoptive TCR T-cell therapies from autologous donor are expensive, time-consuming and depends on quality of T-cells in patients. One of the key challenges for autologous TCR therapy is the ...requirement of cell numbers that are orders of magnitude higher than CAR-T cells. This has several implications including the inability to manufacture enough cells for a repeat dosing regimen. To this end, we have developed a scalable method by which TCR+ CD8+ lymphocytes can be generated from induced pluripotent stem cells (iPSCs) using 3D engineered thymic niche (ETN) comprised of DLL4- and VCAM-conjugated paramagnetic microbeads.MethodsWe have successfully developed a gene-editing workflow for generation and characterization of iPSC clones engineered to express an exogenous TCR. We utilized a defined scalable differentiation process to generate lymphoid competent CD34+ HPCs from multiple iPSC clones. Cryopreserved CD34 cells were differentiated to Pro T cells and CD8+TCR+ cells by leveraging stage specific control of Notch signalling using the 3D ETN. Flow cytometry and single-cell RNA sequencing was used to characterize the phenotypic and transcriptional state of iPSC derived effector cells. Incucyte-based cytotoxic killing assay was used to demonstrate antigen specific effector cell proliferation and cytotoxic function. We have developed a computational tool to quantify the average number of target cells killed by each input effector cell per unit time.ResultsMultiple iPSC engineered clones expressing a TCR were successfully differentiated to hematopoietic precursor cells with an average efficiency of ~2.5 lympho-competent HPCs per input iPSC without magnetic sorting. HPCs were further differentiated in the presence of proprietary ETN beads to generate mature single positive T cells expressing TCR. The end stage cells expressed T-cell markers mimicking mature peripheral blood T-cells with a 90% TCR expression detected by an antigen-loaded tetramer. Transcriptional profiling of iPSC-derived and peripheral blood-derived CD8+ T-cells revealed similar gene expression signatures. Cryopreserved end-of-process CD8+ cells displayed target-specific cytotoxic activity against antigen expressing tumor cell lines in vitro across 4 rounds of stimulation in a long-term serial killing assay. iPSC derived CD8 TCR T-cells secreted perforin, granzyme B, IFNg, TNFa and GM-CSF and expanded ~1000-fold in response to target antigen.ConclusionsWe have successfully generated CD8+TCR+ T-cells from iPSCs using a defined process that is amenable to scale up. iPSCs derived TCR T-cells, when combined with genetic manipulations to enhance persistence in a suppressive tumor microenvironment and overcome allogeneic rejection, could lead to a new generation of TCR T-cell therapies.
Human papillomaviruses (HPVs) are frequently detected in a variety of lesions in the oral mucosa and upper respiratory tract. The pathogenesis in these areas is not as clearly elucidated as in other ...anatomical regions, but most experts agree that HPVs are responsible for the commonly observed benign lesions, such as squamous papillomas, verruca vulgaris and recurrent respiratory papillomatosis. Transformation of these benign lesions is well described, but it is not clear what role the virus plays, if any, in carcinogenesis. HPV types 6 and 11 are most frequently detected in oral cavity and respiratory tract lesions, though several other types have also been reported. Despite an opaque understanding of these lesions' pathogeneses, it is essential for the clinician to recognize these diseases, to provide appropriate treatment and to promote patient awareness of potential oral transmission. In this paper, we review the major HPV-associated diseases of the oral mucosa and upper respiratory tract, focusing specifically on clinical features, histopathological characteristics and disease management.
Mitochondrial dysfunction has been implicated in the pathophysiology of bipolar disorder (BD). Impediment of mitochondrial oxidative phosphorylation results in a shift toward anaerobic respiration ...and lactate production. Elevated CNS lactate levels in adults with BD inform the need to evaluate lactate in peripheral samples and early in the course of BD. Furthermore, there exists a recent surge of investigations looking at circulating cell-free mitochondrial DNA (ccf-mtDNA) as a potential biomarker as they are released from cells under physiological stress, apoptosis, or bioenergetic compromise.
To compare lactate and ccf-mtDNA, two different ways in assessing the mitochondrial health and function, in adolescents with BD versus healthy control adolescents (HC).
One-hundred and five adolescents (n = 64 BD, n = 41 HC) were included. Serum lactate level was measured using a commercially available colorimetric kit. Serum ccf-mtDNA concentration was measured using quantitative polymerase chain reaction from ccfDNA purified by commercially available spin columns. Diagnosis and mood symptoms were evaluated using semi-structured interviews.
There is an increase in serum lactate level of adolescents with BD (1.319 ± 0.444 nmol/uL) versus HC (1.168 ± 0.353 nmol/uL; p = 0.043), but not ccf-mtDNA. Among BD adolescents, depression symptoms were negatively correlated with ccf-mtDNA levels (ρ = −0.289; p = 0.038) but loses significance when corrected for multiple comparison. Lactate was positively correlated with ccf-mtDNA in the overall sample (ρ = 0.201; p = 0.043). When examined by diagnosis, this association remained in BD (ρ = 0.273; p = 0.032), but not HC.
These preliminary results indicate that elevated lactate is observed even among adolescents early in their course of BD, that the association between lactate and ccf-mtDNA appears to be specific to BD, and that ccf-mtDNA is potentially associated with depression symptoms in adolescent BD. In addition, the effect of psychotropic medications used in the treatment of BD on peripheral lactate and ccf-mtDNA requires further investigation.
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