Towards Clinical Translation of CD8+ Regulatory T Cells Restricted by Non-Classical Major Histocompatibility Complex Ib Molecules

In central lymphoid tissues, mature lymphocytes are generated and pathogenic autoreactive lymphocytes are deleted. However, it is currently known that a significant number of potentially pathogenic autoreactive lymphocytes escape the deletion and populate peripheral lymphoid tissues. Therefore, peripheral mechanisms are present to prevent these potentially pathogenic autoreactive lymphocytes from harming one’s own tissues. One such mechanism is dictated by regulatory T (Treg) cells. So far, the most extensively studied Treg cells are CD4+Foxp3+ Treg cells. However, recent clinical trials for the treatment of immune-mediated diseases using CD4+ Foxp3+ Treg cells met with limited success. Accordingly, it is necessary to explore the potential importance of other Treg cells such as CD8+ Treg cells. In this regard, one extensively studied CD8+ Treg cell subset is Qa-1(HLA-E in human)-restricted CD8+ Treg cells, in which Qa-1(HLA-E) molecules belong to a group of non-classical major histocompatibility complex Ib molecules. This review will first summarize the evidence for the presence of Qa-1-restricted CD8+ Treg cells and their regulatory mechanisms. Major discussions will then focus on the potential clinical translation of Qa-1-restricted CD8+ Treg cells. At the end, we will briefly discuss the current status of human studies on HLA-E-restricted CD8+ Treg cells as well as potential future directions

Study on the dynamic change of volatile components of white tea in the pile-up processing based on sensory evaluation and ATD-GC–MS Technology

The pile-up processing has a great impact on the flavor of white tea. To investigate the effects of the volatile accumulation of white tea with different piling thickness treatments, tea leaves from different thickness treatments were subjected to sensory quantitative description analysis and ATD-GC–MS detection in this study. As a result, 122 volatile components were identified from white tea with different treatments. A total of 8 key compounds, including isovaleraldehyde, isobutyraldehyde, 2-methyl-butanal, 1-octene-3-ol, linalool, pentanoic acid, hexanal and 1-hexanol were screened out using multivariate statistical analysis, which were characteristic components of grassy, floral-fruity, pekoe aroma and sweet flavors. The results of the selected key characteristic volatile compounds were consistent with the sensory quantitative description. The aroma of mid-pile dried tea (MD) was exhibited a harmonious and pleasant overall flavor. This study provides a novel insight into the accumulation of volatile during the withering step of white tea production

The Effects of Insulin-Like Growth Factor I and BTP-2 on Acute Lung Injury

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1β, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy

IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury

This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy, compared to the untreated group, caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 h. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection

PPP3CA

PPP3CA encodes the catalytic subunit of calcineurin, a calcium-calmodulin-regulated serine-threonine phosphatase. Loss-of-function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain-of-function (GoF) variants in the auto-inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants

Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder

Abstract Background Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting. Methods We retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive “fetal exomes” performed in a clinical diagnostic laboratory between March 2012 and November 2017. We define a fetal exome as one performed on a sample obtained from a fetus or a product of conception with at least one structural anomaly detected by prenatal imaging or autopsy. Statistical comparisons were performed using Fisher’s exact test. Results Prenatal exome yielded an overall molecular diagnostic rate of 32% (n = 46/146). Of the 46 molecular diagnoses, 50% were autosomal dominant disorders (n = 23/46), 41% were autosomal recessive disorders (n = 19/46), and 9% were X-linked disorders (n = 4/46). The molecular diagnostic rate was highest for fetuses with anomalies affecting multiple organ systems and for fetuses with craniofacial anomalies. Out of 146 cases, a prenatal trio exome option designed for ongoing pregnancies was performed on 62 fetal specimens, resulting in a diagnostic yield of 35% with an average TAT of 14 days for initial reporting (excluding tissue culture time). The molecular diagnoses led to refined recurrence risk estimates, altered medical management, and informed reproductive planning for families. Conclusion Exome sequencing is a useful diagnostic tool when fetal structural anomalies suggest a genetic etiology, but other standard prenatal genetic tests did not provide a diagnosis

Reanalysis of Clinical Exome Sequencing Data

As knowledge about genetic causes of disease improves, periodic reanalysis of clinical exome sequence could yield new genetic information. This study showed that a reanalysis of data initially analyzed about 6 years ago almost doubled the diagnostic yield and that a semiautomated approach to sequence analysis had a diagnostic sensitivity of 92.9%