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Corrigendum on: D-Serine Contributes to Seizure Development via ERK Signaling. Ma T, Wu Y, Chen B, Zhang W, Jin L, Shen C, Wang Y, Liu Y. Front Neurosci. 2019 Mar 26;13:254. doi: 10.3389/fnins.201913:254. doi: 10.3389/fnins. .00254. eCollection 2019.In the published article, there was an error in [Figure 5A] as published. [duplicate images were mistakenly displayed in the inserts 1 and 2 of (E-H) Representative frequency images of EEG recordings in rats treated with LaaβH (E), saline (F), MK801(G) and CBIO (H). N = 7-9 rats per group. Compared with the saline control, LaaβH could prolong the onset of seizure occurrence and reduce the mean power of the EEG, while CBIO could shorten the onset of seizure induction and increase the mean power of the EEG.] appear below.

Black garlic is currently attracting interest as a health food and constituent of commercial supplements; however, no data regarding the d-amino acids within black garlic have been reported. Therefore, the amino acid compositions of methanol extracts from fresh and black garlic were compared herein. We investigated the contents of the d- and l-forms of amino acids in commercial fresh, black, and freeze-dried garlic foodstuffs by liquid chromatography–tandem mass spectrometry (LC–MS/MS) using a pre-column chiral derivatization reagent, succinimidyl 2-(3-((benzyloxy)carbonyl)-1-methyl-5-oxoimidazolidin-4-yl) acetate. Several d-amino acids, namely, the d-forms of Asn, Ala, Ser, Thr, Glu, Asp, Pro, Arg, Phe, Orn, Lys, and Tyr, were observed in the methanol extract of black garlic, whereas only d-Ala was detected in that of fresh garlic foodstuffs. These data suggest that several d-amino acids can be produced during fermentation for preparing black garlic.

The synthetic buffer compound TRIS (2-amino-2-(hydroxymethyl)propane-1,3-diol) is used in countless applications, and no detailed information on its degradation has been published so far. Herein, we describe the discovery of a complete bacterial degradation pathway for TRIS. By serendipity, a Pseudomonas strain was isolated from sewage sludge that was able to grow with TRIS as only carbon and nitrogen source. Genome and transcriptome analyses revealed two adjacent gene clusters embedded in a mobile genetic element on a conjugative plasmid to be involved in TRIS degradation. Heterologous gene expression revealed cluster I to encode a TRIS uptake protein, a TRIS alcohol dehydrogenase, and a TRIS aldehyde dehydrogenase, catalyzing the oxidation of TRIS into 2-hydroxymethylserine. Gene cluster II encodes a methylserine hydroxymethyltransferase (mSHMT) and a d-serine dehydratase that plausibly catalyze the conversion of 2-hydroxymethylserine into pyruvate. Conjugational plasmid transfer into Pseudomonas putida KT2440 enabled this strain to grow with TRIS and with 2-hydromethylserine, demonstrating that the complete TRIS degradation pathway can be transmitted by horizontal gene transfer. Subsequent enrichments from wastewater purification systems led to the isolation of further TRIS-degrading bacteria from the Pseudomonas and Shinella genera carrying highly similar TRIS degradation gene clusters. Our data indicate that TRIS degradation evolved recently via gene recruitment and enzyme adaptation from multiple independent metabolic pathways, and database searches suggest that the TRIS degradation pathway is now globally distributed. Overall, our study illustrates how engineered environments can enhance the emergence of new microbial metabolic pathways in short evolutionary time scales.

Glycolysis is the metabolic pathway that converts glucose into pyruvate, whereas fermentation can then produce lactate from pyruvate. Here, we developed single fluorescent protein (FP)-based lactate and pyruvate indicators with low EC 50 for trace detection of metabolic molecules and live cell imaging and named them “Green Lindoblum” and “Green Pegassos,” respectively. Green Lindoblum (EC 50 of 30 µM for lactate) and Green Pegassos (EC 50 of 70 µM for pyruvate) produced a 5.2- and 3.3-fold change in fluorescence intensity in response to lactate and pyruvate, respectively. Green Lindoblum measured lactate levels in mouse plasma, and Green Pegassos in combination with D-serine dehydratase successfully estimated D-serine levels released from mouse primary cultured neurons and astrocytes by measuring pyruvate level. Furthermore, live cell imaging analysis revealed their utility for dual-colour imaging, and the interplay between lactate, pyruvate, and Ca 2+ in human induced pluripotent stem cell-derived cardiomyocytes. Therefore, Green Lindoblum and Green Pegassos will be useful tools that detect specific molecules in clinical use and monitor the interplay of metabolites and other related molecules in diverse cell types.

Duchenne muscular dystrophy (DMD) is an X‐linked disease caused by the absence of functional dystrophin in the muscle cells. Recent untargeted metabolomics studies identified amino acid metabolism alterations as biochemical pathways potentially involved in DMD pathogenesis. Here, in a well‐characterised cohort of DMD children and paediatric controls, we investigated by high‐performance liquid chromatography (HPLC) the serum profile of a selected pool of amino acids in D‐ and L‐configuration, including L‐glutamate, L‐glutamine, glycine, L‐aspartate, D‐aspartate, L‐asparagine, L‐serine, and D‐serine. These amino acids are known to modulate neurotransmission and to play essential roles in energy and skeletal muscle metabolism. HPLC determinations highlighted a general amino acid deregulation in DMD compared to controls, including lower levels of L‐aspartate, L‐asparagine, D‐serine, L‐glutamine, and glycine and D−/Total serine ratio. In control subjects, we observed a significant positive correlation between L‐glutamine and age, which lacked in affected children. Conversely, in DMD, we observed (i) a negative correlation of L‐glutamate and L‐aspartate with serum creatinine and creatine kinase levels; (ii) a direct correlation of serum L‐glutamine/L‐glutamate ratio with the fat‐free mass index (as determined by dual energy X‐ray absorptiometry) and with specific motor function scores (North Star Ambulatory Assessment); and (iii) no correlations between glucocorticoid treatment or cognitive function and the serum amino acid profile. Our study highlights significant correlations between serum L‐glutamate levels, L‐glutamine/L‐glutamate ratio, and the multidimensional measures of muscle wasting and motor impairment, suggesting that peripheral glutamine‐glutamate metabolism can be a suitable biomarker of disease severity and progression in DMD patients.

d-Serine, a rare enantiomer of serine, is a biomarker of kidney disease and function. The level of d-serine in the human body is precisely regulated through the urinary clearance of the kidney, and its clearance serves as a new measure of glomerular filtration rate with a lower bias than creatinine clearance. d-Serine also has a direct effect on the kidneys and mediates the cellular proliferation of tubular cells via mTOR signaling and induces kidney remodeling as a compensatory reaction to the loss of kidney mass. In living kidney donors, the removal of the kidney results in an increase in blood d-serine level, which in turn accelerates kidney remodeling and augments kidney clearance, thus reducing blood levels of d-serine. This feedback system strictly controls d-serine levels in the body. The function of d-serine as a biomarker and modulator of kidney function will be the basis of precision medicine for kidney diseases.

Implantation-caused foreign-body response (FBR) is a commonly encountered issue and can result in failure of implants. The high L-serine content in low immunogenic silk sericin, and the high D-serine content as a neurotransmitter together inspire us to prepare poly-DL-serine (PSer) materials in mitigating the FBR. Here we report highly water soluble, biocompatible and easily accessible PSer hydrogels that cause negligible inflammatory response after subcutaneous implantation in mice for 1 week and 2 weeks. No obvious collagen capsulation is found surrounding the PSer hydrogels after 4 weeks, 3 months and 7 months post implantation. Histological analysis on inflammatory cytokines and RNA-seq assay both indicate that PSer hydrogels show low FBR, comparable to the Mock group. The anti-FBR performance of PSer hydrogels at all time points surpass the poly(ethyleneglycol) hydrogels that is widely utilized as bio-inert materials, implying the potent and wide application of PSer materials in implantable biomaterials and biomedical devices. Implantation-caused foreign-body response is a commonly encountered issue and can result in failure of implants. Here, the authors demonstrate that a highly water soluble, biocompatible, and easily accessible poly-DL-serine hydrogel can mitigate foreign-body response.

Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or exogenous (single astrocyte Ca2+ uncaging) stimuli modulate putative single CA3-CA1 hippocampal synapses. The astrocyte-mediated synaptic modulation was biphasic and consisted of an initial glutamate-mediated potentiation followed by a purinergic-mediated depression of neurotransmitter release. The temporal dynamic properties of this biphasic synaptic regulation depended on the firing frequency and duration of the neuronal activity that stimulated astrocytes. Present results indicate that single astrocytes can decode neuronal activity and, in response, release distinct gliotransmitters to differentially regulate neurotransmission at putative single synapses.

In 2002, the novel human gene G72 was associated with schizophrenia susceptibility. This gene encodes a small protein of 153 amino acids, named pLG72, which represents a rare case of primate-specific protein. In particular, the rs2391191 single nucleotide polymorphism (resulting in in the R30K substitution) was robustly associated to schizophrenia and bipolar disorder. In this review, we aim to summarize the results of 20 years of biochemical investigations on pLG72. The main known role of pLG72 is related to its ability to bind and inactivate the flavoenzyme d-amino acid oxidase, i.e., the enzyme that controls the catabolism of d-serine, the main NMDA receptor coagonist in the brain. pLG72 was proposed to target the cytosolic form of d-amino acid oxidase for degradation, preserving d-serine and protecting the cell from oxidative stress generated by hydrogen peroxide produced by the flavoenzyme reaction. Anyway, pLG72 seems to play additional roles, such as affecting mitochondrial functions. The level of pLG72 in the human body is still a controversial issue because of its low expression and challenging detection. Anyway, the intriguing hypothesis that pLG72 level in blood could represent a suitable marker of Alzheimer’s disease progression (a suggestion not sufficiently established yet) merits further investigations.

Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of L-serine from glucose. Astrocytic L-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain D-serine production, but this hypothesis remains untested. We now report that inhibition of astrocytic Phgdh suppressed the de novo synthesis of L-and D-serine and reduced the NMDAR synaptic potentials and long-term potentiation (LTP) at the Schaffer collaterals-CA1 synapse. Likewise, enzymatic removal of extracellular L-serine impaired LTP, supporting an L-serine shuttle mechanism between glia and neurons in generating the NMDAR coagonist D-serine. Moreover, deletion of serine racemase (SR) in glutamatergic neurons abrogated D-serine synthesis to the same extent as Phgdh inhibition, suggesting that neurons are the predominant source of the newly synthesized D-serine. We also found that the synaptic NMDAR activation in adult SR-knockout (KO) mice requires Phgdh-derived glycine, despite the sharp decline in the postnatal glycine levels as a result of the emergence of the glycine cleavage system. Unexpectedly, we also discovered that glycine regulates D-serine metabolism by a dual mechanism. The first consists of tonic inhibition of SR by intracellular glycine observed in vitro, primary cultures, and in vivo microdialysis. The second involves a transient glycine-induce D-serine release through the Asc-1 transporter, an effect abolished in Asc-1 KO mice and diminished by deleting SR in glutamatergic neurons. Our observations suggest that glycine is a multifaceted regulator of D-serine metabolism and implicate both D-serine and glycine in mediating NMDAR synaptic activation at the mature hippocampus through a Phgdh-dependent shuttle mechanism.