NGL-2 Deletion Leads to Autistic-like Behaviors Responsive to NMDAR Modulation

NGL-2 is a postsynaptic adhesion molecule known to regulate synaptic transmission, but whether NGL-2 regulates synaptic plasticity and specific behaviors remains unknown. Um et al. find that mice lacking NGL-2 display suppressed NMDA receptor-dependent synaptic plasticity and autistic-like social deficits and repetitive behaviors that are responsive to NMDA receptor activation.Netrin-G ligand 2 (NGL-2)/LRRC4, implicated in autism spectrum disorders and schizophrenia, is a leucine-rich repeat-containing postsynaptic adhesion molecule that interacts intracellularly with the excitatory postsynaptic scaffolding protein PSD-95 and trans-synaptically with the presynaptic adhesion molecule netrin-G2. Functionally, NGL-2 regulates excitatory synapse development and synaptic transmission. However, whether it regulates synaptic plasticity and disease-related specific behaviors is not known. Here, we report that mice lacking NGL-2 (Lrrc4−/− mice) show suppressed N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampus. NGL-2 associates with NMDARs through both PSD-95-dependent and -independent mechanisms. Moreover, Lrrc4−/− mice display mild social interaction deficits and repetitive behaviors that are rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-2 promotes synaptic stabilization of NMDARs, regulates NMDAR-dependent synaptic plasticity, and prevents autistic-like behaviors from developing in mice, supporting the hypothesis that NMDAR dysfunction contributes to autism spectrum disorders. © 2018 The Author(s

Migration Inhibitory Factor in Conditioned Medium from Human Umbilical Cord Blood-Derived Mesenchymal Stromal Cells Stimulates Hair Growth

Conventional therapeutic applications of mesenchymal stromal cells (MSCs) focus on cell replacement and differentiation; however, increasing evidence suggests that most of their therapeutic effects are carried out by their various secretions. This study investigated the application of conditioned medium (CM) from human umbilical cord blood-derived MSCs (hUCB-MSCs) to improve hair growth and developed a method to reliably produce this optimized CM. Primed MSC-derived CM (P-CM) with combinations of TGF-β1 and LiCl was optimized by comparing its effects on the cell viability of dermal papilla cells (DPCs). P-CM significantly increased the viability of DPCs compared to CM. The secretion of vascular endothelial growth factor (VEGF) in DPCs was regulated by the macrophage migration inhibitory factor (MIF) in the P-CM secreted by MSCs. These findings suggest that P-CM can improve the efficacy in hair growth via a paracrine mechanism and that MIF in P-CM exerts hair growth-promoting effects via a VEGF-related β-catenin and p-GSK-3β [SER9] signaling pathway. Furthermore, clinical trials have shown that 5% P-CM improved androgenetic alopecia through producing an increased hair density, thickness, and growth rate, suggesting that this topical agent may be a novel and effective treatment option for patients with androgenetic alopecia

Coprisamides A and B, New Branched Cyclic Peptides from a Gut Bacterium of the Dung Beetle Copris tripartitus

Coprisamides A and B (1 and 2) were isolated from a bacterium in the gut of the dung beetle Copris tripartitus. Spectroscopic analysis revealed that the planar structures of 1 and 2 are novel cyclic heptapeptides bearing unusual units, such as beta-methylaspartic acid and 2,3-diaminopropanoic acid branched to valine and 2-heptatrienyl cinnamic acid. Absolute configurations were established by chemical derivatization and chiroptical spectroscopy. The coprisamides displayed significant activity for induction of quinone reductase.N

High Integrity and Fidelity of Long-Term Cryopreserved Umbilical Cord Blood for Transplantation

Umbilical cord blood (UCB) is used as a source of donor cells for hematopoietic stem cell (HSC) transplantation. The success of transplantation is dependent on the quality of cord blood (CB) units for maximizing the chance of engraftment. Improved outcomes following transplantation are associated with certain factors of cryopreserved CB units: total volume and total nucleated cell (TNC) count, mononuclear cell (MNC) count, and CD34+ cell count. The role of the storage period of CB units in determining the viability and counts of cells is less clear and is related to the quality of cryopreserved CB units. Herein, we demonstrate the recovery of viable TNCs and CD34+ cells, as well as the MNC viability in 20-year-old cryopreserved CB units in a CB bank (MEDIPOST Co., Ltd., Seongnam-si, Gyeonggi-do, Korea). In addition, cell populations in CB units were evaluated for future clinical applications. The stable recovery rate of the viability of cryopreserved CB that had been stored for up to 20 years suggested the possibility of uses of the long-term cryopreservation of CB units. Similar relationships were observed in the recovery of TNCs and CD34+ cells in units of cryopreserved and fresh CB. The high-viability recovery of long-term cryopreserved CB suggests that successful hematopoietic stem cell (HSC) transplantation and other clinical applications, which are suitable for treating incurable diseases, may be performed regardless of long-term storage

Longitudinal Analysis of Memory T-Cell Responses in Survivors of Middle East Respiratory Syndrome

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]: Middle East respiratory syndrome (MERS) is a highly lethal respiratory disease caused by a zoonotic betacoronavirus. The development of effective vaccines and control measures requires a thorough understanding of the immune response to this viral infection. METHODS: We investigated cellular immune responses up to 5 years after infection in a cohort of 59 MERS survivors by performing enzyme-linked immunospot assay and intracellular cytokine staining after stimulation of peripheral blood mononuclear cells with synthetic viral peptides. RESULTS: Memory T-cell responses were detected in 82%, 75%, 69%, 64%, and 64% of MERS survivors from 1-5 years post-infection, respectively. Although the frequency of virus-specific interferon gamma (IFN-γ)-secreting T cells tended to be higher in moderately/severely ill patients than in mildly ill patients during the early period of follow-up, there was no significant difference among the different clinical severity groups across all time points. While both CD4+ and CD8+ T cells were involved in memory T-cell responses, CD4+ T cells persisted slightly longer than CD8+ T cells. Both memory CD4+ and CD8+ T cells recognized the E/M/N proteins better than the S protein and maintained their polyfunctionality throughout the period examined. Memory T-cell responses correlated positively with antibody responses during the initial 3-4 years but not with maximum viral loads at any time point. CONCLUSIONS: These findings advance our understanding of the dynamics of virus-specific memory T-cell immunity after MERS-coronavirus infection, which is relevant to the development of effective T cell-based vaccines.N

Development and evaluation of an anti-rabies virus phosphoprotein-specific monoclonal antibody for detection of rabies neutralizing antibodies using RFFIT

<div><p>Background</p><p>Rabies is a major public health problem with a fatality rate close to 100%; however, complete prevention can be achieved through pre- or post-exposure prophylaxis. The rapid fluorescent focus inhibition test (RFFIT) is one of the recommended testing methods to determine the production of neutralizing antibodies after vaccination. Here, we report the development of a new monoclonal antibody (mAb) designed to react specifically with <i>Rabies virus</i> (RABV) phosphoprotein (P protein), and the evaluation of its applicability to the RFFIT and its effectiveness as a diagnostic reagent for human rabies.</p><p>Methodology/principal findings</p><p>The mAb KGH P 16B8 was produced to target the P protein of the Korean KGH RABV strain. An indirect immunofluorescence assay (IFA) was conducted to detect various strains of RABV in various cell lines. Alexa-conjugated KGH P 16B8 (16B8-Alexa) was developed for the RFFIT. The IFA test could detect RABV up to a 1:2,500 dilution, with a detection limit comparable to that of a commercial diagnostic reagent. The sensitivity, specificity, positive predictive value, and negative predictive value of the RFFIT using 16B8-Alexa in 414 clinical specimens were 98.67%, 99.47%, 99.55%, and 98.42%, respectively. The results of the RFFIT with 16B8-Alexa were strongly correlated with those obtained using an existing commercial diagnostic reagent (r = 0.995, <i>p</i><0.001).</p><p>Conclusions/significance</p><p>The mAb developed in this study shows high sensitivity and specificity, confirming its clinical utility with the RFFIT to measure the rabies neutralizing antibody titer and establish a diagnosis in human. Thus, 16B8-Alexa is expected to serve as an alternative diagnostic reagent that is widely accessible, with potentially broad applications beyond those of the RFFIT in Korea. Further studies with 16B8-Alexa should provide insight into the immunological mechanism of the P protein of Korean RABV.</p></div

IFA reactivity according to RABV strain and infected cell type.

<p>(A) BHK-21 cells and (B) N2a cells. The cells were infected with the KGH, CVS-11, and ERA strains for 48 h. The results were observed under a fluorescence microscope at a magnification 400×.</p

Comparison of the detection limits of the 16B8-Alexa diagnostic antibody with that of the DFA.

<p>(A) 16B8-Alexa and (B) commercial DFA reagent were five-fold serially diluted in PBS containing 0.00025% Evans blue to dilutions ranging from 1:100 to 1:12,500. Fluorescence microscopic images are shown at a magnification of 400×.</p

Correlation of RFFIT results of 414 clinical specimens, using DFA reagent and 16B8-Alexa.

<p>Significant correlation was observed (r = 0.995, <i>p</i><0.001).</p