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Fabry disease (FD) is a lysosomal storage disorder in which α-galactosidase (GLA) deficiency leads to a build-up of globo-triaosylceramide (Gb3) in various cell types. Gb3 accumulation leads to the abnormalities of microvascular function associated with FD. Previously, we discovered significant abnormalities in vascular endothelial cells (VECs) derived from FD-induced pluripotent stem cells. We then used a cell-based system to screen a group of clinical compounds for candidates capable of rescuing those abnormalities. Lomerizine was one of the most promising candidates because it alleviated a variety of FD-associated phenotypes both in vitro and in vivo. Lomerizine reduced mitochondria Ca 2+  levels, ROS generation, and the maximal respiration of FD-VECs in vitro. This led to a suppression of the endothelial-to-mesenchymal transition (EndMT) and rescued FD-VEC function. Furthermore, FD-model mice (Gla−/−/TSP1Tg) treated orally with lomerizine for 6 months showed clear improvement of several FD phenotypes, including left ventricular hypertrophy, renal fibrosis, anhidrosis, and heat intolerance. Thus, our results suggest lomerizine as a novel candidate for FD therapy.

Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite important roles during development and neurological disorders, the eat-me signal that initiates glia-mediated phagocytosis of synapses remains largely elusive. Here, by generating inducible conditional knockout mice of Cdc50a, we induced stable exposure of phosphatidylserine in the neuronal outer membrane. Surprisingly, acute Cdc50a deletion in neurons causes specific loss of inhibitory post-synapses without affecting other synapses, thereby generating excessive excitability with appearance of seizure. Ablating microglia or deleting microglial Mertk rescues the loss of inhibitory post-synapses, indicating that microglial phagocytosis is responsible for inhibitory post-synapse elimination. Moreover, inhibitory post-synapses in normal juvenile brains also use phosphatidylserine for synapse pruning by microglia, suggesting that phosphatidylserine may serve as a general eat-me signal for inhibitory post-synapse elimination. Competing Interest Statement The authors have declared no competing interest.

The topics include Advent, Transfiguration, Palm Sunday, Maundy Thursday, Pentecost, Trinity, All Saints, Thanksgiving, anniversary, bells, benediction, Bible, commission, communion, dedication, funeral/ memorial service, marriage, mission and service, Mother's day, stewardship, unity, and more. Throughout the collection, this reviewer, who has yet to meet the author, hears a passionate, exuberant, and unpretentious voice of a preacher who calls God \"our (Holy) Friend\" (11, 42, 46) and us \"sisters and brothers\" (1, 3, 14). JUNGJOO PARK Jungjoo Park is a recent graduate from Indiana University Jacobs School of Music, and is the organist at Southern Hills United Methodist Church in Lexington, Kentucky.

The TBM disc cutter, which is the main cutting tool of tunnel boring machines (TBMs), is replaced when it is excessively worn during the boring process. Disc cutters are usually monitored by workers at cutterhead chambers, and they check the status and wear of disc cutters. Manual measurement occasionally results in inaccurate measurement results. In order to overcome these limitations, real-time disc cutter monitoring techniques have been developed with different types of sensors. This study evaluates the distance measurement performance of an eddy-current sensor for measuring disc cutter wear via a series of laboratory experiments. This study focused on identifying the effects of various measurement environments on the sensor’s accuracy. The study considered conditions that the eddy-current sensor may encounter in shield TBM chambers, including air, water, slurry, and excavated muck. Experiments were conducted using both a small-scale disc cutter and a 17-inch full-scale disc cutter. The results indicate that the eddy-current sensor can accurately measure the distance to the disc cutter within a specific range and that its performance remains unaffected by different measurement environments.

The literature suggests that leisure walking can play an important role in preventing dementia. The purpose of the present study was to investigate the relationship between leisure walking and the prevalence of Alzheimer’s disease (AD) and other dementias among older adults. Using the 2020 Health and Retirement Study (HRS), 4581 responses constituted the sample for the present study. A hierarchical logit regression analysis was conducted to investigate the relationship between leisure walking and the prevalence of AD and dementia. The results show that leisure walking has been negatively associated with the prevalence of AD and other dementias—that is, they indicate that older adults who frequently engaged in leisure walking were less likely to develop AD and other dementias. This finding suggests the importance of leisure walking as a dementia prevention program for older adults.

Dengue virus (DV) is a mosquito-borne virus that is endemic to many tropical and subtropical areas. Recently, the annual incidence of DV infection has increased worldwide, including in Korea, due to global warming and increased global travel. We therefore sought to characterize the molecular and evolutionary features of DV-1 and DV-4 isolated from Korean overseas travelers. We used phylogenetic analysis based on the full coding region to classify isolates of DV-1 in Korea into genotype I (43251, KP406802), genotype IV (KP406803), and genotype V (KP406801). In addition, we found that strains of DV-4 belonged to genotype I (KP406806) and genotype II (43257). Evidence of positive selection in DV-1 strains was identified in the C, prM, NS2A, and NS5 proteins, whereas DV-4 showed positive selection only in the non-structural proteins NS2A, NS3, and NS5. The substitution rates per site per year were 5.58 × 10-4 and 6.72 × 10-4 for DV-1 and DV-4, respectively, and the time of the most recent common ancestor was determined using the Bayesian skyline coalescent method. In this study, the molecular, phylogenetic, and evolutionary characteristics of Korean DV-1 and DV-4 isolates were evaluated for the first time.

In Korea, dengue infection has been frequently reported in travelers to tropical and subtropical countries. Global warming increases the probability of autochthonous dengue outbreaks in Korea. In this report, the molecular and evolutionary properties of four dengue virus (DENV) type 2 isolates from Korean overseas travelers were examined. Three of these isolates were classified as Cosmopolitan genotypes and further divided into sublineages 1 (43,253, 43,254) and 2 (43,248), while the other isolate (KBPV-VR29) was related to American genotypes. The variable amino acid motifs related to virulence and replication were identified in the structural and non-structural proteins. A negative selection mechanism was clearly verified in all of the DENV proteins. Potential recombination events were identified in the NS5 protein of the XSBN10 strain. The substitution rate (5.32 × 10−4 substitutions per site) and the time of the most recent common ancestor (TMRCA) for each evolutionary group were determined by the Bayesian skyline coalescent method. This study shows that DENV type 2 strains with distinct phylogenetic, evolutionary, and virulence characteristics have been introduced into Korea by overseas travelers and have the potential to trigger autochthonous dengue outbreaks.

Several COVID-19 platforms have been licensed across the world thus far, but vaccine platform research that can lead to effective antigen delivery is still ongoing. Here, we constructed AdCLD-CoV19 that could modulate humoral immunity by harboring SARS-CoV-2 antigens onto a chimeric adenovirus 5/35 platform that was effective in cellular immunity. By replacing the S1/S2 furin cleavage sequence of the SARS-CoV-2 Spike (S) protein mounted on AdCLD-CoV19 with the linker sequence, high antigen expression was confirmed in various cell lines. The high levels of antigen expression contributed to antigen-specific antibody activity in mice and non-human primates (NHPs) with a single vaccination of AdCLD-CoV19. Furthermore, the adenovirus-induced Th1 immune response was specifically raised for the S protein, and these immune responses protected the NHP against live viruses. While AdCLD-CoV19 maintained neutralizing antibody activity against various SARS-CoV-2 variants, it was reduced to single vaccination for β and ο variants, and the reduced neutralizing antibody activity was restored with booster shots. Hence, AdCLD-CoV19 can prevent SARS-CoV-2 with a single vaccination, and the new vaccine administration strategy that responds to various variants can maintain the efficacy of the vaccine.

We have carried out a survey toward the central regions of 85 starless cores in HCN J = 1-0 to study inward motions in the cores. Sixty-four cores were detected with HCN lines. The infall asymmetry in the HCN spectra is found to be more prevalent, and more prominent than in any other previously used infall tracers such as CS J = 2-1, DCO+ J = 2-1, and N2H+ J = 1-0. We found close relation between the intensities of the HCN and N2H+ lines. This implies that the HCN is not much depleted in the central regions of the cores. In some cores, the HCN spectra show different sign of asymmetry from other molecular lines. A few cores show various signs of asymmetry in individual HCN hyperfine lines. The distribution of the velocity shift dV of the HCN profiles with respect to the systemic velocity of the optically thin tracer is found to be more shifted toward bluer side than those of other infall tracers, indicating that the HCN traces inward motions more frequently. The dV distribution of each HCN hyperfine line for all sources is similar. Moreover the dV values obtained from different HCN hyperfine lines for each source are nearly similar. These may mean that most of starless cores are in similar kinematic states across the layers of the cores. We identify 17 infall candidates using all available indicators such as the velocity shift dV and the blue to red peak intensity ratio of double peaked profiles for HCN J = 1-0, CS J = 2-1, J = 3-2, DCO+ J = 2-1, and N2H+ J = 1-0. Four of them, L63, L492, L694-2, and L1197 are found to show higher blue to red ratio in the HCN hyperfine line along the lower opacity, suggesting that infall speed becomes higher toward the center.