PRDM14 Drives OCT3/4 Recruitment via Active Demethylation in the Transition from Primed to Naive Pluripotency

Primordial germ cells (PGCs) are specified from epiblast cells in mice. Genes associated with naive pluripotency are repressed in the transition from inner cell mass to epiblast cells, followed by upregulation after PGC specification. However, the molecular mechanisms underlying the reactivation of pluripotency genes are poorly characterized. Here, we exploited the in vitro differentiation of epiblast-like cells (EpiLCs) from embryonic stem cells (ESCs) to elucidate the molecular and epigenetic functions of PR domain-containing 14 (PRDM14). We found that Prdm14 overexpression in EpiLCs induced their conversion to ESC-like cells even in the absence of leukemia inhibitory factor in adherent culture. This was impaired by the loss of Kruppel-like factor 2 and ten-eleven translocation (TET) proteins. Furthermore, PRDM14 recruited OCT3/4 to the enhancer regions of naive pluripotency genes via TET-base excision repair-mediated demethylation. Our results provide evidence that PRDM14 establishes a transcriptional network for naive pluripotency via active DNA demethylation

CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS

The molecular machinery responsible for cytosolic accumulation of misfolded TDP-43 in amyotrophic lateral sclerosis (ALS) remains elusive. Here we identified a cullin-2 (CUL2) RING complex as a novel ubiquitin ligase for fragmented forms of TDP-43. The von Hippel Lindau protein (VHL), a substrate binding component of the complex, preferentially recognized misfolded TDP-43 at Glu246 in RNA-recognition motif 2. Recombinant full-length TDP-43 was structurally fragile and readily cleaved, suggesting that misfolded TDP-43 is cleared by VHL/CUL2 in a step-wise manner via fragmentation. Surprisingly, excess VHL stabilized and led to inclusion formation of TDP-43, as well as mutant SOD1, at the juxtanuclear protein quality control center. Moreover, TDP-43 knockdown elevated VHL expression in cultured cells, implying an aberrant interaction between VHL and mislocalized TDP-43 in ALS. Finally, cytoplasmic inclusions especially in oligodendrocytes in ALS spinal cords were immunoreactive to both phosphorylated TDP-43 and VHL. Thus, our results suggest that an imbalance in VHL and CUL2 may underlie oligodendrocyte dysfunction in ALS, and highlight CUL2 E3 ligase emerges as a novel therapeutic potential for ALS

Efficacy of anti-PD-1 monotherapy for recurrent or metastatic olfactory neuroblastoma

BackgroundOlfactory neuroblastoma (ONB) is a rare malignant tumor of the head and neck. Due to its rarity, standard systemic therapy for this condition has yet to be established. In particular, the use of immune checkpoint inhibitors (ICIs) for the recurrent or metastatic (R/M) ONB population remains unclear.MethodsWe retrospectively evaluated 11 patients with R/M ONB who received any systemic chemotherapy at two Japanese institutions (National Cancer Center Hospital East and Kyushu Medical Center) between January 2002 and March 2022 and analyzed outcomes by use of anti-PD-1 antibody (nivolumab or pembrolizumab) monotherapy.ResultsOf the 11 patients, 6 received ICI (ICI-containing treatment group) and the remaining 5 were treated with systemic therapy but not including ICI (ICI-non-containing treatment group). Overall survival (OS) was significantly longer in the ICI-containing group (median OS: not reached vs. 6.4 months, log-rank p-value: 0.035). The fraction of ICI systemic therapy in the entire treatment period of this group reached 85.9%. Four patients (66.7%) in the ICI-containing treatment group experienced immune-related adverse events (irAE), with grades of 1/2. No irAE of grade 3 or more was seen, and no patient required interruption or discontinuation of treatment due to toxicity.ConclusionICI monotherapy appears to be effective and to contribute to prolonged survival in R/M ONB

Comparison of the swimming ability and upstream-migration behavior between chum salmon and masu salmon

The spawning ground of chum salmon (Oncorhynchus keta) is usually located farther downriver than that of masu salmon (Oncorhynchus masou) in Hokkaido, Japan. To compare the swimming abilities of these two species, the relationship between swimming speed and oxygen consumption was compared using a swim tunnel in the laboratory. Then, the upstream-migration behaviors of chum salmon and masu salmon were compared using electromyogram telemetry at fish passages in the Toyohira River, Hokkaido. In the laboratory study, the standard metabolic rate of masu salmon was lower and the critical swimming speed (U-crit) was faster than those of chum salmon. In the field study, the holding time needed to recover the swimming performance exceeding U-crit at the fish passages and the trial number needed to pass the fish passages were significantly lower for masu salmon than chum salmon. These results revealed that masu salmon are more adaptable to extended swimming in high water velocity conditions than chum salmon and that masu salmon are better equipped for a long distance upstream migration to their spawning ground than chum salmon

The Occurrence of Delayed Stem Senescence in Relation to trans-Zeatin Riboside Level in the Xylem Exudate in Soybeans Grown under Excess-Wet and Drought Soil Conditions

Delayed stem senescence (DSS) after pod maturation in soybean (Glycine max) lowers the quality of products in the mechanized harvest. The effects of drought and excess wet soil conditions on the occurrence of DSS were studied with special reference to remobilization of vegetative nitrogen and supply of cytokinin via xylem. Excess wet soil treatment was applied throughout the reproductive period to field-grown soybean in 2003 (Exp.1) and short-term drought stress treatment was applied during the reproductive period to pot-grown soybean plants in 2004 (Exp.2). The degree of DSS at pod maturing was evaluated by the DSS score from “1” for severe DSS to “5” for completely synchronous senescence of pods and vegetative parts. The DSS score in Exp.1 varied from 2.2 to 2.5 and that in Exp.2 from 2.8 to 3.7. Excess wet soil treatment in Exp.1 promoted the occurrence of DSS, while drought stress treatments during the periods of flowering to pod elongation, later seed-filling and seed maturing decreased it. The soybean plants that showed distinct DSS had lower ratios of seed number to vegetative dry weight at seed maturity and a lower rate of nitrogen remobilization from vegetative organs to seeds during the latter half of the reproductive period. The trans-zeatin riboside (t-ZR) level in xylem exudate tended to be higher in soybeans with severer DSS than in those normally matured in both experiments showing increased t-ZR concentration and/or higher exudation rate. These results suggest that DSS can be caused by a wet soil water condition, which lowers pod/seed number and increases vegetative organs mediated by the increased supply of cytokinin through xylem during seed-filling

Improvements in asymmetry in knee flexion motion during landing are associated with the postoperative period and quadriceps strength after anterior cruciate ligament reconstruction

This study investigated the relationship between quadriceps strength and knee kinematics during a drop vertical jump (DVJ) at 6, 9 and 12 months after anterior cruciate ligament reconstruction (ACLR) in 9 male and 22 female athletes (16.6 +/- 2.1 years old). Isokinetic quadriceps strength was measured by a dynamometer (Biodex System 3). Knee flexion excursion was assessed using two-dimensional analysis. Knee flexion excursion at 6 months was significantly smaller in the involved limb than in the uninvolved limb independent of quadriceps strength (56.7 degrees +/- 9.3 degrees, 63.4 degrees +/- 11.4 degrees, P < 0.001). At 9 months, only the low quadriceps strength group demonstrated a similar interlimb difference (57.2 degrees +/- 12.3 degrees, 63.3 degrees +/- 10.5 degrees, P < 0.001). At 12 months, there was no significant interlimb difference in knee flexion excursion regardless of quadriceps strength. These findings indicate that restoration in symmetrical knee flexion excursion during a DVJ requires rehabilitation as well as quadriceps strength

Structural basis for the activation of peroxisome proliferator-activated receptor-gamma by telmisartan

Telmisartan, a selective angiotensin receptor blocker, has been recently shown to act as a partial agonist for peroxisome proliferator-activated receptor-gamma (PPAR&#x3b3;). To understand the activation mechanism of PPAR&#x3b3; by telmisartan, we determined the ternary complex structure of PPAR&#x3b3;, telmisartan and coactivator peptide from SRC1 at 2.25 &#xc5; resolution. The overall fold of PPAR&#x3b3; is almost identical to previously-determined complex structures with agonists. However, telmisartan exhibits an unexpected binding mode, devoid of some essential hydrogen bonds for full activation of PPAR&#x3b3;