Regulators specifying cell fate activate cell cycle regulator genes to determine cell numbers in ascidian larval tissues.

In animal development, most cell types stop dividing before terminal differentiation; thus, cell cycle control is tightly linked to cell differentiation programmes. In ascidian embryos, cell lineages do not vary among individuals, and rounds of the cell cycle are determined according to cell lineages. Notochord and muscle cells stop dividing after eight or nine rounds of cell division depending on their lineages. In the present study, we showed that a Cdk inhibitor, Cdkn1.b, is responsible for stopping cell cycle progression in these lineages. Cdkn1.b is also necessary for epidermal cells to stop dividing. In contrast, mesenchymal and endodermal cells continue to divide even after hatching, and Myc is responsible for maintaining cell cycle progression in these tissues. Expression of Cdkn1.b in notochord and muscle is controlled by transcription factors that specify the developmental fate of notochord and muscle. Likewise, expression of Myc in mesenchyme and endoderm is under control of transcription factors that specify the developmental fate of mesenchyme and endoderm. Thus, cell fate specification and cell cycle control are linked by these transcription factors.

Microglia sense astrocyte dysfunction and prevent disease progression in an Alexander disease model.

Alexander disease (AxD) is an intractable neurodegenerative disorder caused by GFAP mutations. It is a primary astrocyte disease with a pathological hallmark of Rosenthal fibres within astrocytes. AxD astrocytes show several abnormal phenotypes. Our previous study showed that AxD astrocytes in model mice exhibit aberrant Ca2+ signals that induce AxD aetiology. Here, we show that microglia have unique phenotypes with morphological and functional alterations, which are related to the pathogenesis of AxD. Immunohistochemical studies of 60TM mice (AxD model) showed that AxD microglia exhibited highly ramified morphology. Functional changes in microglia were assessed by Ca2+ imaging using hippocampal brain slices from Iba1-GCaMP6-60TM mice and two-photon microscopy. We found that AxD microglia showed aberrant Ca2+ signals, with high frequency Ca2+ signals in both the processes and cell bodies. These microglial Ca2+ signals were inhibited by pharmacological blockade or genetic knockdown of P2Y12 receptors but not by tetrodotoxin, indicating that these signals are independent of neuronal activity but dependent on extracellular ATP from non-neuronal cells. Our single-cell RNA sequencing data showed that the expression level of Entpd2, an astrocyte-specific gene encoding the ATP-degrading enzyme NTPDase2, was lower in AxD astrocytes than in wild-type astrocytes. In situ ATP imaging using the adeno-associated virus vector GfaABC1D ATP1.0 showed that exogenously applied ATP was present longer in 60TM mice than in wild-type mice. Thus, the increased ATP level caused by the decrease in its metabolizing enzyme in astrocytes could be responsible for the enhancement of microglial Ca2+ signals. To determine whether these P2Y12 receptor-mediated Ca2+ signals in AxD microglia play a significant role in the pathological mechanism, a P2Y12 receptor antagonist, clopidogrel, was administered. Clopidogrel significantly exacerbated pathological markers in AxD model mice and attenuated the morphological features of microglia, suggesting that microglia play a protective role against AxD pathology via P2Y12 receptors. Taken together, we demonstrated that microglia sense AxD astrocyte dysfunction via P2Y12 receptors as an increase in extracellular ATP and alter their morphology and Ca2+ signalling, thereby protecting against AxD pathology. Although AxD is a primary astrocyte disease, our study may facilitate understanding of the role of microglia as a disease modifier, which may contribute to the clinical diversity of AxD.

Neural representations of others' traits predict social decisions.

To guide social interaction, people often rely on expectations about the traits of other people, based on markers of social group membership (i.e., stereotypes). Although the influence of stereotypes on social behavior is widespread, key questions remain about how traits inferred from social-group membership are instantiated in the brain and incorporated into neural computations that guide social behavior. Here, we show that the human lateral orbitofrontal cortex (OFC) represents the content of stereotypes about members of different social groups in the service of social decision-making. During functional MRI scanning, participants decided how to distribute resources across themselves and members of a variety of social groups in a modified Dictator Game. Behaviorally, we replicated our recent finding that inferences about others' traits, captured by a two-dimensional framework of stereotype content (warmth and competence), had dissociable effects on participants' monetary-allocation choices: recipients' warmth increased participants' aversion to advantageous inequity (i.e., earning more than recipients), and recipients' competence increased participants' aversion to disadvantageous inequity (i.e., earning less than recipients). Neurally, representational similarity analysis revealed that others' traits in the two-dimensional space were represented in the temporoparietal junction and superior temporal sulcus, two regions associated with mentalizing, and in the lateral OFC, known to represent inferred features of a decision context outside the social domain. Critically, only the latter predicted individual choices, suggesting that the effect of stereotypes on behavior is mediated by inference-based decision-making processes in the OFC.

Triplet-Mediator Ligand-Protected Metal Nanocluster Sensitizers for Photon Upconversion.

Triplet-triplet annihilation photon upconversion (TTA-UC) is attracting a great deal of attention as a viable approach to exploit unutilized wavelengths of light in solar-driven devices. Recently, ligand-protected metal nanoclusters have emerged as a compelling platform for serving as triplet sensitizers for TTA-UC. In this study, we developed an atomically precise, triplet-mediator ligand (TL)-protected metal nanocluster, Au2Cu6(S-Adm)6[P(DPA)3]2 (Au2Cu6DPA; S-Adm = 1-adamanthanethiolate, DPA = 9,10-diphenylanthracene). In Au2Cu6DPA, the excitation of the Au2Cu6 core rapidly generates a metal-to-ligand charge transfer state, followed by the formation of the long-lived triplet state (approximately 150 µs) at a DPA site in the TL. By combining Au2Cu6DPA with a DPA annihilator, we achieved a red-to-blue upconversion quantum yield (ΦUCg) of 20.7 ± 0.4% (50% max.) with a low threshold excitation intensity of 36 mW cm-2 at 640 nm. This quantum yield almost reaches the maximum limit achievable using a DPA annihilator and establishes a record-setting value, outperforming previously reported nanocrystal and nanocluster sensitizers. Furthermore, strong upconversion emission based on a pseudo-first-order TTA process was observed under 1 sun illumination, indicating that the Au2Cu6DPA sensitizer holds promise for applications in solar-energy-based systems.

Robotic versus open and laparoscopic pelvic exenterations for pelvic cancer: a multicenter propensity-matched analysis in Japan.

BACKGROUND: Pelvic exenteration (PE) is the last resort for achieving a complete cure for pelvic cancer; however, it is burdensome for patients. Minimally invasive surgeries, including robot-assisted surgery, have been widely used to treat malignant tumors and have also recently been used in PE. This study aimed to evaluate the safety and efficacy of robot-assisted PE (RPE) by comparing the outcomes of open PE (OPE) with those of conventional laparoscopic PE (LPE) for treating pelvic tumors. METHODS: Following the ethics committee approval, a multicenter retrospective analysis of patients who underwent pelvic exenteration between January 2012 and October 2022 was conducted. Data on patient demographics, tumor characteristics, and perioperative outcomes were collected. A 1:1 propensity score-matched analysis was performed to minimize group selection bias. RESULTS: In total, 261 patients met the study criteria, of whom 61 underwent RPE, 90 underwent OPE, and 110 underwent LPE. After propensity score matching, 50 pairs were created for RPE and OPE and 59 for RPE and LPE. RPE was associated with significantly less blood loss (RPE vs. OPE: 408 mL vs. 2385 ml, p < 0.001), lower transfusion rate (RPE vs. OPE: 32% vs. 82%, p < 0.001), and lower rate of complications over Clavien-Dindo grade II (RPE vs. OPE: 48% vs. 74%, p = 0.013; RPE vs. LPE: 48% vs. 76%, p = 0.002). CONCLUSION: This multicenter study suggests that RPE reduces blood loss and transfusion compared with OPE and has a lower rate of complications compared with OPE and LPE in patients with locally advanced and recurrent pelvic tumors.

Solo surgery in robot-assisted gastrectomy versus laparoscopic gastrectomy for gastric cancer: a propensity score-matched analysis.

BACKGROUND: Robot-assisted gastrectomy (RG) for gastric cancer is still not well standardized. This study aimed to explore the feasibility and effectiveness of solo surgery in robot-assisted gastrectomy (SRG) for gastric cancer compared to laparoscopic gastrectomy (LG). METHODS: This was a single-center retrospective comparative study between SRG and conventional LG. Between April 2015 and December 2022, 510 patients underwent gastrectomy, and data from a prospectively collected database were analyzed. We identified 372 patients who underwent LG (n = 267) and SRG (n = 105) and the remaining 138 patients were excluded because of remnant gastric cancer, esophagogastric junction cancer, open gastrectomy, concurrent surgery for concomitant malignancies, RG before starting SRG, or cases in which the author was unable to perform or supervise gastrectomy. Propensity score matching was performed at a ratio of 1:1 to reduce bias from confounding patient-related variables, and short-term outcomes were compared between the groups. RESULTS: After propensity score matching, 90 pairs of patients who underwent LG and SRG were selected. In the propensity-matched cohort, the operation time was significantly shorter in the SRG group than that in the LG group (SRG = 305.7 ± 74.0 min vs. LG = 340.3 ± 91.65 min, p < 0.0058), less estimated blood loss was observed in the SRG group than that in the LG group (SRG = 25.6 ± 50.6 mL vs. LG = 76.1 ± 104.2 mL, p < 0.0001) and postoperative hospital stay was shorter in the SRG group than that in the LG group (SRG = 7.1 ± 0.8 days vs. LG = 9.1 ± 7.7 days, p = 0.015). CONCLUSION: We found that SRG for gastric cancer was technically feasible and effective with favorable short-term outcomes, including shorter operative time, less estimated blood loss, shorter hospital stays, and lower postoperative morbidity than those in LG.

Relationship between lumbar facet joint osteoarthritis and comorbidities: A cross-sectional study in the Japanese community.

BACKGROUND: Few epidemiological studies have evaluated associations between lumbar facet joint (LFJ) osteoarthritis (OA) and comorbidities. This study aimed to investigate the prevalence of LFJ OA in a Japanese community population and associations between LFJ OA and underlying diseases, including lower extremity OA. METHODS: This epidemiological cross-sectional study evaluated LFJ OA in 225 Japanese community residents (81 males, 144 females; median age, 66 years) using magnetic resonance imaging (MRI). LFJ OA from L1-L2 to L5-S1 was evaluated using a 4-grade classification. Associations between LFJ OA and comorbidities were examined using multiple logistic regression analyses adjusting for age, sex, and body mass index. RESULTS: Prevalences of LFJ OA were 28.6% at L1-L2, 36.4% at L2-L3, 48.0% at L3-L4, 57.3% at L4-L5, and 44.2% at L5-S1. Males were significantly more likely to have LFJ OA at several spinal levels (L1-L2 45.7% vs 18.9%, p < 0.001; L2-L3 46.9% vs 30.6%, p < 0.05; L4-L5 67.9% vs 51.4%, p < 0.05). LFJ OA was present in 50.0% of residents <50 years old, 68.4% at 50-59 years old, 86.3% at 60-69 years old, and 85.1% at ≥70 years old. Multiple logistic regression analysis showed no associations between LFJ OA and comorbidities. CONCLUSIONS: The prevalence of LFJ OA as evaluated by MRI was >85% at ≥60 years old and highest at the L4-L5 spinal level. Males were significantly more likely to have LFJ OA at several spinal levels. Comorbidities were not associated with LFJ OA.

Protein kinases and protein phosphatases encoded in the Ciona robusta genome.

Protein kinases (PKs) and protein phosphatases (PPs) regulate the phosphorylation of proteins that are involved in a variety of biological processes. To study such biological processes systematically, it is important to know the whole repertoire of PKs and PPs encoded in a genome. In the present study, we surveyed the genome of an ascidian (Ciona robusta or Ciona intestinalis type A) to comprehensively identify the genes that encoded PKs and PPs. Because ascidians belong to the sister group of vertebrates, a comparison of the whole repertoire of PKs and PPs of ascidians with those of vertebrates may help to delineate the complements of these proteins that were present in the last common ancestor of these two groups of animals. Our results show that the repertory of PPs was much more expanded in vertebrates than the repertory of PKs. We also showed that approximately 75% of PKs and PPs were expressed during development from eggs to larvae. Thus, the present study provides catalogs for PKs and PPs encoded in the ascidian genome. These catalogs will be useful for systematic studies of biological processes that involve phosphorylation and for evolutionary studies of the origin of vertebrates.

Dynamic Representation of the Subjective Value of Information.

To improve future decisions, people should seek information based on the value of information (VOI), which depends on the current evidence and the reward structure of the upcoming decision. When additional evidence is supplied, people should update the VOI to adjust subsequent information seeking, but the neurocognitive mechanisms of this updating process remain unknown. We used a modified beads task to examine how the VOI is represented and updated in the human brain of both sexes. We theoretically derived, and empirically verified, a normative prediction that the VOI depends on decision evidence and is biased by reward asymmetry. Using fMRI, we found that the subjective VOI is represented in the right dorsolateral prefrontal cortex (DLPFC). Critically, this VOI representation was updated when additional evidence was supplied, showing that the DLPFC dynamically tracks the up-to-date VOI over time. These results provide new insights into how humans adaptively seek information in the service of decision-making.SIGNIFICANCE STATEMENT For adaptive decision-making, people should seek information based on what they currently know and the extent to which additional information could improve the decision outcome, formalized as the VOI. Doing so requires dynamic updating of VOI according to outcome values and newly arriving evidence. We formalize these principles using a normative model and show that information seeking in people adheres to them. Using fMRI, we show that the underlying subjective VOI is represented in the dorsolateral prefrontal cortex and, critically, that it is updated in real time according to newly arriving evidence. Our results reveal the computational and neural dynamics through which evidence and values are combined to inform constantly evolving information-seeking decisions.

Common neural code for reward and information value.

Adaptive information seeking is critical for goal-directed behavior. Growing evidence suggests the importance of intrinsic motives such as curiosity or need for novelty, mediated through dopaminergic valuation systems, in driving information-seeking behavior. However, valuing information for its own sake can be highly suboptimal when agents need to evaluate instrumental benefit of information in a forward-looking manner. Here we show that information-seeking behavior in humans is driven by subjective value that is shaped by both instrumental and noninstrumental motives, and that this subjective value of information (SVOI) shares a common neural code with more basic reward value. Specifically, using a task where subjects could purchase information to reduce uncertainty about outcomes of a monetary lottery, we found information purchase decisions could be captured by a computational model of SVOI incorporating utility of anticipation, a form of noninstrumental motive for information seeking, in addition to instrumental benefits. Neurally, trial-by-trial variation in SVOI was correlated with activity in striatum and ventromedial prefrontal cortex. Furthermore, cross-categorical decoding revealed that, within these regions, SVOI and expected utility of lotteries were represented using a common code. These findings provide support for the common currency hypothesis and shed insight on neurocognitive mechanisms underlying information-seeking behavior.

Important risk factors for gallstones after laparoscopic gastrectomy: a retrospective study.

BACKGROUND: The frequency of gallstones is higher in patients who have undergone gastrectomy than in the general population. While there have been some studies of gallstone formation after open gastrectomy, there are few reports of gallstones after laparoscopic gastrectomy (LG). Therefore, this study aimed to evaluate the incidence of gallstones after LG. METHODS: We retrospectively reviewed the records of 184 patients who underwent LG between January 2011 and May 2016 at Saiseikai Utsunomiya Hospital. After gastrectomy, abdominal ultrasonography was generally performed every 6 months for 5 years. Patients who underwent cholecystectomy before LG, underwent simultaneous cholecystectomy, and did not undergo abdominal ultrasonography, with an observation period of < 24 months, were excluded from the study. Finally, 90 patients were analyzed. Laparoscopic cholecystectomy was performed whenever biliary complications occurred. Patient characteristics were compared using the two-tailed Fisher's exact test or Chi-square test. In addition, the risk factors for postoperative gallstones were analyzed using logistic regression analysis. RESULTS: Among the 90 patients included in this study, 60 were men (78%), and the mean age was 65.5 years. Laparoscopic total gastrectomy was performed for 15 patients and laparoscopic distal gastrectomy for 75 patients. D2 lymph node dissection was performed for 8 patients (9%), whereas 68 patients underwent LG with Roux-en-Y reconstruction (76%). Gallstones were detected after LG in 27 of the 90 (30%) patients. Multivariate analysis identified Roux-en-Y reconstruction and male sex as significant risk factors of gallstones after gastrectomy. The incidence of gallstones was significantly higher (53%) in male patients who underwent Roux-en-Y reconstruction. Symptomatic gallstones after laparoscopic cholecystectomy were found in 6 cases (6/27, 22%), and all patients underwent laparoscopic cholecystectomy. CONCLUSION: Roux-en-Y reconstruction and male sex were identified as significant risk factors for gallstones after LG.

Clinical characteristics of early-stage lumbar spondylolysis detected by magnetic resonance imaging in male adolescent baseball players.

BACKGROUND: Many adolescent athletes experience low back pain; the most common cause is lumbar spondylolysis. Although early identification of lumbar spondylolysis in adolescent athletes is critical, few studies have focused on identifying the early stages of spondylolysis in baseball players. This study aimed to investigate the clinical characteristics of early-stage spondylolysis in male adolescent baseball players. METHODS: The participants comprised male junior and high school baseball players. Before magnetic resonance imaging, we recorded their demographic data, low back pain characteristics, and physical findings (lumbar flexion, extension, Kemp's test and the provocative tenderness of a spinous process). After the imaging evaluation, the association among low back pain characteristics, physical findings and the final diagnosis (early-stage spondylolysis or not) were investigated using univariate and multivariable analyses. RESULTS: A total of 171 players were included in this study. Univariate analyses indicated that the characteristics associated with early-stage spondylolysis were longer duration of low back pain (P = 0.0085), low back pain-related interference while running (P = 0.0022), low back pain starting with laterality (P = 0.0001), lumbar extension (P = 0.022), positive Kemp's test (P = 0.020), and the tenderness of a spinous process (P = 0.0003). After adjusting for confounding factors (age and position), we found that early-stage spondylolysis was significantly associated with low back pain duration ≥4 weeks (odds ratio 3.13, 95% confidence interval 1.42-6.92; P = 0.0048), low back pain-related interference while running (odds ratio 2.89, 95% confidence interval 1.30-6.46; P = 0.0094), low back pain starting with laterality (odds ratio 2.78, 95% confidence interval 1.24-6.27; P = 0.0133), and the tenderness of a spinous process (odds ratio 3.00, 95% confidence interval 1.36-6.57; P = 0.0062). CONCLUSIONS: Male adolescent baseball players with early-stage spondylolysis might have low back pain duration of more than four weeks, low back pain-related interference while running, and a history of low back pain starting with laterality. The tenderness of a spinous process might be helpful in the diagnosis of early-stage spondylolysis in male adolescent baseball players.

Gata is ubiquitously required for the earliest zygotic gene transcription in the ascidian embryo.

In ascidian embryos, the earliest transcription from the zygotic genome begins between the 8-cell and 16-cell stages. Gata.a, a maternally expressed Gata transcription factor, activates target genes specifically in the animal hemisphere, whereas the complex of ß-catenin and Tcf7 antagonizes the activity of Gata.a and activates target genes specifically in the vegetal hemisphere. Here, we show that genes zygotically expressed at the 16-cell stage have significantly more Gata motifs in their upstream regions. These genes included not only genes with animal hemisphere-specific expression but also genes with vegetal hemisphere-specific expression. On the basis of this finding, we performed knockdown experiments for Gata.a and reporter assays, and found that Gata.a is required for the expression of not only genes with animal hemisphere-specific expression, but also genes with vegetal hemisphere-specific expression. Our data indicated that weak Gata.a activity that cannot induce animal hemisphere-specific expression can allow ß-catenin/Tcf7 targets to be expressed in the vegetal cells. Because genes zygotically expressed at the 32-cell stage also had significantly more Gata motifs in their upstream regions, Gata.a function may not be limited to the genes expressed specifically in the animal or vegetal hemispheres at the 16-cell stage, and Gata.a may play an important role in the earliest transcription of the zygotic genome.

Distinct regulation of Snail in two muscle lineages of the ascidian embryo achieves temporal coordination of muscle development.

The transcriptional repressor Snail is required for proper differentiation of the tail muscle of ascidian tadpole larvae. Two muscle lineages (B5.1 and B6.4) contribute to the anterior tail muscle cells, and are consecutively separated from a transcriptionally quiescent germ cell lineage at the 16- and 32-cell stages. Concomitantly, cells of these lineages begin to express Tbx6.b (Tbx6-r.b) at the 16- and 32-cell stages, respectively. Meanwhile, Snail expression begins in these two lineages simultaneously at the 32-cell stage. Here, we show that Snail expression is regulated differently between these two lineages. In the B5.1 lineage, Snail was activated through Tbx6.b, which is activated by maternal factors, including Zic-r.a. In the B6.4 lineage, the MAPK pathway was cell-autonomously activated by a constitutively active form of Raf, enabling Zic-r.a to activate Snail independently of Tbx6.b As a result, Snail begins to be expressed at the 32-cell stage simultaneously in these two lineages. Such shortcuts might be required for coordinating developmental programs in embryos in which cells become separated progressively from stem cells, including germline cells.

Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis.

The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-ß-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-ß-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-ß signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.

Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis.

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)-induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)-treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain-containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1ß-mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

Comparative analysis of polypoidal choroidal vasculopathy with and without hemorrhage treated by anti-VEGF monotherapy.

PURPOSE: Visual function and treatment response after anti-vascular endothelial growth factor monotherapy were compared between polypoidal choroidal vasculopathy (PCV) with and without hemorrhage. METHODS: We conducted a retrospective, observational study (mean, 26 months) for 49 eyes of 49 treatment-naive patients with PCV. Patients were classified into PCV with hemorrhage (26 eyes) or without hemorrhage (23 eyes). PCV with massive hemorrhage subgroup has four or more disc-hemorrhagic areas and included five eyes. RESULTS: There were no significant differences in patient age, sex, systolic blood pressure, diastolic blood pressure, presence of choroidal vascular hyperpermeability, number of polyps, maximum polyp size, lesion area, and presence of pigment epithelium detachment (PED) between the two groups. Except for the course of PCV-related hemorrhage, treatment number and its response were similar between the groups. Best-corrected visual acuity at the last visit in PCV with hemorrhage was 0.33 ± 0.51 logMAR (20/41) comparable with 0.28 ± 0.41 logMAR (20/38) without hemorrhage at the last visit (p = 0.944). Maximum polyp size in massive hemorrhagic PCV was significantly larger (314.6 ± 111.4 µm) than that of small hemorrhagic PCV (229.0 ± 119.1 µm; p = 0.037). All PCV with massive hemorrhage was accompanied by large hemorrhagic PED. CONCLUSION: There were no significant differences in the baseline characteristics, treatment intervention, or suppression of disease activity between PCV with and without hemorrhage. Final visual acuity of PCV did not differ with or without hemorrhage. Development of massive hemorrhaging in PCV may be associated with both large polyps and hemorrhagic PED.

Synthesis and Properties of a Cyclohexa-2,7-anthrylene Ethynylene Derivative.

The synthesis of a cyclohexa-2,7-(4,5-diaryl)anthrylene ethynylene (1) was achieved for the first time by using 1,8-diaryl-3,6-diborylanthracene and 1,8-diaryl-3,6-diiodoanthracene as key synthetic intermediates. Macrocycle 1 possesses a planar conformation of approximately D6h symmetry, because of the triple-bond linker between the anthracene units at the 2,7-positions. It was confirmed that macrocycle 1, bearing bulky substituents at the outer peripheral positions, behaves as a monomeric form in solution without π-stacking self-association. Macrocycle 1 has an inner-cavity size that allows specific inclusion of [9]cycloparaphenylene ([9]CPP), but not [8]CPP or [10]CPP, through an aromatic edge-to-face CH-π interaction.

Tfap2 and Sox1/2/3 cooperatively specify ectodermal fates in ascidian embryos.

Epidermis and neural tissues differentiate from the ectoderm in animal embryos. Although epidermal fate is thought to be induced in vertebrate embryos, embryological evidence has indicated that no intercellular interactions during early stages are required for epidermal fate in ascidian embryos. To test this hypothesis, we determined the gene regulatory circuits for epidermal and neural specification in the ascidian embryo. These circuits started with Tfap2-r.b and Sox1/2/3, which are expressed in the ectodermal lineage immediately after zygotic genome activation. Tfap2-r.b expression was diminished in the neural lineages upon activation of fibroblast growth factor signaling, which is known to induce neural fate, and sustained only in the epidermal lineage. Tfap2-r.b specified the epidermal fate cooperatively with Dlx.b, which was activated by Sox1/2/3 This Sox1/2/3-Dlx.b circuit was also required for specification of the anterior neural fate. In the posterior neural lineage, Sox1/2/3 activated Nodal, which is required for specification of the posterior neural fate. Our findings support the hypothesis that the epidermal fate is specified autonomously in ascidian embryos.

Differential gene expression along the animal-vegetal axis in the ascidian embryo is maintained by a dual functional protein Foxd.

In many animal embryos, a specific gene expression pattern is established along the animal-vegetal axis soon after zygotic transcription begins. In the embryo of the ascidian Ciona intestinalis, soon after the division that separates animal and vegetal hemispheres into distinct blastomeres, maternal Gata.a and ß-catenin activate specific genes in the animal and vegetal blastomeres, respectively. On the basis of these initial distinct gene expression patterns, gene regulatory networks promote animal cells to become ectodermal tissues and vegetal cells to become endomesodermal tissues and a part of the nerve cord. In the vegetal hemisphere, ß-catenin directly activates Foxd, an essential transcription factor gene for specifying endomesodermal fates. In the present study, we found that Foxd also represses the expression of genes that are activated specifically in the animal hemisphere, including Dmrt1, Prdm1-r.a (Bz1), Prdm1-r.b (Bz2), and Otx. A reporter assay showed that Dmrt1 expression was directly repressed by Foxd, and a chromatin immunoprecipitation assay showed that Foxd was bound to the upstream regions of Dmrt1, Prdm1-r.a, Prdm1-r.b, and Otx. Thus, Foxd has a dual function of activating specific gene expression in the vegetal hemisphere and of repressing the expression of genes that are normally expressed in the animal hemisphere. This dual function stabilizes the initial patterning along the animal-vegetal axis by ß-catenin and Gata.a.