PABPC1 mediates degradation of C9orf72-FTLD/ALS GGGGCC repeat RNA.

GGGGCC hexanucleotide repeat expansion in C9orf72 causes frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Expanded GGGGCC repeat RNA accumulates within RNA foci and is translated into toxic dipeptide repeat proteins; thus, efficient repeat RNA degradation may alleviate diseases. hnRNPA3, one of the repeat RNA-binding proteins, has been implicated in the destabilization of repeat RNA. Using APEX2-mediated proximity biotinylation, here, we demonstrate PABPC1, a cytoplasmic poly (A)-binding protein, interacts with hnRNPA3. Knockdown of PABPC1 increased the accumulation of repeat RNA and RNA foci to the same extent as the knockdown of hnRNPA3. Proximity ligation assays indicated PABPC1-hnRNPA3 and PABPC1-RNA exosomes, a complex that degrades repeat RNA, preferentially co-localized when repeat RNA was present. Our results suggest that PABPC1 functions as a mediator of polyadenylated GGGGCC repeat RNA degradation through interactions with hnRNPA3 and RNA exosome complex.

Improvement of postural control in the frail older adults through foot care: A pre- and post-intervention study.

Frailty in older adults often leads to foot issues, increasing fall-related fracture risk. Mechanoreceptors, the pressure receptors in the foot sole, are pivotal for postural control. Foot problems can impair mechanoreceptor function, compromising balance. This study aimed to examine the effect of foot care on postural control in frail older adults. Forty-eight participants underwent a five-month monthly foot care intervention. Measurements were taken before and after this intervention. Participants stood for 45 s in a static, open-eyed position on a stabilometer. Center-of-pressure (CoP) analysis included total trajectory length, integrated triangle area, rectangular area, and range of motion in anterior-posterior and medio-lateral directions. Results indicated that foot care significantly increased toe ground contact area by 1.3 times and improved anterior-posterior motion control during static standing. Enhanced postural control resulted from improved skin condition due to foot care that intensified mechanoreceptor signal input and improved postural control output. These findings underscore the potential for reducing fracture risks in older adults through proactive foot care. The study highlights the vital role of foot care in enhancing postural control, with broader implications for aging population well-being and safety.

Valid Indicators for Predicting Falls in Community-Dwelling Older Adults Under Ongoing Exercise Intervention to Prevent Care Requirement.

Physical exercise interventions to prevent falls for older adults at risk of falling are widespread in many countries; however, there is insufficient knowledge of the impact of long-term exercise on the fall discriminating ability of existing fall-prediction indicators. This study measured physical and cognitive indicators of the fall risk, including the timed up and go (TUG), walking speed (WS), and plantar tactile threshold (PTT), in 124 community-dwelling older adults with care needs who were continuing an exercise program. Logistic regression analyses were used to determine factors associated with falls in the 87 participants who could adhere to the exercise continuously for 12 months. The PTT was significantly higher in fallers, while the TUG and WS did not differ significantly between fallers and non-fallers. The only index significantly associated with falls was the PTT (OR = 1.20). The fall identification ability was better for PTT (AUC = 0.63), whereas TUG (AUC = 0.57) and WS (AUC = 0.52) were lower than previously reported scores. In conclusion, long-term exercise was found to improve scores on the fallprediction indicators by physical performance, but to decrease their ability to identify future falls. PTT may complement the ability to identify falls in such elderly populations.

eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS.

Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2α. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.

Effect of COVID-19 on the Activity Level of Elderly people with Dementia.

Measures against physical and social frailty after the COVID-19 epidemic in elderly people with dementia are required. However, there are no studies that have systematically examined the level of activity maintained by elderly people with dementia. In this study, we developed an ICT-based steps monitoring system and investigated changes in the number of steps taken by 13 community-dwelling elderly people with dementia from before the COVID-19 epidemic to during the epidemic. Six of the thirteen subjects maintained approximately 7,000 steps, which was the same level as that before the epidemic. However, some subjects showed a significant decrease in their frequency of going out. This system indicated the construction of a health promotion strategy based on quantitative daily step count data for community-dwelling elderly people with dementia.

Trophoblast cell surface antigen-2 phosphorylation triggered by binding of galectin-3 drives metastasis through down-regulation of E-cadherin.

The expression of trophoblast cell surface antigen-2 (Trop-2) is enhanced in many tumor tissues and is correlated with increased malignancy and poor survival of patients with cancer. Previously, we demonstrated that the Ser-322 residue of Trop-2 is phosphorylated by protein kinase Cα (PKCα) and PKCδ. Here, we demonstrate that phosphomimetic Trop-2 expressing cells have markedly decreased E-cadherin mRNA and protein levels. Consistently, mRNA and protein of the E-cadherin-repressing transcription factors zinc finger E-Box binding homeobox 1 (ZEB1) were elevated, suggesting transcriptional regulation of E-cadherin expression. The binding of galectin-3 to Trop-2 enhanced the phosphorylation and subsequent cleavage of Trop-2, followed by intracellular signaling by the resultant C-terminal fragment. Binding of ß-catenin/transcription factor 4 (TCF4) along with the C-terminal fragment of Trop-2 to the ZEB1 promoter upregulated ZEB1 expression. Of note, siRNA-mediated knockdown of ß-catenin and TCF4 increased the expression of E-cadherin through ZEB1 downregulation. Knockdown of Trop-2 in MCF-7 cells and DU145 cells resulted in downregulation of ZEB1 and subsequent upregulation of E-cadherin. Furthermore, wild-type and phosphomimetic Trop-2 but not phosphorylation-blocked Trop-2 were detected in the liver and/or lung of some nude mice bearing primary tumors inoculated intraperitoneally or subcutaneously with wild-type or mutated Trop-2 expressing cells, suggesting that Trop-2 phosphorylation, plays an important role in tumor cell mobility in vivo, too. Together with our previous finding of Trop-2 dependent regulation of claudin-7, we suggest that the Trop-2-mediated cascade involves concurrent derangement of both tight and adherence junctions, which may drive metastasis of epithelial tumor cells.

The Interplay Between Metabolites and MicroRNAs in Aqueous Humor to Coordinate Corneal Endothelium Integrity.

Purpose: The purpose of the study was to clarify the interplay between metabolites and microRNAs (miRs) in the aqueous humor (AqH) of bullous keratopathy (BK) patients to retain human corneal endothelium (HCE) integrity. Design: Prospective, comparative, observational study. Participants: A total of 55 patients with BK and 31 patients with cataract (Cat) as control. Methods: A biostatic analysis of miRs and metabolites in the AqH, hierarchical clustering, and a least absolute shrinkage and selection operator (Lasso) analysis were employed. The miR levels in AqH of BK (n = 18) and Cat (n = 8) patients were determined using 3D-Gene human miR chips. Hierarchical clusters of metabolites detected by liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry in AqH specimens from 2 disease groups, BK (total n = 55) and Cat (total n = 31), were analyzed twice to confirm the reproducibility. The analytical procedure applied for investigating the association between metabolites and miRs in AqH was the exploratory data analysis of biostatistics to avoid any kind of prejudice. This research procedure includes a heat-map, cluster analysis, feature extraction techniques by principal component analysis, and a regression analysis method by Lasso. The cellular and released miR levels were validated using reverse transcription polymerase chain reaction and mitochondria membrane potential was assessed to determine the functional features of the released miRs. Main Outcome Measures: Identification of interacting metabolites and miRs in AqH attenuating HCE degeneration. Results: The metabolites that decreased in the AqH of BK patients revealed that 3-hydroxyisobutyric acid (HIB), 2-aminobutyric acid (AB) and branched-chain amino acids, and serine were categorized into the same cluster by hierarchical clustering of metabolites. The positive association of HIB with miR-34a-5p was confirmed (P = 0.018), and the Lasso analysis identified the interplay between miR-34a-5p and HIB, between miR-24-3p and AB, and between miR-34c-5p and serine (P = 0.041, 0.027, and 0.009, respectively). 3-hydroxyisobutyric acid upregulated the cellular miR-34a expression, mitochondrial membrane potential, and release of miR-184 in dedifferentiated cultured HCE cells. Conclusions: Metabolites and miRs in AqH may synchronize in ensuring the integrity of the HCE to maintain efficient dehydration from the stroma. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Spatiotemporal Coordination of RPE Cell Quality by Extracellular Vesicle miR-494-3p Via Competitive Interplays With SIRT3 or PTEN.

Purpose: To reveal the molecular mechanism underlying degeneration in human retinal pigment epithelial (hRPE) cells with dysfunctional mitochondrial homeostasis. Methods: The expression of recently identified miR-494-3p in extracellular vesicles (EV) released from induced-pluripotential-stem-cell-derived human RPE (iPS-hRPE), during coculture with macrophages (Mps) was investigated in iPS-hRPE and ARPE cells differentiated in the presence of nicotinamide (Nic-ARPE). The expression of phosphatase and tensin homolog (PTEN), sirtuin3 (SIRT3), and mitochondrial marker proteins before and after the transfection of miR-494-3p inhibitor and mimic, and the changes in mitochondrial metabolism, membrane potential, and oxidative phosphorylation (OXPHOS) were monitored. Results: Compared with senescent dedifferentiated ARPE19 cells, iPS-hRPE and Nic-ARPE cells expressed elevated levels of mitochondrial marker proteins but a repressed cellular miR-494-3p level. The expression of target proteins of miR-494-3p, PTEN, and SIRT3 was upregulated along with the differentiation disposition of these RPE cells. The ratio of PTEN/SIRT3 in de-differentiated ARPE19 cells was surprisingly elevated by around 20 times compared with that in iPS-hRPE and Nic-ARPE cells. The novel molecular interplay of EV miR-494-3p either with mitochondria selective SIRT3 or organelle nonselective PTEN was found to participate in the degeneration of hRPE cells by inducing mitochondrial dysfunctions and repressed OXPHOS, mitochondrial membrane potential, and ATP and NAD+ production. Conclusions: Our results demonstrate a clear causal link between miR-494-3p and hRPE cell degeneration via the regulation of mitochondrial integrity. EV miR-494-3p may play a pivotal role in pathogenic spreading of degenerated hRPE cells from the local perifovea throughout the macula.

Cellular Interplay Through Extracellular Vesicle miR-184 Alleviates Corneal Endothelium Degeneration.

Objective: The objective of the study was to reveal the presence of cellular interplay through extracellular vesicle (EV) microRNAs (miRs), to dampen the vicious cycle to degenerate human corneal endothelium (HCE) tissues. Design: Prospective, comparative, observational study. Methods: The miR levels in neonate-derived corneal tissues, in the aqueous humor (AqH) of bullous keratoplasty and cataract patients, as well as in the culture supernatant (CS) and EV of cultured human corneal endothelial cells (hCECs), were determined using 3D-Gene human miR chips and then validated using the real-time polymerase chain reaction. The extracellularly released miRs were profiled after the forced downregulation of cellular miR-34a, either by an miR-34a inhibitor or exposure to H2O2. The senescence-associated secretory phenotypes and mitochondrial membrane potential (MMP) were assessed to determine the functional features of the released miRs. Main Outcome Measures: Identification of functional miRs attenuating HCE degeneration. Results: The miRs in AqH were classified into 2 groups: expression in 1 group was significantly reduced in neonate-derived tissues, whereas that in the other group remained almost constant, independent of aging. The miR-34a and -29 families were typical in the former group, whereas miR-184 and -24-3p were typical in the latter. Additionally, a larger amount of the latter miRs was detected in AqH compared with those of the former miRs. There was also a greater abundance of miR-184 and -24-3p in hCECs, EV, and CS in fully mature CD44-/dull hCEC, leading to sufficient clinical tissue regenerative capacity in cell injection therapy. The repression of cellular miR-34a, either due to miR-34a inhibitors or exposure to oxidative stress, unexpectedly resulted in the elevated release of miR-184 and -24-3p. Secretions of VEGF, interleukin 6, monocyte chemotactic protein-1, and MMP were all repressed in both mature CD44-/dull and degenerated CD44+++ hCEC, transfected with an miR-184 mimic. Conclusions: The elevated release of miR-184 into AqH may constitute cellular interplay that prevents the aggravation of HCE degeneration induced by oxidative stress, thereby sustaining tissue homeostasis in HCE.

Effectiveness of COVID-19 vaccination in healthcare workers in Shiga Prefecture, Japan.

This study, which included serological and cellular immunity tests, evaluated whether coronavirus disease 2019 (COVID-19) vaccination adequately protected healthcare workers (HCWs) from COVID-19. Serological investigations were conducted among 1600 HCWs (mean ± standard deviation, 7.4 ± 1.4 months after the last COVID-19 vaccination). Anti-SARS-CoV-2 antibodies N-Ig, Spike-Ig (Roche), N-IgG, Spike-IgM, and -IgG (Abbott), were evaluated using a questionnaire of health condition. 161 HCWs were analyzed for cellular immunity using T-SPOT® SARS-CoV-2 kit before, and 52 HCWs were followed up until 138.3 ± 15.7 days after their third vaccination. Spike-IgG value was 954.4 ± 2282.6 AU/mL. Forty-nine of the 1600 HCWs (3.06%) had pre-existing SARS-CoV-2 infection. None of the infectious seropositive HCWs required hospitalization. T-SPOT value was 85.0 ± 84.2 SFU/106 cells before the third vaccination, which increased to 219.4 ± 230.4 SFU/106 cells immediately after, but attenuated later (to 111.1 ± 133.6 SFU/106 cells). Poor counts (< 40 SFU/106 cells) were present in 34.8% and 38.5% of HCWs before and after the third vaccination, respectively. Our findings provide insights into humoral and cellular immune responses to repeated COVID-19 vaccinations. COVID-19 vaccination was effective in protecting HCWs from serious illness during the original Wuhan-1, Alpha, Delta and also ongoing Omicron-predominance periods. However, repeated vaccinations using current vaccine versions may not induce sufficient cellular immunity in all HCWs.

Analysis of skeletal characteristics of flat feet using three-dimensional foot scanner and digital footprint.

BACKGROUND: Flat feet increase the risk of knee osteoarthritis and contribute to frailty, which may lead to worse life prognoses. The influence of the foot skeletal structure on flat feet is not yet entirely understood. Footprints are often used to evaluate feet. However, footprint-based measurements do not reflect the underlying structures of feet and are easily confounded by soft tissue. Three-dimensional evaluation of the foot shape can reveal the characteristics of flat feet. Therefore, foot shape evaluations have garnered increasing research interest. This study aimed to determine the correlation between the three-dimensional (3D) features of the foot and the measurement results of footprint and to predict the evaluation results of flat feet from the footprint based on the 3D features. Finally, the three-dimensional characteristics of flat feet, which cannot be revealed by footprint, were determined. METHODS: A total of 403 individuals (40-89 years) participated in this study. The proposed system was developed to identify seven skeletal features that were expected to be associated with flat feet. The loads on the soles of the feet were measured in a static standing position and with a digital footprint device. Specifically, two footprint indices were calculated: the Chippaux-Smirak index (CSI) and the Staheli index (SI). In the analysis, comparisons between male and female measurement variables were performed using the Student's t test. The relationships between the 3D foot features and footprint index parameters were determined by employing the Pearson correlation coefficient. Multiple linear regression was utilized to identify 3D foot features that were strongly associated with the CSI and SI. Foot features identified as significant in the multivariate regression analysis were compared based on a one-way analysis of variance (ANOVA) with Tukey's post hoc test. RESULTS: The CSI and SI were highly correlated with the instep height (IH) and navicular height (NH) of the 3D foot scanning system and were also derived from multiple regression analysis. In addition to the NH and IH, the indicators of the forefoot, transverse arch width, and transverse arch height were considered. In the flat foot group with CSI values above 62.7%, NH was 13.5% (p < 0.001) for males and 14.9% (p = 0.01) for females, and the axis of the bone distance was 5.3% (p = 0.05) for males and 4.9% (p = 0.10) for females. In particular, for CSI values above 62.7% and NH values below 13%, the axis of the bone distance was large and the foot skeleton was deformed. CONCLUSIONS: Decreased navicular bone height could be evaluated with the 3D foot scanning system even when flat feet were not detected from the footprint. The results indicate that the use of quantitative indices for 3D foot measurements is important when evaluating the flattening of the foot. Trial registration number UMIN000037694. Name of the registry: University Hospital Medical Information Network Registry. Date of registration: August 15, 2019.

Serology suggests adequate safety measures to protect healthcare workers from COVID-19 in Shiga Prefecture, Japan.

Healthcare workers (HCWs), especially frontline workers against coronavirus disease 2019 (COVID-19), are considered to be risky because of occupational exposure to infected patients. This study evaluated the correlation between seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies among HCWs and the implementation of personal protective equipment (PPE) & infection prevention and control (IPC). We recruited 1237 HCWs from nine public COVID-19-designated hospitals in Shiga Prefecture, central Japan, between 15-26 February 2021. All participants answered a self-administered questionnaire and provided blood samples to evaluate SARS-CoV-2 antibodies. A total of 22 cases (1·78%) were seropositive among the 1237 study participants. An unavoidable outbreak of SARS-CoV-2 had occurred at the terminal care unit of one hospital, before identifying and securely isolating this cluster of cases. Excluding with this cluster, 0·68% of HCWs were suspected to have had previous SARS-CoV-2 infections. Binomial logistic regression from individual questionnaires and seropositivity predicted a significant correlation with N95 mask implementation under aerosol conditions (p = 8.63e-06, aOR = 2.47) and work duration in a red zone (p = 2.61e-04, aOR = 1.99). The institutional questionnaire suggested that IPC education was correlated with reduced seropositivity at hospitals. Seroprevalence and questionnaire analyses among HCWs indicated that secure implementation of PPE and re-education of IPC are essential to prevent SARS-CoV-2 infection within healthcare facilities. Occupational infections from SARS-CoV-2 in healthcare settings could be prevented by adhering to adequate measures and appropriate use of PPE. With these measures securely implemented, HCWs should not be considered against as significantly risky or dirty by local communities.

Repressed miR-34a Expression Dictates the Cell Fate to Corneal Endothelium Failure.

Purpose: To reveal the mechanism triggering the functional disparity between degenerated and non-degenerated corneal endothelium cells in the water efflux from corneal stroma to the anterior chamber. Methods: The varied levels of the microRNA (miR)-34, miR-378, and miR-146 family in human corneal endothelium and cultured cells thereof were investigated using 3D-Gene Human miRNA Oligo Chips. Concomitantly, CD44, p53, c-Myc, matrix metalloprotease (MMP)-2 expression, and Ras homolog gene family member A (Rho A) activity was correlated to the expression intensities of these microRNAs, partly complemented with their altered expression levels with the transfection of the corresponding mimics and inhibitors. The levels of miRs were further associated with intracellular pH (pHi) and mitochondrial energy homeostasis. Results: P53-inducible miR-34a/b repressed CD44 expression, and CD44 was repressed with the elevated c-Myc. The repressed miR-34a activated the CD44 downstream factors Rho A and MMP-2. MiR-34a mimics downregulated pHi, inducing the skewing of mitochondrial respiration to oxidative phosphorylation. The oxidative stress (H2O2) induced on human corneal endothelial cells, which repressed miR-34a/b expression, may account for the impaired signaling cascade to mitochondrial metabolic homeostasis necessary for an efficient water efflux from the corneal stroma. Conclusions: The upregulated expression of CD44, through repressed miR-34a/b by reactive oxygen species and elevated c-Myc by oxidative stress, may impair mitochondrial metabolic homeostasis, leading to human corneal endothelial failure.

Intracellular pH affects mitochondrial homeostasis in cultured human corneal endothelial cells prepared for cell injection therapy.

This study aimed to uncover the mechanism responsible for the clinical efficacy of cell injection therapy with fully differentiated cultured cells. Analysis of polarized expression of ion transporters on cultured human corneal endothelial cells (CECs) subpopulations (SPs) was performed. The intracellular pH (pHi) between two CEC SPs, distinct in the proportion of differentiated cells, was measured, and the association with mitochondrial respiration homeostasis was investigated. The effects of the ion transporter inhibition by their selective inhibitors or siRNA transfection were also explored. Na+/K+-ATPase, Aquaporin 1, SLC4A11, NBCe1, NHE1 as transporters, and ZO-1, were all selectively expressed in differentiated SPs, but were almost null in the cell-state-transitioned SPs. We also confirmed that the pHi of CEC SPs affected their mitochondrial respiration by modulating the expression of these ion transporters via inhibitors or siRNA transfection. Ion and water transporters might participate in the maintenance of pHi and mitochondria homeostasis in differentiated SPs, which may contribute, combined with integral barrier functions, to efficient water efflux. The differences in intracellular pH between the two SPs is attributed to variations in the expression profile of specific ion transporters and mitochondrial functions, which may associate with the efficacy of the SPs in cell injection therapy.

Foot-surface-structure analysis using a smartphone-based 3D foot scanner.

BACKGROUND: A thorough understanding of the influence of the foot skeletal structure on hallux valgus (HV) is required for HV prevention. We developed a system using a 3D foot scanner on a smartphone to clarify the relationships between foot features and HV risk. METHODS: Two-dimensional video images were recorded on a smartphone, sent to a computer or cloud server, and used to construct a 3D foot-feature model, considering 10 foot features associated with HV. The participants (419 individuals, aged 40-89 years) stood with their toes 12 cm apart and heels 8 cm apart during video recording. The height and weight were measured for body-mass index calculation. RESULTS: Age-dependent foot-feature variations were observed slightly for males and distinctively for females. For females, the great toe-first metatarsal head-heel (GFH) angle associated with HV increased with age, i.e., the GFH angle increased with age, suggesting that HV increased with age. Multiple regression analysis revealed that the features determining the GFH angle are the second toe-heel-navicular angle, bone distance axis, and transverse arch length and height. The adjusted coefficients of determination were 0.54 and 0.52 for males and females, respectively. CONCLUSION: This approach enables simple foot structure assessment for HV risk evaluation.

The porphyrin TMPyP4 inhibits elongation during the noncanonical translation of the FTLD/ALS-associated GGGGCC repeat in the C9orf72 gene.

GGGGCC (G4C2) repeat expansion in the C9orf72 gene has been shown to cause frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Dipeptide repeat proteins produced through repeat-associated non-AUG (RAN) translation are recognized as potential drivers for neurodegeneration. Therefore, selective inhibition of RAN translation could be a therapeutic avenue to treat these neurodegenerative diseases. It was previously known that the porphyrin TMPyP4 binds to G4C2 repeat RNA. However, the consequences of this interaction have not been well characterized. Here, we confirmed that TMPyP4 inhibits C9orf72 G4C2 repeat translation in cellular and in in vitro translation systems. An artificial insertion of an AUG codon failed to cancel the translation inhibition, suggesting that TMPyP4 acts downstream of non-AUG translation initiation. Polysome profiling assays also revealed polysome retention on G4C2 repeat RNA, along with inhibition of translation, indicating that elongating ribosomes stall on G4C2 repeat RNA. Urea-resistant interaction between G4C2 repeat RNA and TMPyP4 likely contributes to this ribosome stalling and thus to selective inhibition of RAN translation. Taken together, our data reveal a novel mode of action of TMPyP4 as an inhibitor of G4C2 repeat translation elongation.

Changes in respiratory mechanics of artificial pneumothorax two-lung ventilation in video-assisted thoracoscopic esophagectomy in prone position.

We aimed to clarify the changes in respiratory mechanics and factors associated with them in artificial pneumothorax two-lung ventilation in video-assisted thoracoscopic esophagectomy in the prone position (PP-VATS-E) for esophageal cancer. Data of patients with esophageal cancer, who underwent PP-VATs-E were retrospectively analyzed. Our primary outcome was the change in the respiratory mechanics after intubation (T1), in the prone position (T2), after initiation of the artificial pneumothorax two-lung ventilation (T3), at 1 and 2 h (T4 and T5), in the supine position (T6), and after laparoscopy (T7). The secondary outcome was identifying factors affecting the change in dynamic lung compliance (Cdyn). Sixty-seven patients were included. Cdyn values were significantly lower at T3, T4, and T5 than at T1 (p < 0.001). End-expiratory flow was significantly higher at T4 and T5 than at T1 (p < 0.05). Body mass index and preoperative FEV1.0% were found to significantly influence Cdyn reduction during artificial pneumothorax and two-lung ventilation (OR [95% CI]: 1.29 [1.03-2.24] and 0.20 (0.05-0.44); p = 0.010 and p = 0.034, respectively]. Changes in driving pressure were nonsignificant, and hypoxemia requiring treatment was not noted. This study suggests that in PP-VATs-E, artificial pneumothorax two-lung ventilation is safer for the management of anesthesia than conventional one-lung ventilation (UMIN Registry: 000042174).

Preoperative disseminated intravascular coagulation complicated by thoracic aortic aneurysm treated using recombinant human soluble thrombomodulin: A case report.

RATIONALE: Chronic disseminated intravascular coagulation (DIC) associated with thoracic aortic aneurysm is characterized by enhanced fibrinolysis and is thought to be stable in the compensated/asymptomatic stage, with few bleeding symptoms. However, DIC can lead to decompensated/hemorrhagic stage disseminated intravascular coagulation, resulting in severe bleeding diathesis, and there is currently no established strategy for treatment of DIC in aortic aneurysms. PATIENT CONCERNS: A 77-year-old woman underwent angiography and cardiac catheterization, before descending aortic replacement surgery. She developed DIC in postprocedure week 2 with extensive, uncontrollable massive subcutaneous hemorrhage. DIAGNOSES: Her acute-phase DIC score was 7 points, and the risk of mortality within 30 days after surgery according to the JapanSCORE was estimated to be 33.6%. INTERVENTIONS: Therapy was a combination of recombinant human soluble thrombomodulin (rhTM) and an aortic stent-graft treatment. OUTCOMES: Short-term improvements were seen in both DIC and bleeding diathesis. The thoracic aortic aneurysm with severe DIC was eventually corrected by administration of rhTM. LESSONS: We report the use of rhTM as an effective, novel anticoagulant drug with anti-inflammatory activity for treating DIC with suppressed fibrinolysis, which is typically associated with sepsis. In patients with a high hemorrhagic diathesis, in whom preoperative control of DIC cannot be achieved with conventional anticoagulation and radical surgical repair cannot be performed, a combination of rhTM and endovascular therapy may be a powerful new treatment option.

Early prophylaxis of central venous catheter-related thrombosis using 1% chlorhexidine gluconate and chlorhexidine-gel-impregnated dressings: a retrospective cohort study.

To determine the prophylactic effect of using combined 1% alcoholic chlorhexidine gluconate and chlorhexidine gel-impregnated dressings (CGCD) on catheter-related thrombosis (CRT) in critically ill patients. This retrospective cohort study was performed in an intensive care unit from November 2009 to August 2014. The CRT incidence diagnosed with ultrasound examination was compared between patients applying CGCD and combined 10% aqueous povidone-iodine and standard transparent dressings (PITD) after central venous catheter insertion into the internal jugular vein for ≥ 48 h. CRT was stratified into early (within 7 days) and late (days 8-14) thromboses. Multivariate analyses using logistic regression models clarified the relationships between early- and late-CRT risks and skin antiseptic and catheter site dressing combinations. CRT occurred in 74 of 134 patients (55%), including 52 with early CRT and 22 with late CRT. Patients receiving CGCD had a significantly lower incidence of early CRT than those receiving PITD (odds ratio = 0.18; 95% confidence interval = 0.07-0.45, p < .001). No significant association was evident between using CGCD and late CRT (p = .514). Compared to PITD, CGCD reduced the CRT risk over 7 days in critically ill patients.UMIN Clinical Trials Registry: UMIN000037492.

The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS.

Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72-derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient-derived cells. Cells expressing toxic poly-GR or poly-PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine-rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine-rich DPR-mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72-FTLD/ALS pathologies in a vicious cycle.