The onset of star formation 250 million years after the Big Bang.

A fundamental quest of modern astronomy is to locate the earliest galaxies and study how they influenced the intergalactic medium a few hundred million years after the Big Bang1-3. The abundance of star-forming galaxies is known to decline4,5 from redshifts of about 6 to 10, but a key question is the extent of star formation at even earlier times, corresponding to the period when the first galaxies might have emerged. Here we report spectroscopic observations of MACS1149-JD1 6 , a gravitationally lensed galaxy observed when the Universe was less than four per cent of its present age. We detect an emission line of doubly ionized oxygen at a redshift of 9.1096 ± 0.0006, with an uncertainty of one standard deviation. This precisely determined redshift indicates that the red rest-frame optical colour arises from a dominant stellar component that formed about 250 million years after the Big Bang, corresponding to a redshift of about 15. Our results indicate that it may be possible to detect such early episodes of star formation in similar galaxies with future telescopes.

Machine learning for observational cosmology.

An array of large observational programs using ground-based and space-borne telescopes is planned in the next decade. The forthcoming wide-field sky surveys are expected to deliver a sheer volume of data exceeding an exabyte. Processing the large amount of multiplex astronomical data is technically challenging, and fully automated technologies based on machine learning (ML) and artificial intelligence are urgently needed. Maximizing scientific returns from the big data requires community-wide efforts. We summarize recent progress in ML applications in observational cosmology. We also address crucial issues in high-performance computing that are needed for the data processing and statistical analysis.

Impact of Repetitive Transcranial Magnetic Stimulation to the Cerebellum on Performance of a Ballistic Targeting Movement.

This study aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) of the cerebellum on changes in motor performance during a series of repetitive ballistic-targeting tasks. Twenty-two healthy young adults (n = 12 in the active-rTMS group and n = 10 in the sham rTMS group) participated in this study. The participants sat on a chair in front of a monitor and fixed their right forearms to a manipulandum. They manipulated the handle with the flexion/extension of the wrist to move the bar on the monitor. Immediately after a beep sound was played, the participant moved the bar as quickly as possible to the target line. After the first 10 repetitions of the ballistic-targeting task, active or sham rTMS (1 Hz, 900 pulses) was applied to the right cerebellum. Subsequently, five sets of 100 repetitions of this task were conducted. Participants in the sham rTMS group showed improved reaction time, movement time, maximum velocity of movement, and targeting error after repetition. However, improvements were inhibited in the active-rTMS group. Low-frequency cerebellar rTMS may disrupt motor learning during repetitive ballistic-targeting tasks. This supports the hypothesis that the cerebellum contributes to motor learning and motor-error correction in ballistic-targeting movements.

Laparoscopic left hepatectomy in a goat as a training model for laparoscopic anatomic liver resection: results of training courses with a total of 70 goats.

BACKGROUND: To create a suitable animal model for the training of laparoscopic anatomic liver resection, we performed left hepatectomy using a goat and found its suitability. We have since started using goats for wet-lab training and have gradually standardized the relevant procedures. Herein, we report our standardized training procedures using a goat and discuss its feasibility as a novel training model. METHODS: The standardized wet-lab training courses of laparoscopic liver resection conducted on 62 tables with a total of 70 goats were reviewed. The training course began by encircling the hepatoduodenal ligament for the Pringle maneuver, which was repeated during the parenchymal dissection. Following partial liver resection of the left lateral section, left hepatectomy was performed by a standardized procedure for humans in which the liver was split, exposing the entire length of the middle hepatic vein trunk from the dorsal side after extrahepatic transection of the left Glissonean pedicle. If a goat deceased before initiating left hepatectomy, the training was restarted with a new goat. The surgical procedures were performed by surgeons of varying skill levels. RESULTS: A total of 184 surgeons including 10 surgical residents participated in the training. Partial liver resection was initiated in 62 tables, with 8 (13%) dying during or after the procedure of partial liver resection. Subsequently, left hepatectomy was initiated in 61 and completed in 59 tables (98%), regardless of whether the goat survived or deceased, and was not completed in 2 tables (3%) due to time limitation. In 14 tables (23%), the goats deceased during the procedure, however, the procedure was completed. The causes of death were multifactorial, including massive bleeding, reperfusion injury after the Pringle maneuver, and carbon dioxide gas embolism. CONCLUSIONS: Left hepatectomy in a goat is useful as a training model for laparoscopic anatomic liver resection.

The Absence of Osmoregulated Periplasmic Glucan Confers Antimicrobial Resistance and Increases Virulence in Escherichia coli.

Clarifying the molecular mechanisms by which bacteria acquire virulence traits is important for understanding the bacterial virulence system. In the present study, we utilized a bacterial evolution method in a silkworm infection model and revealed that deletion of the opgGH operon, encoding synthases for osmoregulated periplasmic glucan (OPG), increased the virulence of a nonpathogenic laboratory strain of Escherichia coli against silkworms. The opgGH knockout mutant exhibited resistance to host antimicrobial peptides and antibiotics. Compared with the parent strain, the opgGH knockout mutant produced greater amounts of colanic acid, which is involved in E. coli resistance to antibiotics. RNA sequence analysis revealed that the opgGH knockout altered the expression of various genes, including the evgS/evgA two-component system that functions in antibiotic resistance. In both a colanic acid-negative background and an evgS-null background, the opgGH knockout increased E. coli resistance to antibiotics and increased the silkworm-killing activity of E. coli. In the null background of the envZ/ompR two-component system, which genetically interacts with opgGH, the opgGH knockout increased antibiotic resistance and virulence in silkworms. These findings suggest that the absence of OPG confers antimicrobial resistance and virulence in E. coli in a colanic acid-, evgS/evgA-, and envZ/ompR-independent manner. IMPORTANCE The gene mutation types that increase the bacterial virulence of Escherichia coli remain unclear, in part due to the limited number of methods available for isolating bacterial mutants with increased virulence. We utilized a bacterial evolution method in the silkworm infection model, in which silkworms were infected with mutagenized bacteria and highly virulent bacterial mutants were isolated from dead silkworms. We revealed that knockout of OPG synthases increased E. coli virulence against silkworms. The OPG knockout mutants were resistant to host antimicrobial peptides as well as antibiotics. Our findings not only suggest a novel mechanism for virulence acquisition in E. coli but also support the usefulness of the bacterial experimental evolution method in the silkworm infection model.

Feasibility of Hyaluronate Carboxymethylcellulose-Based Bioresorbable Membrane in Two-Staged Pancreatojejunostomy.

BACKGROUND: Two-staged pancreatoduodenectomy with exteriorization of pancreatic juice is a safe procedure for high-risk patients. However, two-staged pancreatoduodenectomy requires complex re-laparotomy and adhesion removal. We analyzed whether using hyaluronate carboxymethylcellulose-based bioresorbable membrane (HCM) reduced the time required for the second operation and facilitated good fistula formation in two-staged pancreatoduodenectomy. METHODS: Between April 2011 and December 2018, data were collected from 206 consecutive patients who underwent two-staged pancreatoduodenectomy. HCM has been used for all patients since 2015. Patients for whom HCM was used (HCM group; n = 61) were compared to historical controls (before 2015) without HCM (control group; n = 145) in terms of feasibility of the second operation (operation time, adhesion grade, and complications) and optimal granulation around the external tube at the second laparotomy. RESULTS: The HCM group showed significantly shorter median operation time [105 min (30-228 min) vs. 151 min (30-331 min); p < 0.001] and smaller median blood loss [36 mL (8-118 mL) vs. 58 mL (12-355 mL); p < 0.001] for the second operation. Neither overall postoperative complication rate (p = 0.811) nor severe-grade complication rate (p = 0.857) differed significantly. Both groups showed good fistula formation, with no significant difference in rate of optimal fistula formation (HCM group, 95.1% vs. control, 95.9%; p = 0.867). CONCLUSION: HCM placement significantly improved safety and duration for the second operation, while preserving good fistula formation.

New-Onset or Exacerbation of Diabetes Mellitus Is a Clue to the Early Diagnosis of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), which accounts for majority of pancreatic cancers, is one of the most lethal human malignancies. Most patients are diagnosed at an advanced stage after symptom development. Early diagnosis of PDAC in asymptomatic subjects is important to improve prognosis. Diabetes mellitus (DM) is a risk factor for PDAC, and DM, especially new-onset DM, has attracted attentions as a diagnostic clue to PDAC. However, the impact of DM as a diagnostic opportunity on the prognosis of PDAC is unclear. We here retrospectively reviewed 489 PDAC patients and compared the clinical characteristics and prognosis according to the opportunities for PDAC diagnosis. PDAC was diagnosed upon presentation of symptoms, such as pain and jaundice, in 318 cases including 151 DM patients, upon new-onset or exacerbation of long-standing DM in 53 asymptomatic patients, and upon incidental detection by medical check-up or follow-up/work-up of other diseases in 118 asymptomatic patients. Asymptomatic patients including those with DM had smaller tumors, earlier disease stage, and higher resectability rates than symptomatic patients. Asymptomatic patients diagnosed in association with DM had better prognosis (median survival time, 771 days) than those diagnosed due to symptoms (343 days, P < 0.001), and similar to those diagnosed by incidental detection (869 days). The survival advantage was not evident in symptomatic patients with DM-associated signs. In conclusion, patients diagnosed in association with DM at asymptomatic stages had better prognosis than those diagnosed with symptoms. DM-associated signs might provide a clue to the early diagnosis of PDAC among asymptomatic subjects.

Focal Parenchymal Atrophy and Fat Replacement Are Clues for Early Diagnosis of Pancreatic Cancer with Abnormalities of the Main Pancreatic Duct.

Pancreatic cancer is one of the most dangerous solid tumors, but its early diagnosis is difficult. The abnormality of the main pancreatic duct (MPD), such as a single localized stricture and upstream dilatation, might be useful in the early detection of pancreatic cancer. However, these findings are often observed in benign inflammatory cases. This study aimed to clarify whether early pancreatic cancer presenting MPD abnormalities has characteristic features different from those of benign cases. This is a single-center, retrospective study. We analyzed 20 patients who underwent pancreatectomy presenting with a single, localized MPD stricture without identifiable masses on imaging: 10 patients with pancreatic ductal adenocarcinoma (cancer group; 6 with stage 0 and 4 with stage I) and 10 patients with benign strictures (benign group; 8 with inflammation and 2 with low-grade pancreatic intraepithelial neoplasms). Pancreatectomy was performed in these benign cases because high-grade intraepithelial neoplasm was suspected. Although the proportion of patients with diabetes mellitus tended to be higher in the cancer group (6/10) than that in the benign group (1/10) (P = 0.058), other clinical characteristics were not different between the groups. Preoperative cytological malignancies were detected in four patients in the cancer group (4/10) but not in the benign group (P = 0.09). Focal parenchymal atrophy and fat replacement were more frequently detected on computed tomography in the cancer group (7/10) than in the benign group (1/10) (P = 0.02). In conclusion, focal parenchymal atrophy and fat replacement may provide clues for the early diagnosis of pancreatic cancer.

Formation of the first generation of stars and blackholes in the Universe.

Modern sky surveys using large ground-based telescopes have discovered a variety of celestial objects. Prominent structures such as galaxies and galaxy clusters are found virtually everywhere, and their collective distribution forms the large-scale structure of the Universe. It is thought that all of the rich content in the present-day Universe developed through gravitational amplification of primeval density fluctuations generated in the very early phase of cosmic evolution. The standard theoretical model based on an array of recent observations accurately predicts the physical conditions in the early Universe, and powerful super-computers allow us to simulate in detail the formation and evolution of cosmic structure to the present epoch. We review recent progress in the study on the first generation of stars and blackholes. We focus on the physics of early structure formation, while identifying several key issues and open questions. Finally, we discuss prospects for future observations of the first stars, galaxies and blackholes.

Proteomic study on neurite responses to oxidative stress: search for differentially expressed proteins in isolated neurites of N1E-115 cells.

Reactive oxygen species attack several living organs and induce cell death. Previously, we found axonal/dendrite degeneration before the induction of cell death in hydrogen peroxide-treated neuroblastoma: N1E-115 cells and primary neurons. This phenomenon may be connected with membrane oxidation, microtubule destabilization and disruption of intracellular calcium homeostasis. However, its detailed mechanisms are not fully understood. Here, we identified proteins after treatment with hydrogen peroxide using isolated neurites by liquid chromatography-matrix-assisted laser desorption/ionization-time of flight/time of flight analysis. Twenty-one proteins were increased after treatment with hydrogen peroxide. Specifically, 5 proteins which were secretogranin-1, heat shock protein family D member 1, Brain acid soluble protein 1, heat shock 70-kDa protein 5 and superoxide dismutase 1, were identified of all experiments and increased in isolated neurites of hydrogen peroxide-treated cells compared to the controls. Furthermore, secretogranin-1 and heat shock protein family D member 1 protein expressions were significantly increased in normal aged and Alzheimer's transgenic mice brains. These results indicate that secretogranin-1 and heat shock protein family D member 1 might contribute to reactive oxygen species-induced neurite degeneration. Both proteins have been related to neurodegenerative disorders, so their study may shed light on neurite dysfunction.

Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells.

Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of α-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor ß1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment.

Effect of tannic acid on skin barrier function.

In this study, we investigated how tannic acid (TA) protects the skin from inflammation caused by external irritation. The effects of TA were evaluated using a mouse 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin inflammation model and a reconstructed human epidermal model. We then used Lucifer Yellow for visual confirmation of TA's suppression effect at the stratum corneum (SC) surface. TA treatment of the skin prevented Lucifer Yellow from permeating the skin. This result suggests that TA acts as a barrier against external stimulants such as TPA and artificial sweat on the SC surface.

Diabetes mellitus not an unfavorable factor on the prognosis of hepatitis C virus-related hepatocellular carcinoma.

AIM: Diabetes mellitus (DM) is a potential risk factor for hepatocarcinogenesis, especially in patients with hepatitis C virus (HCV) infection. We aimed to elucidate whether DM influences the surgical outcomes of patients with hepatocellular carcinoma (HCC). METHODS: Our patients were routinely controlled to keep urinary glucose excretion to less than 3.0 g/day before surgery, and the serum glucose level under 200 mg/dL after surgery. The surgical outcomes and postoperative complications of 112 patients with HCV-related HCC with DM (DM group) were compared to those of 112 propensity-matched patients without DM (non-DM group). RESULTS: After a median follow-up of 3.2 years (range, 0.2-11.3 years), the median overall (5.2 years; 95% confidence interval, 3.8-6.5 years) and recurrence-free survival (2.2 years; 1.7-2.9 years) in the DM group were not significantly different from those (6.3 years; 5.4-7.1 years, P = 0.337; and 2.2 years; 1.7-3.6 years, P = 0.613) in the non-DM group. The independent factors related to overall survival were the background liver (hazard ratio, 2.06; 95% confidence interval, 1.27-3.39, P = 0.014) and tumor differentiation grade (2.07; 1.14-4.05, P = 0.015). Thirty-two patients (28.5%) in the DM group and 32 patients (28.5%) in the non-DM group had morbidities after operation, with no significant difference between the groups (P = 1.000). Furthermore, postoperative control status of DM did not affect the prognostic outcome. CONCLUSION: Diabetes mellitus does not affect the surgical outcomes of patients with HCV-related HCC, and it is not an unfavorable factor when selecting candidates for liver resection of HCC.

Pyruvate Kinase Isozyme M2 Plays a Critical Role in the Interactions Between Pancreatic Stellate Cells and Cancer Cells.

BACKGROUND: The interaction between pancreatic cancer cells and pancreatic stellate cells plays a pivotal role in the progression of pancreatic cancer. Pyruvate kinase isozyme M2 is a key enzyme in glycolysis. Previous studies have shown that pyruvate kinase isozyme M2 is overexpressed in pancreatic cancer and that it regulates the aggressive behaviors of pancreatic cancer cells. AIMS: To clarify the role of pyruvate kinase isozyme M2 in the interactions between pancreatic cancer cells and pancreatic stellate cells. METHODS: Pyruvate kinase isozyme M2-knockdown pancreatic cancer cells (Panc-1 and SUIT-2 cells) and pancreatic stellate cells were generated by the introduction of small interfering RNA-expressing vector against pyruvate kinase isozyme M2. Cell proliferation, migration, and epithelial-mesenchymal transition were examined in vitro. The impact of pyruvate kinase isozyme M2 knockdown on the growth of subcutaneous tumors was examined in nude mice in vivo. RESULTS: Pyruvate kinase isozyme M2-kockdown pancreatic cancer cells and pancreatic stellate cells showed decreased proliferation and migration compared to their respective control cells. Pancreatic stellate cell-induced proliferation, migration, and epithelial-mesenchymal transition were inhibited when pyruvate kinase isozyme M2 expression was knocked down in pancreatic cancer cells. In vivo, co-injection of pancreatic stellate cells increased the size of the tumor developed by the control SUIT-2 cells, but the effects were less evident when pyruvate kinase isozyme M2 was knocked down in SUIT-2 cells or pancreatic stellate cells. CONCLUSIONS: Our results suggested a critical role of pyruvate kinase isozyme M2 in the interaction between pancreatic cancer cells and pancreatic stellate cells.

Glycyrrhetinic acid inhibits contact hypersensitivity induced by trichophytin via dectin-1.

Trichophyton infection is highly prevalent and tends to be recurrent. Therefore, it is important to develop new therapeutic agents. Previously, we established a mouse model of Trichophyton-induced contact hypersensitivity (CHS) and demonstrated that dectin-1 was involved in inflammation induced by trichophytin, the Trichophyton antigen. Here, we used that model to investigate glycyrrhetinic acid (GA) from plants of the genus Glycyrrhiza as a potential anti-inflammatory agent against superficial mycoses. GA suppressed swelling and the expression of inflammatory cytokines, including macrophage inflammatory protein (MIP)-2, interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ mRNA. Anti-MIP-2 antibody suppressed trichophytin-induced inflammation, and antidectin-1 antibody suppressed zymosan-induced MIP-2 production in keratinocyte cells. These results suggest that MIP-2 is produced by dectin-1 activation and is involved in inflammation associated with CHS to trichophytin. GA also suppressed zymosan-induced MIP-2 and interleukin (IL)-8, production in mouse and human macrophages and keratinocytes. Furthermore, GA suppressed the phosphorylation of spleen tyrosine kinase (Syk) and inhibitor of nuclear factor-kappa B (IκBα) and the degradation of IκBα in zymosan-simulated RAW264.7 cells. The results of this study suggest that GA suppresses inflammation induced by trichophytin, partly by the downregulation of Syk phosphorylation.

Risk factors for recurrent biliary obstruction following placement of self-expandable metallic stents in patients with malignant perihilar biliary stricture.

BACKGROUND AND STUDY AIM: Self-expandable metallic stents (SEMSs) are used for palliation in patients with malignant perihilar biliary strictures. However, recurrent biliary obstruction occasionally causes cholangitis and jaundice. This study aimed to identify risk factors for recurrent biliary obstruction in such patients. METHODS: Data from consecutive patients with malignant perihilar biliary strictures treated with endoscopic placement of SEMSs between 2007 and 2014 in Tohoku University Hospital were retrospectively reviewed. Risk factors for recurrent biliary obstruction were calculated using the Cox proportional hazards models (with hazard ratios [HRs] and 95 % confidence interval [95 %CIs]), and SEMS patency period was examined using the Kaplan - Meier method. SEMS patency was defined as the period between SEMS insertion and the development of recurrent biliary obstruction. RESULTS: 104 patients were included. Median survival time was 281 days; and 85 patients died during a median follow-up period of 320 days. Recurrent biliary obstruction occurred in 35 patients. Median SEMS patency period was 549 days. Multivariable analyses showed that: compared with bile duct carcinoma, gallbladder carcinoma was associated with shorter SEMS patency (HR 8.18, 95 %CI 2.41 - 26.83); patency of left-sided SEMS was inferior to that of bilateral (HR 0.5, 95 %CI 0.32 - 0.93) and right-sided SEMS (HR 0.1, 95 %CI 0.02 - 0.65). Cholangitis before SEMS placement increased the risk of recurrent biliary obstruction (HR 11.44; 95 %CI 4.48 - 32.35) and reduced the SEMS patency period (746 vs. 210 days). CONCLUSION: Gallbladder carcinoma, left-sided stent placement, and cholangitis before SEMS placement are risk factors for recurrent biliary obstruction after SEMS placement.

IL-6/STAT3 Plays a Regulatory Role in the Interaction Between Pancreatic Stellate Cells and Cancer Cells.

BACKGROUND: Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis, a characteristic feature of pancreatic cancer. Although it is still controversial, previous studies have suggested that PSCs promote the progression of pancreatic cancer by regulating the cell functions of cancer cells. PSCs produce large amounts of IL-6, which promotes the accumulation of myeloid-derived suppressor cells via a signal transducers and activator of transcription 3 (STAT3)-dependent mechanism. But the role of IL-6/STAT3 pathway in the interaction between PSCs and pancreatic cancer cells remains largely unknown. AIMS: To clarify the role of IL-6/STAT3 in the interaction between PSCs and cancer cells. METHODS: Human pancreatic cancer cells (Panc-1 and SUIT-2 cells) were treated with conditioned medium of immortalized human PSCs (PSC-CM). The effects of PSC-CM and IL-6 neutralization on the mRNA expression profiles were examined using Agilent's microarray. Activation of STAT3 was assessed by Western blotting using an anti-phospho-specific antibody. Cellular migration was examined by a two-chamber assay. The expression of markers related to epithelial-mesenchymal transition (EMT) was assessed by real-time reverse transcription PCR. RESULTS: PSC-CM induced the activation of STAT3 in pancreatic cancer cells. Neutralization of IL-6 suppressed the PSC-CM-induced upregulation of genes including complement factor B, lipocalin, and chemokine (C-C motif) ligand 20. Inhibition of IL-6/STAT3 pathway by anti-IL-6 antibody or a STAT3 inhibitor (NSC74859) inhibited the PSC-CM-induced migration and the expression of EMT-related markers (Snail and cadherin-2) in pancreatic cancer cells. CONCLUSION: IL-6/STAT3 pathway regulates the PSC-induced EMT and alterations in gene expression in pancreatic cancer cells.