X-ray polarization evidence for a 200-year-old flare of Sgr A.

The centre of the Milky Way Galaxy hosts a black hole with a solar mass of about 4 million (Sagittarius A* (Sgr A)) that is very quiescent at present with a luminosity many orders of magnitude below those of active galactic nuclei1. Reflection of X-rays from Sgr A* by dense gas in the Galactic Centre region offers a means to study its past flaring activity on timescales of hundreds and thousands of years2. The shape of the X-ray continuum and the strong fluorescent iron line observed from giant molecular clouds in the vicinity of Sgr A* are consistent with the reflection scenario3-5. If this interpretation is correct, the reflected continuum emission should be polarized6. Here we report observations of polarized X-ray emission in the direction of the molecular clouds in the Galactic Centre using the Imaging X-ray Polarimetry Explorer. We measure a polarization degree of 31% ± 11%, and a polarization angle of -48° ± 11°. The polarization angle is consistent with Sgr A* being the primary source of the emission, and the polarization degree implies that some 200 years ago, the X-ray luminosity of Sgr A* was briefly comparable to that of a Seyfert galaxy.

The Biosynthetic Gene Cluster of Mushroom-Derived Antrocin Encodes Two Dual-Functional Haloacid Dehalogenase-like Terpene Cyclases.

(-)-Antrocin (1), produced by the medicinal mushroom Antrodia cinnamomea, is a potent antiproliferative compound. The biosynthetic gene cluster of 1 was identified, and the pathway was characterized by heterologous expression. We characterized a haloacid dehalogenase-like terpene cyclase AncC that biosynthesizes the drimane-type sesquiterpene (+)-albicanol (2) from farnesyl pyrophosphate (FPP). Biochemical characterization of AncC, including kinetic studies and mutagenesis, demonstrated the functions of two domains: a terpene cyclase (TC) and a pyrophosphatase (PPase). The TC domain first cyclizes FPP to albicanyl pyrophosphate, and the PPase domain then removes the pyrophosphate to form 2. Intriguingly, AncA (94 % sequence identity to AncC), in the same gene cluster, converts FPP into (R)-trans-γ-monocyclofarnesol instead of 2. Notably, Y283/F375 in the TC domain of AncA serve as a gatekeeper in controlling the formation of a cyclofarnesoid rather than a drimane-type scaffold.

Anaerobic spondylodiscitis: a retrospective analysis.

BACKGROUND: This retrospective study analyzed the clinical characteristics and outcomes of patients with anaerobic spondylodiscitis. METHODS: From a total of 382 patients with infectious spondylodiscitis, nine patients (2.4%; two male and seven female with an average age of 67 years) with anaerobic spondylodiscitis between March 2003 and March 2017 were analyzed. RESULTS: Most of the patients (77.8%) initially presented with afebrile back pain. Hematogenous spread occurred in seven patients and postoperative infection in two patients. Bacteroid fragilis was the most common pathogen isolated from three patients. Atypical radiographic characteristics, including a vertebral fracture with the preservation of disk height or coexisting spondylolytic spondylolisthesis, occurred in four patients with hematogenous anaerobic spondylodiscitis. The eradication rate of anaerobic infection was significantly higher in the patients with hematogenous infection than in those with postoperative infection (100% vs. 0%, p = 0.0476). Anaerobic spondylodiscitis accounted for 2.4% of cases of infectious spondylodiscitis and predominantly affected the female patients. CONCLUSIONS: Diagnostic delay may occur because of atypical spinal radiographs if the patient reports only back pain but no fever. Anaerobic infection following elective spinal instrumentation has a higher recurrence rate.

Ultrasound-Guided Femoral Nerve Block in Geriatric Patients with Hip Fracture in the Emergency Department.

Background and Objectives: Systemic analgesics, including opioids, are commonly used for acute pain control in traumatic hip fracture patients in the emergency department (ED). However, their use is associated with high rates of adverse reactions in the geriatric population. As such, the aim of this study was to investigate the impact of lidocaine-based single-shot ultrasound-guided femoral nerve block (USFNB) on the standard care for acute pain management in geriatric patients with traumatic hip fracture in the ED. Methods: This retrospective, single-center, observational study included adult patients aged ≥60 years presenting with acute traumatic hip fracture in the ED between 1 January 2017 and 31 December 2020. The primary outcome measure was the difference in the amount of opioid use, in terms of morphine milligram equivalents (MME), between lidocaine-based single-shot USFNB and standard care groups. The obtained data were evaluated through a time-to-event analysis (time to meaningful pain relief), a time course analysis, and a multivariable analysis. Results: Overall, 607 adult patients (USFNB group, 66; standard care group, 541) were included in the study. The patients in the USFNB group required 80% less MME than those in the standard care group (0.52 ± 1.47 vs. 2.57 ± 2.53, p < 0.001). The multivariable Cox proportional hazards regression models showed that patients who received USFNB achieved meaningful pain relief 2.37-fold faster (hazard ratio (HR) = 2.37, 95% confidence intervals (CI) = 1.73−3.24, p < 0.001). Conclusions: In geriatric patients with hip fractures, a lidocaine-based single-shot USFNB can significantly reduce opioid consumption and provide more rapid and effective pain reduction.

Development of Next-Generation Probiotics by Investigating the Interrelationships between Gastrointestinal Microbiota and Diarrhea in Preruminant Holstein Calves.

(1) Background: We aimed to isolate and identify potential next-generation probiotics (NGP) by investigating the interrelationships between gastrointestinal microbiota and diarrhea in preruminant Holstein calves. (2) Material and methods: Twenty preruminant Holstein calves were divided into healthy and diarrheic groups after the combination outcomes of veterinary diagnosis and fecal scores. The fecal microbiome, plasma cytokines, plasma immunoglobulin (Ig) G and haptoglobin were analyzed. The potential probiotic bacteria were identified by comparing the microbiota difference between healthy and diarrheic calves and correlation analysis with fecal scores and inflammatory markers. The identified bacteria were also isolated for further evaluation for antimicrobial activities and immunoregulatory effects. (3) Results: Microbiota analysis suggested that Ruminococcaceae_UCG_014, Bifidobacterium and Pseudoflavonifractor positively correlated with bovine IgG and negatively correlated with fecal score; inflammatory factors, bovine HP, and IL-8 were classified as beneficial bacteria contributing to the health of the calves. The alternation of gut microbial composition also induced changes in the functional gene enrichment of gut microbiota in calves. The gathering of microbiomic data strongly indicated the possible beneficial effects of Bifidobacterium longum subsp. longum, expected to develop as NGP. After isolation and evaluation of the potential functionality in vitro, two specific bifidobacterial strains demonstrated antimicrobial activities and immunoregulatory effects. (4) Conclusions: The results provide a new probiotic searching approach for preventing gastrointestinal disorders in preruminant calves. Further animal study is necessary to verify the results.

A modified theory of planned behavioral: A case of tourist intention to visit a destination post pandemic Covid-19 in Indonesia.

The Pandemic covid-19 spread globally has been given impact in the tourism industry, especially in the tourism destination. This study investigated to build the concept and theoretical framework that explains the decision of local tourist intention to visit a local destination in Indonesia post-pandemic covid-19. This study was considered the perception of Covid-19, non-pharmaceutical intervention and health consciousness by implying of Theory of Planned Behavior constructs. This study, health consciousness is the moderator variable to predict the decision of tourist to visit a destination. Structural Equation Model-Partial Least Square (SEM-PLS) was used to analyze the construct of study. The model found that the Theory of Planned Behavior was successfully broadened in making the decision of tourist to visit a destination post-covid-19 with considering non-pharmaceutical intervention and health consciousness. The results showed that generally the constructs of Theory Planned Behavior are significantly impacted in intention to visit a local destination in Indonesia, except Hypothesis of subjective norm and intention to visit was rejected. The variable health consciousness through intention to visit also was rejected. The framework also used moderating variable health consciousness between subjective norm and intention to visit was rejected. This study was given insight an issue of covid-19 in the tourism sector, and the implication was providing government, stakeholders, tourism marketers and policy-making with considering non-pharmaceutical and health consciousness during and post-pandemic covid-19.

Genetic co-expression networks contribute to creating predictive model and exploring novel biomarkers for the prognosis of breast cancer.

Genetic co-expression network (GCN) analysis augments the understanding of breast cancer (BC). We aimed to propose GCN-based modeling for BC relapse-free survival (RFS) prediction and to discover novel biomarkers. We used GCN and Cox proportional hazard regression to create various prediction models using mRNA microarray of 920 tumors and conduct external validation using independent data of 1056 tumors. GCNs of 34 identified candidate genes were plotted in various sizes. Compared to the reference model, the genetic predictors selected from bigger GCNs composed better prediction models. The prediction accuracy and AUC of 3 ~ 15-year RFS are 71.0-81.4% and 74.6-78% respectively (rfm, ACC 63.2-65.5%, AUC 61.9-74.9%). The hazard ratios of risk scores of developing relapse ranged from 1.89 ~ 3.32 (p < 10-8) over all models under the control of the node status. External validation showed the consistent finding. We found top 12 co-expressed genes are relative new or novel biomarkers that have not been explored in BC prognosis or other cancers until this decade. GCN-based modeling creates better prediction models and facilitates novel genes exploration on BC prognosis.

Six novel immunoglobulin genes as biomarkers for better prognosis in triple-negative breast cancer by gene co-expression network analysis.

Gene co-expression network analysis (GCNA) can detect alterations in regulatory activities in case/control comparisons. We propose a framework to detect novel genes and networks for predicting breast cancer recurrence. Thirty-four prognosis candidate genes were selected based on a literature review. Four Gene Expression Omnibus Series (GSE) microarray datasets (n = 920) were used to create gene co-expression networks based on these candidates. We applied the framework to four comparison groups according to node (+/-) and recurrence (+/-). We identified a sub-network containing two candidate genes (LST1 and IGHM) and six novel genes (IGHA1, IGHD, IGHG1, IGHG3, IGLC2, and IGLJ3) related to B cell-specific immunoglobulin. These novel genes were correlated with recurrence under the control of node status and were found to function as tumor suppressors; higher mRNA expression indicated a lower risk of recurrence (hazard ratio, HR = 0.87, p = 0.001). We created an immune index score by performing principle component analysis and divided the genes into low and high groups. This discrete index significantly predicted relapse-free survival (RFS) (high: HR = 0.77, p = 0.019; low: control). Public tool KM Plotter and TCGA-BRCA gene expression data were used to validate. We confirmed these genes are correlated with RFS and distal metastasis-free survival (DMFS) in triple-negative breast cancer (TNBC) and general breast cancer.

Early achievement of full donor chimerism after allogeneic hematopoietic stem cell transplantation predicts lower relapse risk in patients with acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) remains one of the most difficult-to-cure hematological malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) provides curative potential but a substantial proportion of patients eventually will relapse. It is unknown if there are any modifiable factors exists that could improve survival or predict relapse immediately after HSCT is unknown. The aim of this study was to explore whether achieving early (<30 days) full donor chimerism (FDC) could predict disease relapse after allogeneic HSCT in ALL patients. A second objective is to examine the impact of achieving early donor chimerism on survival. METHODS: This study retrospectively enrolled 55 ALL patients undergoing allogeneic HSCT during the 10-year period from 1999 to 2008. Analysis of short tandem repeats (STR) was used to determine donor chimerism, and was prospectively followed at the time of engraftment and on days 30. Patients with early treatment-related mortality (<30 days), without STR analysis, or who were lost to follow-up before FDC were excluded. Survival analyses were performed using Kaplan-Meier Methods. Cox proportional hazard analyses were performed for poor prognostic factors associated with overall survival (OS) and relapse-free survival (RFS). RESULTS: The general characteristics were comparable between patients with early donor chimerism (n = 31) and those with late donor chimerism (n = 24). Survival analyses showed patients with early FDC had both lower probability of relapse (χ2 = 5.770, p = 0.022) and longer RFS than those with late chimerism. The OS was not different according to the chimerism status on days 30. In the Cox proportional hazard analyses, early FDC is a significant factor predictive for longer RFS (HR = 0.264, p = 0.010). CONCLUSION: Our results indicate that the achievement of early FDC within 30 days after allogenic HSCT can be used as a significant predictor of RFS. The results underscored the need to improve outcome in ALL patients with late FDC.

Correction: Characteristics and risk of chronic graft-versus-host disease of liver in allogeneic hematopoietic stem cell transplant recipients.

[This corrects the article DOI: 10.1371/journal.pone.0185210.].

Characteristics and risk of chronic graft-versus-host disease of liver in allogeneic hematopoietic stem cell transplant recipients.

Chronic graft-versus-host-disease (cGvHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among various organ-specific cGvHD, the cGvHD of liver is less well-characterized. In this study, we applied the National Institutes of Health 2014 scoring criteria of cGvHD to analyze a retrospective cohort of 362 allo-HSCT recipients focusing on cGvHD of liver. The overall incidence of liver cGvHD with a score of 3 by 1.5 years post-transplant was 5.8% (21/362). Poor outcome, in terms of overall survival (OS), were observed in patients with scores of 3 liver cGvHD, comparing to those with scores less than 3 (hazard ratio [HR] 2.037, 95% confidence interval [CI] 1.123-3.696, P = 0.019). In multivariate analysis, male gender (HR 4.004, P = 0.042) and chronic hepatitis C virus (HCV) infection status (HR 19.087, P < 0.001) were statistically significant risk factors for scores of 3 liver cGvHD. Our results indicate that liver cGvHD with scores of 3 has a grave prognosis following allo-HSCT, and that HCV carrier status and male are risk factors. Early recognition of this devastating complication might help in prompt immunosuppressive therapy and reducing late poor outcome.

Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines.

The okaramines are a class of complex indole alkaloids isolated from Penicillium and Aspergillus species. Their potent insecticidal activity arises from selectively activating glutamate-gated chloride channels (GluCls) in invertebrates, not affecting human ligand-gated anion channels. Okaramines B (1) and D (2) contain a polycyclic skeleton, including an azocine ring and an unprecedented 2-dimethyl-3-methyl-azetidine ring. Owing to their complex scaffold, okaramines have inspired many total synthesis efforts, but the enzymology of the okaramine biosynthetic pathway remains unexplored. Here, we identified and characterized the biosynthetic gene cluster (oka) of 1 and 2, then elucidated the pathway with target gene inactivation, heterologous reconstitution, and biochemical characterization. Notably, we characterized an α-ketoglutarate-dependent non-heme FeII dioxygenase that forged the azetidine ring on the okaramine skeleton.

Gene expression profile of peripheral blood in colorectal cancer.

AIM: Optimal molecular markers for detecting colorectal cancer (CRC) in a blood-based assay were evaluated. METHODS: A matched (by variables of age and sex) case-control design (111 CRC and 227 non-cancer samples) was applied. Total RNAs isolated from the 338 blood samples were reverse-transcribed, and the relative transcript levels of candidate genes were analyzed. The training set was made of 162 random samples of the total 338 samples. A logistic regression analysis was performed, and odds ratios for each gene were determined between CRC and non-cancer. The samples (n = 176) in the testing set were used to validate the logistic model, and an inferred performance (generality) was verified. By pooling 12 public microarray datasets(GSE 4107, 4183, 8671, 9348, 10961, 13067, 13294, 13471, 14333, 15960, 17538, and 18105), which included 519 cases of adenocarcinoma and 88 controls of normal mucosa, we were able to verify the selected genes from logistic models and estimate their external generality. RESULTS: The logistic regression analysis resulted in the selection of five significant genes (P < 0.05; MDM2, DUSP6, CPEB4, MMD, and EIF2S3), with odds ratios of 2.978, 6.029, 3.776, 0.538 and 0.138, respectively. The five-gene model performed stably for the discrimination of CRC cases from controls in the training set, with accuracies ranging from 73.9% to 87.0%, a sensitivity of 95% and a specificity of 95%. In addition, a good performance in the test set was obtained using the discrimination model, providing 83.5% accuracy, 66.0% sensitivity, 92.0% specificity, a positive predictive value of 89.2% and a negative predictive value of 73.0%. Multivariate logistic regressions analyzed 12 pooled public microarray data sets as an external validation. Models that provided similar expected and observed event rates in subgroups were termed well calibrated. A model in which MDM2, DUSP6, CPEB4, MMD, and EIF2S3 were selected showed the result in logistic regression analysis (H-L P = 0.460, R2= 0.853, AUC = 0.978, accuracy = 0.949, specificity = 0.818 and sensitivity = 0.971). CONCLUSION: A novel gene expression profile was associated with CRC and can potentially be applied to blood-based detection assays.

Concurrent sunitinib and stereotactic body radiotherapy for patients with oligometastases: final report of a prospective clinical trial.

Preliminary results demonstrated that concurrent sunitinib and stereotactic body radiation therapy (SBRT) is an active regimen for metastases limited in number and extent. This analysis was conducted to determine the long-term survival and cancer control outcomes for this novel regimen. Forty-six patients with oligometastases, defined as five or fewer clinical detectable metastases from any primary site, were treated on a phase I/II trial from February 2007 to September 2010. The majority of patients were treated with 37.5 mg sunitinib (days 1-28) and SBRT 50 Gy (days 8-12 and 15-19) and maintenance sunitinib was used in 39 % of patients. Median follow up for surviving patients is 3.6 years. The 4-year estimates for local control, distant control, progression-free and overall survival were 75 %, 40 %, 34 % and 29 %, respectively. At last follow-up, 26 % of patients were alive without evidence of disease, 7 % were alive with distant metastases, 48 % died from distant metastases, 2 % died from local progression, 13 % died from comorbid illness, and 4 % died from treatment-related toxicities. Patients with kidney and prostate primary tumors were associated with a significantly improved overall survival (hazard ratio = 0.25, p = 0.04). Concurrent sunitinib and SBRT is a promising approach for the treatment of oligometastases and further study of this novel combination is warranted.

How to interpret current-voltage relationships of blocking grain boundaries in oxygen ionic conductors.

A new model based on a linear diffusion equation is proposed to explain the current-voltage characteristics of blocking grain boundaries in Y-doped CeO2 in particular. One can also expect that the model can be applicable to the ionic conductors with blocking grain boundaries, in general. The model considers an infinitely long chain of identical grains separated by grain boundaries, which are treated as regions in which depletion layers of mobile ions are formed due to trapping of immobile charges that do not depend on the applied voltage as well as temperature. The model assumes that (1) the grain boundaries do not represent physical blocking layers, which implies that if there is a second phase at the grain boundaries, then it is too thin to impede ion diffusion and (2) the ions follow Boltzmann distribution throughout the materials. Despite its simplicity, the model successfully reproduces the "power law": current proportional to voltage power n and illustrated with the experimental example of Y-doped ceria. The model also correctly predicts that the product nT, where T is the temperature in K, is constant and is proportional to the grain boundary potential as long as the charge at the grain boundaries remains trapped. The latter allows its direct determination from the current-voltage characteristics and promises considerable simplification in the analysis of the electrical characteristics of the grain boundaries with respect to the models currently in use.

Competing causes of death in patients with oropharyngeal cancer treated with radiotherapy.

Radiation with or without chemotherapy is considered the mainstay of treatment for the majority of patients with oropharyngeal cancer. The goal of this study was to analyze competing causes of mortality in patients with oropharyngeal cancer with long-term follow-up. We queried the Surveillance, Epidemiology and End Results (SEER) database and identified 3728 patients with oropharyngeal cancer treated between 1988 and 2001 with definitive radiotherapy. We analyzed predictors of overall survival and risks of mortality from index oropharyngeal cancer, second primary cancer, cardiovascular disease and other causes using a cumulative incidence analysis and Cox multivariate analysis. With a median follow-up of 6.8 years, the 5- and 10-year overall survival was 37 and 22%, respectively. At 5 years, the risk of mortality from primary oropharyngeal cancer was 35%. Between years 3 and 10, 69% of mortalities were attributed to causes other than the index cancer. Despite advances in the non-surgical treatment of oropharyngeal cancer, patients remain at significant risk of cancer- and non-cancer-related mortality.

Current-voltage characteristics of grain boundaries in polycrystalline Sr-doped LaGaO3.

The oxide-ion current across grain boundaries in a polycrystalline LaGaO(3) ceramic doped with 1 mol% Sr(2+) increases non-linearly with the applied dc-bias to present a transition from ohmic to superohmic where the bias exceeds the thermal voltage, verifying that a Schottky-type potential barrier exists at the grain boundary in acceptor-doped LaGaO(3) to limit the internal current.

Toxicity profile and clinical outcomes in locally advanced head and neck cancer patients treated with induction chemotherapy prior to concurrent chemoradiation.

The use of induction chemotherapy prior to chemoradiation for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) remains controversial. We explored whether toxicity from induction chemotherapy influenced the delivery of concurrent chemoradiation. Among 171 consecutive previously unirradiated patients with HNSCC treated with combined chemotherapy and radiation, we identified 66 patients with stage III-IVB head and neck carcinoma who were treated with induction chemotherapy prior to planned chemoradiation. The most common induction regimen was docetaxel, cisplatin and 5-FU (TPF; 80%) for 2 to 3 cycles. Mean radiation dose was 72 Gy (range, 36-75 Gy). Concurrent chemotherapy regimens included cisplatin (26%), cetuximab (5%) and 5-fluorouracil/hydroxyurea (65%)-based regimens. At a median follow-up of 27 months (range, 9-56 months), the 2-year locoregional control and distant control rates were 85 and 86%, respectively. The 2-year disease-free survival and overall survival rates were 74 and 80%, respectively. Although there were no grade 5 toxicities during induction chemotherapy, 26% of patients required hospitalization for adverse events, including 5% needing intensive care. The most common high grade adverse events were grade 4 neutropenia (21%) and neutropenic fever (17%). Six percent of patients were unable to tolerate concurrent chemotherapy. The 2-year disease-free survival was significantly higher in patients able to complete induction and concurrent chemoradiation as planned (83 vs. 27%, p<0.001). Induction chemotherapy followed by concurrent chemoradiation results in promising survival rates in our cohort of advanced head and neck carcinoma patients. Due to severe toxicities in a subset of patients, this strategy is only recommended in selected high-risk patients who are carefully followed by an experienced multidisciplinary team.

Synthesis and in vitro anticancer activity of 6,7-methylenedioxy (or 5-hydroxy-6-methoxy)-2-(substituted selenophenyl)quinolin-4-one analogs.

6,7-Methylenedioxy (or 5-hydroxy-6-methoxy)-2-(substituted selenophenyl)quinolin-4-ones and their isosteric compounds were synthesized and evaluated for anticancer activity. Structure-activity relationships (SAR) of these compounds were established. Among all tested compounds, 6,7-methylenedioxy-2-(5-methylselenophen-2-yl)quinolin-4-one (4d) was found to be the most promising anticancer agent. In screening against NCI's 60 human tumor cell line panel, 4d exhibited highly selective and potent inhibitory activity against MDA-MB-435 melanoma. Furthermore, the results of COMPARE analysis suggested that 4d is an antimitotic agent with a different mechanism of action from the conventional antimitotic agents, such as colchicine, vinca alkaloids and paclitaxel. Therefore, 4d was identified as a new lead compound that merits further optimization.