Miracle-dz/UniFAR-FTUs huggingface dataset:
Oligonucleotides stimulate genomic alterations of Legionella pneumophila

Genetic variation generates diversity in all kingdoms of life. The corresponding mechanisms can also be harnessed for laboratory studies of fundamental cellular processes. Here we report that oligonucleotides (oligos) generate mutations on the Legionella pneumophila chromosome by a mechanism that requires homologous DNA, but not RecA, RadA or any known phage recombinase. Instead we propose that DNA replication contributes, as oligo‐induced mutagenesis required ≥ 21 nucleotides of homology, was strand‐dependent, and was most efficient in exponential phase. Mutagenesis did not require canonical 5′ phosphate or 3′ hydroxyl groups, but the primosomal protein PriA and DNA Pol I contributed. After electroporation, oligos stimulated excision of 2.1 kb of chromosomal DNA or insertion of 18 bp, and non‐homologous flanking sequences were also processed. We exploited this endogenous activity to generate chromosomal deletions and to insert an epitope into a chromosomal coding sequence. Compared with Escherichia coli, L. pneumophila encodes fewer canonical single‐stranded exonucleases, and the frequency of mutagenesis increased substantially when either its RecJ and ExoVII nucleases were inactivated or the oligos modified by nuclease‐resistant bases. In addition to genetic engineering, oligo‐induced mutagenesis may have evolutionary implications as a mechanism to incorporate divergent DNA sequences with only short regions of homology.
Highly efficient induction of primate iPS cells by combining RNA transfection and chemical compounds

Induced pluripotent stem (iPS) cells hold great promise for regenerative medicine and the treatment of various diseases. Before proceeding to clinical trials, it is important to test the efficacy and safety of iPS cell‐based treatments using experimental animals. The common marmoset is a new world monkey widely used in biomedical studies. However, efficient methods that could generate iPS cells from a variety of cells have not been established. Here, we report that marmoset cells are efficiently reprogrammed into iPS cells by combining RNA transfection and chemical compounds. Using this novel combination, we generate transgene integration‐free marmoset iPS cells from a variety of cells that are difficult to reprogram using conventional RNA transfection method. Furthermore, we show this is similarly effective for human and cynomolgus monkey iPS cell generation. Thus, the addition of chemical compounds during RNA transfection greatly facilitates reprogramming and efficient generation of completely integration‐free safe iPS cells in primates, particularly from difficult‐to‐reprogram cells.
Pharmacokinetics and Safety of Iomeprol in Healthy Volunteers and in Patients with Renal Impairment or End-Stage Renal Disease Requiring Hemodialysis

Lorusso V, Taroni P, Alvino S, et al. Pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with renal impairment or end-stage renal disease requiring hemodialysis. Invest Radiol 2001;36:309–316. rationale and objectives. To present the results of two studies conducted to evaluate the pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with various degrees of renal impairment. methods. In these two open-label, single-dose, phase I studies, a 50-mL dose of iomeprol 400 was administered intravenously to a total of 30 subjects of either sex. In study 1, six healthy volunteers with normal renal function, six patients with mild renal failure, six patients with moderate renal failure, and four patients with severe renal failure were enrolled. In study 2, eight patients with end-stage renal disease requiring hemodialysis were enrolled. Safety was determined by predose and postdose (up to 10 days) measurement of vital signs, hematology, blood chemistry, urinalysis, electrocardiogram, physical examinations, and the incidence of adverse events. Pharmacokinetics was determined by measuring iomeprol levels in plasma, urine, feces, and dialysate samples, by using a validated high-performance liquid chromatography assay, up to 7 days after administration. results. The plasma concentration of iomeprol declined biexponentially in both healthy subjects and patients. As expected, mean body and renal clearances decreased progressively with increasing renal impairment, with a significant correlation with the glomerular filtration rate. The elimination half-life increased progressively with increasing renal impairment. The extraction efficiency of dialyser was estimated as approximately 40%, and dialysis clearance of iomeprol was approximately 1.26 mL · min−1 · kg−1 (80.6 mL/min), slightly less than the body clearance previously observed in healthy subjects. It appears that dialysis is almost as efficient as renal function in healthy subjects in the removal of iomeprol. After a single dialysis session, approximately 58% of the dose was recovered in dialysate. Mild to moderate adverse events were reported by 17 of 30 subjects; none was clinically meaningful. One serious adverse event, unrelated to iomeprol, was reported. No clinically meaningful findings were noted for other safety parameters. conclusions. Iomeprol was almost completely eliminated both in patients with renal impairment and in patients receiving dialysis. No dose adjustment appears to be necessary either in patients with renal impairment or with end-stage renal disease requiring hemodialysis. In this risk population, iomeprol 400 was safe and well tolerated.
Overall Survival of Patients With ALK-Positive Metastatic Non–Small-Cell Lung Cancer in the Russian Federation: Nationwide Cohort Study

PURPOSE The overall survival (OS) results in patients with ALK-positive metastatic non–small-cell lung cancer (NSCLC) have rarely been reported. The aim of this prospective-retrospective cohort study was to obtain real-world data on the use of crizotinib or chemotherapy in patients with ALK-positive metastatic NSCLC in Russia. PATIENTS AND METHODS Patients with epidermal growth factor receptor–negative metastatic NSCLC were screened in 23 cancer centers. To be eligible, patients were required to have confirmation of ALK rearrangement. Patients were treated with crizotinib (250 mg twice daily; n = 96) or the investigator’s choice of platinum-based chemotherapy (n = 53). The primary end point was OS. RESULTS A total of 149 ALK-positive patients were included. Mean age was 53 years in both groups. Patients were predominately women (59%) and never-smokers (74%), and most patients had adenocarcinoma histology (95%). At a median follow-up time of 15 months, 79 of the 149 patients included in the analysis had died. Median OS from the start of treatment was 31 months (95% CI, 28.5 to 33.5 months) in the crizotinib group and 15.0 months (95% CI, 9.0 to 21.0 months) in the chemotherapy group (P < .001). The objective response rate was 34% in the crizotinib group. Among patients with brain metastasis, one complete response (6%) and five partial responses (31%) were achieved. Grade 3 adverse events were observed in three patients (3%) in the crizotinib group. CONCLUSION The improved OS observed in crizotinib clinical trials in ALK-positive NSCLC was also observed in the less selective patient populations treated in daily practice in Russia. The use of standard chemotherapy in these patients remains common but seems inappropriate as a result of the effectiveness of newer treatments, such as crizotinib.
Breast cancer molecular subtype as a predictor of the utility of preoperative MRI.

OBJECTIVE The purpose of this study was to discern whether breast cancer molecular subtype, a known prognostic indicator, can be used to select patients with the highest likelihood of having clinically significant additional findings on breast MRI. MATERIALS AND METHODS A database review from January 2010 through December 2013 identified 299 patients who underwent preoperative breast MRI with tumors classifiable into molecular subtypes. Subtypes were classified on the basis of immunohistochemical staining surrogates as luminal A (hormone receptor [ER or PR] positive, ERBB2 [formerly HER2 or HER2/neu] negative, luminal B (hormone receptor positive, ERBB2 positive), ERBB2 (hormone receptor negative, ERBB2 positive), or basal (hormone receptor and ERBB2 negative). Univariate and multivariate logistic regression analyses were used to determine the association between subtype and additional breast MRI findings, including multicentric or multifocal disease, contralateral disease, chest wall involvement, skin and nipple involvement, and internal mammary and axillary lymphadenopathy. RESULTS The subtype distribution was luminal A, 70.6% (211/299); luminal B, 14.1% (42/299); ERBB2, 5.4% (16/299); and basal, 10.0% (30/299). ERBB2 and luminal B sub-types were more often associated with multicentric disease (25.0% and 26.2%), multifocal disease (37.5% and 35.7%), and axillary disease (50.0% and 45.2%) than were luminal A cancers (multicentric disease, 10.9%; multifocal disease 20.4%; axillary disease, 22.7%) (p < 0.001). In multivariate analysis, after control for patient age, tumor size, and nuclear grade, patients with ERBB2-overexpressing tumors were 2.4 times as likely as patients with luminal A tumors to have multicentric disease (p = 0.016), 2.0 times as likely to have multifocal disease (p = 0.024), 1.7 times as likely to have skin and nipple involvement (p = 0.013), and 1.9 times as likely to have axillary disease (p = 0.011). CONCLUSION Preoperative MRI may most benefit patients with tumors with ERBB2 overexpression because of the increased likelihood of the presence of additional disease.
New approach to cathodoluminescence studies in application to InGaN/GaN laser diode degradation

Cathodoluminescence (CL) studies are widely applied in semi‐conductor science and technology. However, for structures with a p‐n junction the CL spatial distribution can be strongly affected by internal current flows of the electron beam induced current generated within the structure. This influence is the investigated in application to CL studies of degradation in aged laser diodes with InGaN multiquantum wells.
The Protective Effect of Alpha-Mangostin against Cisplatin-Induced Cell Death in LLC-PK1 Cells is Associated to Mitochondrial Function Preservation

Cis-dichlorodiammineplatinum II (CDDP) is a chemotherapeutic agent that induces nephrotoxicity by different mechanisms, including oxidative stress, mitochondrial dysfunction, autophagy, and endoplasmic reticulum stress. This study aimed to evaluate if the protective effects of the antioxidant alpha-mangostin (αM) in CDDP-induced damage in proximal tubule Lilly laboratory culture porcine kidney (LLC-PK1) cells, are related to mitochondrial function preservation. It was found that αM co-incubation prevented CDDP-induced cell death. Furthermore, αM prevented the CDDP-induced decrease in cell respiratory states, in the maximum capacity of the electron transfer system (E) and in the respiration associated to oxidative phosphorylation (OXPHOS). CDDP also decreased the protein levels of voltage dependence anion channel (VDAC) and mitochondrial complex subunits, which together with the reduction in E, the mitofusin 2 decrease and the mitochondrial network fragmentation observed by MitoTracker Green, suggest the mitochondrial morphology alteration and the decrease in mitochondrial mass induced by CDDP. CDDP also induced the reduction in mitochondrial biogenesis observed by transcription factor A, mitochondria (TFAM) decreased protein-level and the increase in mitophagy. All these changes were prevented by αM. Taken together, our results imply that αM’s protective effects in CDDP-induced toxicity in LLC-PK1 cells are associated to mitochondrial function preservation.
Hsa_circ_0101432 promotes the development of hepatocellular carcinoma (HCC) by adsorbing miR-1258 and miR-622

Statement of Retraction Hsa_circ_0101432 promotes the development of hepatocellular carcinoma (HCC) by adsorbing miR-1258 and miR-622 We, the Editors and Publisher of the journal Cell Cycle, have retracted the following article: Haibo Zou, Xiangang Xu, Lanyun Luo, Yu Zhang, Le Luo, Yutong Yao, Guangming Xiang, Xiaolun Huang, and Guan Wang. Hsa_circ_0101432 promotes the development of hepatocellular carcinoma (HCC) by adsorbing miR-1258 and miR-622. Cell Cycle. 2019;18(19):2398-2413. doi: 10.1080/15384101.2019. 1618120. Since publication, significant concerns have been raised about the integrity of the data and reported results in the article. When approached for an explanation, the authors did not provide their original data or any necessary supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The corresponding author listed in this publication has been informed. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.
Zero-Bias Visible to Near-Infrared Horizontal p-n-p TiO2 Nanotubes Doped Monolayer Graphene Photodetector

We present a p-n-p monolayer graphene photodetector doped with titanium dioxide nanotubes for detecting light from visible to near-infrared (405 to 1310 nm) region. The built-in electric field separates the photo-induced electrons and holes to generate photocurrent without bias voltage, which allows the device to have meager power consumption. Moreover, the detector is very sensitive to the illumination area, and we analyze the reason using the energy band theory. The response time of the detector is about 30 ms. The horizontal p-n-p device is a suitable candidate in zero-bias optoelectronic applications.
The Medial Axis of a Multi-Layered Environment and Its Application as a Navigation Mesh

Path planning for walking characters in complicated virtual environments is a fundamental task in simulations and games. A navigation mesh is a data structure that allows efficient path planning. The Explicit Corridor Map (ECM) is a navigation mesh based on the medial axis. It enables path planning for disk-shaped characters of any radius. In this article, we formally extend the medial axis (and therefore the ECM) to 3D environments in which characters are constrained to walkable surfaces. Typical examples of such environments are multi-storey buildings, train stations, and sports stadiums. We give improved definitions of a walkable environment (WE: a description of walkable surfaces in 3D) and a multi-layered environment (MLE: a subdivision of a WE into connected layers). We define the medial axis of such environments based on projected distances on the ground plane. For an MLE with n boundary vertices and k connections, we show that the medial axis has size O(n), and we present an improved algorithm that constructs the medial axis in O(n log n log k) time. The medial axis can be annotated with nearest-obstacle information to obtain the ECM navigation mesh. Our implementations show that the ECM can be computed efficiently for large 2D and multi-layered environments and that it can be used to compute paths within milliseconds. This enables simulations of large virtual crowds of heterogeneous characters in real-time.
Symptomatogenic zone and network of oroalimentary automatisms in mesial temporal lobe epilepsy

Oroalimentary automatisms (OAAs) are common clinical manifestations of medial temporal lobe epilepsy. Nevertheless, the location of the symptomatogenic zone of OAAs remains unclear. The generation mechanism of OAAs also has not been clarified. We attempt to explain these problems by analyzing interictal [18F]‐fluorodeoxyglucose positron emission tomography (18FDG‐PET) imaging and ictal stereo‐electroencephalography (SEEG) recordings in patients with medial temporal lobe epilepsy.
Efficacy and safety of direct-acting antiviral therapy for chronic hepatitis C genotype 6

Background: Because of the heterogeneity of hepatitis C virus (HCV) distribution of different genotypes, large-scale clinical trials on direct-acting antiviral (DAA) mainly included patients with genotype 1 and genotype 3 infection. Data on the efficacy of direct-acting antiviral agents in patients with chronic genotype 6 HCV infection are limited. Methods: The PubMed, Embase, and the Cochrane Libraries were searched comprehensively. All published clinical trials assessing the efficacy of DAA therapy for patients with chronic genotype 6 HCV infection were included. Sustained virological response (SVR) and rapid virological response (RVR) were pooled. Additional meta-analyses were also performed to compare the efficacy of DAA therapy in HCV-6 versus HCV-1 or HCV-3 patients. Results: Seventeen studies met the inclusion criteria and were included in our meta-analysis. The pooled SVR of all single arms was 95% [95% confidence interval (CI): 0.90–0.97]. The pooled RVR of all single arms was 97% (95% CI: 0.95–0.99). The SVR and RVR were both similar between HCV-6 and HCV-1 or HCV-3. Adverse events were common but rarely caused treatment interruption. Conclusion: Based on the available data, our results indicate that DAA treatment is effective and safe for patients with genotype 6 HCV infection, and the efficacy was similar compared to patients with genotype 1 HCV or genotype 3 HCV infection.
A subset of breast invasive ductal carcinoma with distinctive cytomorphology, aggressive clinical behavior, and unique immunologic profiles

Invasive ductal carcinoma of the breast is a heterogeneous collection of divergent types of carcinomas. Some subtypes have been characterized by histologic observations. This study describes a distinctive subset recognized through cytomorphologic examination of breast carcinoma specimens obtained by fine‐needle aspiration biopsies (FNAB). Identification of this subset is established further by analyses of its clinical and immunologic characteristics.
The Role of Leaders in Designing Employees’ Work Characteristics: Validation of the Health- and Development-Promoting Leadership Behavior Questionnaire

In this article, we draw upon the notion that employees’ work characteristics are an important pathway through which leaders influence employee well-being and propose a theoretical framework that integrates perspectives on leadership, occupational stress, and job design. Based on this integrative approach, we developed the health- and development-promoting leadership behavior questionnaire (HDLBQ) for assessing job demands emanating from and job resources provided through the leader. Validation of the measure in German, French, and English using an overall sample of 2,934 employees demonstrated adequate psychometric properties. An examination of the factorial structure revealed three higher-order factors: demanding, development-oriented, and support-oriented leadership. Multigroup confirmatory factor analysis indicated structural equivalence across the three language versions of the HDLBQ. Correlations with employee well-being were moderate, and the HDLBQ explained unique variance in employee well-being beyond that explained by transformational leadership. Suggestions for applications of the HDLBQ and approaches to enhance employee well-being at the workplace are discussed.
Increased Lysosomal Exocytosis Induced by Lysosomal Ca2+ Channel Agonists Protects Human Dopaminergic Neurons from α-Synuclein Toxicity

The accumulation of misfolded proteins is a common pathological feature of many neurodegenerative disorders, including synucleinopathies such as Parkinson's disease (PD), which is characterized by the presence of α-synuclein (α-syn)-containing Lewy bodies. However, although recent studies have investigated α-syn accumulation and propagation in neurons, the molecular mechanisms underlying α-syn transmission have been largely unexplored. Here, we examined a monogenic form of synucleinopathy caused by loss-of-function mutations in lysosomal ATP13A2/PARK9. These studies revealed that lysosomal exocytosis regulates intracellular levels of α-syn in human neurons. Loss of PARK9 function in patient-derived dopaminergic neurons disrupted lysosomal Ca2+ homeostasis, reduced lysosomal Ca2+ storage, increased cytosolic Ca2+, and impaired lysosomal exocytosis. Importantly, this dysfunction in lysosomal exocytosis impaired α-syn secretion from both axons and soma, promoting α-syn accumulation. However, activation of the lysosomal Ca2+ channel transient receptor potential mucolipin 1 (TRPML1) was sufficient to upregulate lysosomal exocytosis, rescue defective α-syn secretion, and prevent α-syn accumulation. Together, these results suggest that intracellular α-syn levels are regulated by lysosomal exocytosis in human dopaminergic neurons and may represent a potential therapeutic target for PD and other synucleinopathies. SIGNIFICANCE STATEMENT Parkinson's disease (PD) is the second most common neurodegenerative disease linked to the accumulation of α-synuclein (α-syn) in patient neurons. However, it is unclear what the mechanism might be. Here, we demonstrate a novel role for lysosomal exocytosis in clearing intracellular α-syn and show that impairment of this pathway by mutations in the PD-linked gene ATP13A2/PARK9 contributes to α-syn accumulation in human dopaminergic neurons. Importantly, upregulating lysosomal exocytosis by increasing lysosomal Ca2+ levels was sufficient to rescue defective α-syn secretion and accumulation in patient neurons. These studies identify lysosomal exocytosis as a potential therapeutic target in diseases characterized by the accumulation of α-syn, including PD.
Elongation Inhibition by DRB Sensitivity-Inducing Factor Is Regulated by the A20 Promoter via a Novel Negative Element and NF-κB

ABSTRACT A20 is an immediate-early NF-κB target gene. Prior to NF-κB stimulation, the A20 promoter is bound by the polymerase II machinery to allow rapid transcription activation. Here we show that the basal A20 transcription is repressed at the level of elongation in a promoter-specific fashion. Immunodepletion in vitro and RNA interference in cultured cells suggest that the basal elongation inhibition is conferred by DRB sensitivity-inducing factor (DSIF). We have identified a negative upstream promoter element called ELIE that controls DSIF activity. Remarkably, following NF-κB stimulation, inhibition of the A20 promoter by DSIF persists, but it is now regulated by NF-κB rather than ELIE. Similar regulation by DSIF is shown for another NF-κB-responsive gene, the IκBα gene. These findings reveal an intimate and dynamic relationship between DSIF inhibition of elongation and promoter-bound transcription factors. The potential significance of the differential regulation of DSIF activity by cis-acting elements is discussed.