Miracle-dz/UniFAR-FTUs huggingface dataset:
A Mechanism of Gene Amplification Driven by Small DNA Fragments

DNA amplification is a molecular process that increases the copy number of a chromosomal tract and often causes elevated expression of the amplified gene(s). Although gene amplification is frequently observed in cancer and other degenerative disorders, the molecular mechanisms involved in the process of DNA copy number increase remain largely unknown. We hypothesized that small DNA fragments could be the trigger of DNA amplification events. Following our findings that small fragments of DNA in the form of DNA oligonucleotides can be highly recombinogenic, we have developed a system in the yeast Saccharomyces cerevisiae to capture events of chromosomal DNA amplification initiated by small DNA fragments. Here we demonstrate that small DNAs can amplify a chromosomal region, generating either tandem duplications or acentric extrachromosomal DNA circles. Small fragment-driven DNA amplification (SFDA) occurs with a frequency that increases with the length of homology between the small DNAs and the target chromosomal regions. SFDA events are triggered even by small single-stranded molecules with as little as 20-nt homology with the genomic target. A double-strand break (DSB) external to the chromosomal amplicon region stimulates the amplification event up to a factor of 20 and favors formation of extrachromosomal circles. SFDA is dependent on Rad52 and Rad59, partially dependent on Rad1, Rad10, and Pol32, and independent of Rad51, suggesting a single-strand annealing mechanism. Our results reveal a novel molecular model for gene amplification, in which small DNA fragments drive DNA amplification and define the boundaries of the amplicon region. As DNA fragments are frequently found both inside cells and in the extracellular environment, such as the serum of patients with cancer or other degenerative disorders, we propose that SFDA may be a common mechanism for DNA amplification in cancer cells, as well as a more general cause of DNA copy number variation in nature.
Imaging axonal transport in the rat visual pathway

A technique was developed for assaying axonal transport in retinal ganglion cells using 2 µl injections of 1% cholera toxin b-subunit conjugated to AlexaFluor488 (CTB). In vivo retinal and post-mortem brain imaging by confocal scanning laser ophthalmoscopy and post-mortem microscopy were performed. The transport of CTB was sensitive to colchicine, which disrupts axonal microtubules. The bulk rates of transport were determined to be approximately 80–90 mm/day (anterograde) and 160 mm/day (retrograde). Results demonstrate that axonal transport of CTB can be monitored in vivo in the rodent anterior visual pathway, is dependent on intact microtubules, and occurs by active transport mechanisms.
Impact of sperm DNA fragmentation on clinical in vitro fertilization outcomes

Objective We studied the association between sperm DNA fragmentation (SDF) and several clinical in vitro fertilization outcomes. Methods We retrospectively analyzed 169 consecutive fresh IVF cycles. Semen was collected on the day of oocyte retrieval, and we assessed standard semen parameters and the SDF level (by terminal deoxynucleotidyl transferase dUTP nick-end labeling). Poor ovarian response (POR) was defined as the collection of three or fewer mature oocytes. Oocytes were inseminated by the conventional method or intracytoplasmic sperm injection. Results SDF did not affect the fertilization or pregnancy rate, but did have a significant effect on the miscarriage rate. In the miscarriage group (n=10), the SDF level was significantly higher (23.9% vs. 14.1%) and number of mature oocytes was significantly lower (4.3 vs. 7.6) than in the live birth group (n=45). Multiple regression analysis showed that SDF was an independent predictor of miscarriage (odds ratio, 1.051; 95% confidence interval, 1.001–1.104). The cutoffs for the SDF level and number of mature oocytes that could predict miscarriage were >13% and ≤3, respectively. In the low-SDF group (≤13%), the miscarriage rate was similar in POR patients and those with a normal ovarian response (NOR; 14.2% vs. 4.3%). In the high-SDF group (>13%), the miscarriage rate was significantly higher in the POR group than in the NOR group (60.0% vs. 13.3%, p=0.045). Conclusion Our study demonstrated that a high SDF level (>13%) was associated with a high miscarriage rate, and that it mainly contributed to miscarriage in the POR group. The results suggest that SDF measurements should be considered in couples with POR in order to predict the prognosis of the pregnancy.
P53 codon 11, 72, and 248 gene polymorphisms in endometriosis

Objective: Mutated p53 gene is related to the instability of cell growth and cell cycle progression. We aimed to evaluate the association between endometriosis and p53 codon 11, 72 and 248 gene polymorphisms. Patients and methods: Women were divided into two groups: (1) moderate/severe endometriosis (n=148), and (2) non-endometriosis groups (n=150). P53 gene polymorphisms include codon11 Glu/Gln or Lys (GAG->CAG or AAG), codon 72 Arg/Pro (CGC->CCC), and codon 248 Arg/Thr (CGG->TCG). These gene polymorphisms were amplified by polymerase chain reaction and detected by electrophoresis after restriction enzyme (Taq I, BstU I, Hap II) digestions. Associations between the endometriosis and p53 polymorphisms were evaluated. Results: The distributions of p53 codon 72 polymorphisms in both groups were significantly different. The proportions of Arg homozygotes/heterozygotes/Pro homozygotes in both groups were 9.5/66.2/24.3% and 30.7/50/19.3%. The proportions of Arg/Pro alleles were 42.6/57.4% and 56/44%. The distributions of p53 codon 11 and 248 polymorphisms in both groups were non-significantly different. All individuals appeared the wild genotypes (Glu11 and Arg248 homozygotes). Conclusion: Association between endometriosis and p53 codon 72 polymorphism exists. P53 codon 72*Pro-related genotype and allele are related with higher susceptibility of endometriosis. P53 codon 11 and 248 polymorphisms are not related with endometriosis susceptibility.
Three-Dimensional Optoacoustic and Laser-Induced Ultrasound Tomography System for Preclinical Research in Mice

In this work, we introduce a novel three-dimensional imaging system for in vivo high-resolution anatomical and functional whole-body visualization of small animal models developed for preclinical and other type of biomedical research. The system (LOUIS-3DM) combines a multiwavelength optoacoustic tomography (OAT) and laser-induced ultrasound tomography (LUT) to obtain coregistered maps of tissue optical absorption and speed of sound, displayed within the skin outline of the studied animal. The most promising applications of the LOUIS-3DM include 3D angiography, cancer research, and longitudinal studies of biological distributions of optoacoustic contrast agents.
Streaming Updates for Heart Rate Variability Algorithms

Heart rate variability (HRV) quantifies the fluctuations of the lengths of consecutive heart beat intervals, and is a reliable descriptor of many physiological factors modulating the normal rhythm of the heart. As the heart rate signal is nonstationary, indicators deduced from it may be present at all times, but may also occur episodically at nonpredetermined time instances. The potential for real-time feedback long-term ambulatory recordings is thus apparent. Numerous methods for measuring HRV have been standardized and are in active use, but are typically not designed to operate at real time. In this paper, we study the most popular HRV quantification methods and propose streaming algorithms that maximally utilize previously computed information without altering the output of the methods. We demonstrate speedups of more than two orders of magnitude for typical use-case scenarios. Using our algorithms on embedded systems that compute HRV leads to dramatic decreases in power consumption and in some cases allows for computation of metrics that were not previously possible at real time.
Cellular and molecular basis of cerebellar development

Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function.
Wide and ultra-wide bandgap oxides: where paradigm-shift photovoltaics meets transparent power electronics

Oxides represent the largest family of wide bandgap (WBG) semiconductors and also offer a huge potential range of complementary magnetic and electronic properties, such as ferromagnetism, ferroelectricity, antiferroelectricity and high-temperature superconductivity. Here, we review our integration of WBG and ultra WBG semiconductor oxides into different solar cells architectures where they have the role of transparent conductive electrodes and/or barriers bringing unique functionalities into the structure such above bandgap voltages or switchable interfaces. We also give an overview of the state-of-the-art and perspectives for the emerging semiconductor β- Ga2O3, which is widely forecast to herald the next generation of power electronic converters because of the combination of an UWBG with the capacity to conduct electricity. This opens unprecedented possibilities for the monolithic integration in solar cells of both self-powered logic and power electronics functionalities. Therefore, WBG and UWBG oxides have enormous promise to become key enabling technologies for the zero emissions smart integration of the internet of things.
Phantom limb pain: treatment strategies.

421 ISSN 1758-1869 10.2217/PMT.13. 51 © 2013 Future Medicine Ltd Pain Manage. (2013) 3(6), 421–424 Phantom pain following limb amputation represents a challenge for medical science. Recent wars in Afghanistan and Iraq, combined with civil wars in Syria and other nations, have led to an increase in the number of traumatic limb amputations being carried out on otherwise healthy people. In addition to this, it has been estimated that the number of amputees in the USA will double by the year 2050 to 3.6 million [1]. In western countries few amputations are performed as a result of trauma, the majority occur in elderly patients with vascular disease and a comorbid diagnosis of diabetes mellitus. However, whether the cause is traumatic or medical, amputations are an increasingly prevalent part of the clinician’s reality, and it is for this reason that the problem of phantom limb pain should not be overlooked. Regardless of the reason for amputation, the prevalence of phantom limb pain is reported to be as high as 85%. In most amputees, the frequency and intensity of pain attacks decrease over the years; however, approximately 5–10% of amputees continue to have severe, intractable and disabling phantom limb pain for many years after an amputation [2,3]. Unfortunately, the current treatment available for chronic phantom limb pain is far from satisfactory, and this represents a major challenge for the clinician. There is little evidence from randomized controlled trials to guide clinicians with treatment, and many studies are hindered by major methodological limitations [4]. The current editorial will include a brief discussion of preventive measures, but its primary focus will be on the treatment of phantom limb pain. The opinions expressed in the editorial are based on evidence where available and supported by the authors’ own research on phantom limb pain and their daily practice as pain clinicians. Although only partly supported by the literature, it seems that an effective analgesic treatment of early postoperative stump pain may delay the onset of phantom pain, or at least temporarily decrease its severity. At Aarhus University Hospital (Denmark), epidural or peripheral regional blocks are used, and these are most often
The impact of venous occlusion per se on forearm muscle blood flow: implications for the near‐infrared spectroscopy venous occlusion technique

The purpose of this study was to examine the effect of venous occlusion per se on forearm muscle blood flow, as determined by the near‐infrared spectroscopy (NIRS) venous occlusion technique (NIRS‐VOT). NIRS data were obtained from the flexor digitorum superficialis (FDS) muscle on the dominant arm of 16 young, ostensibly healthy participants (14 men and two women; 30 ± 6 year; 73 ± 7 kg). Participants completed a series of five venous occlusion trials while seated at rest, and a series of 12 venous occlusion trials during a reactive hyperaemia induced by 5 min of forearm arterial occlusion. The NIRS‐VOT was used to assess FDS muscle blood flow ( Q˙mus ), beat‐by‐beat, over the first four cardiac beats during venous occlusions. Q˙mus was also reported as a cumulative value, wherein the first two, first three and first four cardiac beats were used to calculate muscle blood flow. We observed that Q˙mus was highest when calculated over the first cardiac beat during venous occlusions performed at rest and throughout reactive hyperaemia (P<0·05). Moreover, the inclusion of more than one cardiac beat in the calculation of Q˙mus underestimated muscle blood flows, irrespective of the prevailing level of arterial inflow. These findings support the idea that venous occlusion per se affects the measurement of Q˙mus via the NIRS‐VOT. Accordingly, it is recommended that Q˙mus is determined over the first cardiac beat when using the NIRS‐VOT to assess microvascular blood flow of human forearm muscles.
Melanoma-infiltrating dendritic cells

The infiltration of melanoma lesions by dendritic cells (DCs) has been suggested to play a tumorigenic role due to the capacity of DCs to induce tumor tolerance and promote angiogenesis as well as metastasis. However, it has also been shown that tumor-infiltrating DCs (TIDCs) induce antitumor responses and hence may be targeted in cost-effective therapeutic approaches to obtain patient-specific DCs that present relevant tumor antigens, without the need for ex vivo DC expansion or tumor antigen identification. Unfortunately, little is known about the composition, nature and function of TIDCs found in human melanoma. The development of mouse melanoma models has greatly contributed to the molecular understanding of melanoma immunology in mice, but many questions on TIDCs remain unanswered. Here, we discuss current knowledge about melanoma TIDCs in various mouse models with regard to their translational potential and clinical relevance.
Adjuvant aromatase inhibitors

In 1998, the Early Breast Cancer Trialists’ Collaborative Group reported that 5 years of adjuvant tamoxifen therapy yielded a proportional reduction of 26% in mortality over 10 years in women whose breast malignancies had positive or unknown estrogen receptor (ER) status. Because most breast malignancies are ER-positive, this finding had the potential to lead to a substantial decrease in death due to malignant disease. Between 1987 and 1997, there was a decline in breast carcinoma mortality (with no accompanying decrease in incidence) in both the United States and the United Kingdom. A number of interventions probably contributed to this decline, but one likely factor is the widespread use of tamoxifen in the adjuvant setting. Improved hormonal therapies in the adjuvant setting are a promising avenue for further reduction of breast cancer mortality. Randomized trials comparing newer-generation aromatase inhibitors with tamoxifen in the treatment of metastatic disease as well as in preoperative therapy have shown the newer inhibitors to be well tolerated and either as effective as or more effective than tamoxifen. Aromatase inhibitors already are widely used as first-line therapy for metastatic disease in postmenopausal women with hormone receptor–positive tumors. Therefore, there is widespread optimism over the possibility that adjuvant use of these agents could produce survival benefits greater than those generated by tamoxifen. The first reported trial comparing an aromatase inhibitor with tamoxifen in the adjuvant setting was the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial, in which 9366 women were randomized to 5 years of therapy with either tamoxifen 20 mg per day, anastrozole (Arimidex; AstraZeneca, Wilmington, DE) 1 mg per day, or both agents together. The initial findings, published in June 2002, with a median follow-up period of 33 months, indicated that the results of combination therapy were not significantly different from those observed with single-agent tamoxifen, and so the combination arm was discontinued. Nonetheless, the use of single-agent anastrozole yielded a significant disease-free survival (DFS) advantage relative to tamoxifen (hazard ratio [HR], 0.83; P 0.013). There was no overall difference in survival, with identical numbers of deaths after recurrence in both monotherapy groups (n 122). In August 2002, the American Society of Clinical Oncology (ASCO) Technology Assessment Working Group published its unanimous conclusion that the findings of the ATAC trial were preliminary results and that a 5-year tamoxifen regimen still should be considered the standard adjuvant 1779
Dyad of CD40/CD40 Ligand Fosters Neuroinflammation at the Blood–Brain Barrier and Is Regulated via JNK Signaling: Implications for HIV-1 Encephalitis

Human immunodeficiency virus 1 (HIV-1) infection may result in activation of peripheral monocytes followed by their infiltration into the CNS, where the release of proinflammatory mediators causes neurologic disease. Previously, we detected high levels of soluble CD40 ligand (CD40L) in CSF and plasma of HIV-infected patients with cognitive impairment. We now show that CD40, a receptor for CD40L, is highly expressed in brain endothelial cells of patients affected by HIV-1 encephalitis (HIVE), suggesting an important role for the CD40/CD40L dyad in regulating blood–brain barrier (BBB) functions. This concept was further supported by in vitro experiments. Exposure of primary human brain microvascular endothelial cells (BMVECs) to CD40L upregulated the expression of adhesion molecules intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, which caused a fourfold increase in monocyte adhesion to BMVECs and stimulated migration across an in vitro BBB model. Investigations into the intracellular signaling pathways that govern these events revealed that cJUN-N-terminal kinase (JNK) is critical to CD40 activation in the BMVECs. CD40L induced activation of mixed-lineage-kinase-3 and JNK, leading to the subsequent activation of cJUN/AP-1 (activating-protein-1). JNK inhibition in the BMVECs prevented CD40L-mediated induction of adhesion molecules, monocyte adhesion, and transendothelial migration. These new findings support the concept that the CD40/CD40L dyad plays an important role in HIVE neuroinflammation.
Mesenchymal Progenitors Expressing TRAIL Induce Apoptosis in Sarcomas

Sarcomas are frequent tumors in children and young adults that, despite a relative chemo‐sensitivity, show high relapse rates with up to 80% of metastatic patients dying in 5 years from diagnosis. The real ontogeny of sarcomas is still debated and evidences suggest they may derive from precursors identified within mesenchymal stromal/stem cells (MSC) fractions. Recent studies on sarcoma microenvironment additionally indicated that MSC could take active part in generation of a supportive stroma. Based on this knowledge, we conceived to use modified MSC to deliver tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) targeting different sarcoma histotypes. Gene modified MSC expressing TRAIL were cocultured with different osteosarcoma, rhabdomyosarcoma, and Ewing's Sarcoma (ES) cell lines assessing viability and caspase‐8 activation. An in vivo model focused on ES was then implemented considering the impact of MSC‐TRAIL on tumor size, apoptosis, and angiogenesis. MSC expressing TRAIL induced significantly high apoptosis in all tested lines. Sarcoma death was specifically associated with caspase‐8 activation starting from 8 hours of coculture with MSC‐TRAIL. When injected into pre‐established ES xenotransplants, MSC‐TRAIL persisted within its stroma, causing significant tumor apoptosis versus control groups. Additional histological and in vitro studies reveal that MSC‐TRAIL could also exert potent antiangiogenic functions. Our results suggest that MSC as TRAIL vehicles could open novel therapeutic opportunities for sarcoma by multiple mechanisms. Stem Cells 2015;33:859–869
Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions

Objective Helicobacter pylori infection and overexpression of cyclo-oxygenase-2 (COX-2) are associated with gastric cancer and its precursors. To evaluate the effect of a selective COX-2 inhibitor alone and combined with H pylori eradication on the evolution of precancerous gastric lesions, a randomised, placebo-controlled trial was conducted in Linqu County, Shandong Province, China. Methods A total of 1024 participants aged 35–64 years with H pylori infection and advanced gastric lesions were randomly assigned in a factorial design to two interventions or placebo: anti-H pylori treatment for 7 days, and a COX-2 inhibitor (celecoxib) for 24 months. The effects of the interventions were evaluated by the regression or progression of advanced gastric lesions. Results Of the 1024 participants who received anti-H pylori treatment or placebo, 919 completed a subsequent 24-month treatment with celecoxib or placebo. The H pylori eradication rate by per-protocol analysis was 78.2%. Compared with placebo, the proportions of regression of gastric lesions significantly increased in the celecoxib treatment (52.8% vs 41.2%) and anti-H pylori treatment (59.3% vs 41.2%) group, and OR by per-protocol analysis was 1.72 (95% CI 1.07 to 2.76) for celecoxib and 2.19 (95% CI 1.32 to 3.64) for H pylori eradication. No statistically significant effect was found for H pylori eradication followed by celecoxib on the regression of advanced gastric lesions (OR 1.48, 95% CI 0.91 to 2.40). Conclusion This population-based intervention trial revealed that celecoxib treatment or H pylori eradication alone had beneficial effects on the regression of advanced gastric lesions. No favourable effects were seen for H pylori eradication followed by celecoxib treatment. Trial registration HARECCTR0500053 in accordance with WHO ICTRP requirements.