gebhart/patrepeval huggingface dataset:
The magical touch: Genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin (1999)

Gene knockout technology has provided a powerful tool for functional analyses of genes expressed preferentially in a particular tissue. Given marked similarities between human and mouse skin, such studies with epidermally expressed genes have often provided valuable insights into human genetic skin disorders. Efficient silencing of a specified gene in a temporally regulated and epidermal-specific fashion could extend functional analyses to broadly expressed genes and increase the categories of human skin disorders to which parallels could be drawn. We have generated transgenic mice expressing Cre and a fusion protein between Cre recombinase and the tamoxifen responsive hormone-binding domain of the estrogen receptor (CreER(tam)) under the control of the human keratin 14 (K14) promoter. This promoter is strongly active in dividing cells of epidermis and some other stratified squamous epithelia. With K14-Cre, transgenic embryos recombine genetically introduced loxP sequences efficiently and selectively in the genomes of keratinocytes that reside in embryonic day 14.5 skin, tongue, and esophagus. With K14-CreER(tam), postnatal transgenic mice show no Cre activity until tamoxifen is administered. If orally administered, tamoxifen activates keratinocyte-specific CreER(tam), allowing recombination of loxP sequences in epidermis, tongue, and esophagus. If topically administered, tamoxifen allows recombination in the area of skin where tamoxifen was applied. Finally, we show that epidermal cells harboring a Cre-dependent rearranged genome persist for many months after tamoxifen application, indicating that the epidermal stem cell population has been targeted efficiently. These tools now pave the way for testing the functional role of different somatic mutations that may exist in mosaic disorders of the skin, including squamous and basal cell carcinomas.
High-Adiabat High-Foot Inertial Confinement Fusion Implosion Experiments on the National Ignition Facility (2014)

This Letter reports on a series of high-adiabat implosions of cryogenic layered deuterium-tritium (DT) capsules indirectly driven by a "high-foot" laser drive pulse at the National Ignition Facility. High-foot implosions have high ablation velocities and large density gradient scale lengths and are more resistant to ablation-front Rayleigh-Taylor instability induced mixing of ablator material into the DT hot spot. Indeed, the observed hot spot mix in these implosions was low and the measured neutron yields were typically 50% (or higher) of the yields predicted by simulation. On one high performing shot (N130812), 1.7 MJ of laser energy at a peak power of 350 TW was used to obtain a peak hohlraum radiation temperature of ∼300 eV. The resulting experimental neutron yield was (2.4±0.05)×10(15) DT, the fuel ρR was (0.86±0.063) g/cm2, and the measured Tion was (4.2±0.16) keV, corresponding to 8 kJ of fusion yield, with ∼1/3 of the yield caused by self-heating of the fuel by α particles emitted in the initial reactions. The generalized Lawson criteria, an ignition metric, was 0.43 and the neutron yield was ∼70% of the value predicted by simulations that include α-particle self-heating.
APOLIPOPROTEIN E GENOTYPE AND OUTCOME IN ANEURYSMAL SUBARACHNOID HAEMORRHAGE (2001)

Background: Active management of ruptured intracranial aneurysm in subarachnoid haemorrhage is commonly reserved for patient with favourable prognosis. Current clinical grading scales on outcome prediction are imprecise with low inter‐observer reproducibility. We designed a prospective clinical study on the association between Apolipoprotein E genotype and the outcome of patients with subarachnoid haemorrhage. Method: We conducted a prospective study on patients with spontaneous subarachnoid haemorrhage admitted to our unit during a 2 years period. All patients were managed under a standard protocol. Patient’s characteristics, clinical grade, radiological grade and Apolipoprotein E genotype were documented. We focused on the 6 months neurological outcome for this group of patients after discharged. Results: 72 patients with subarachnoid haemorrhage were recruited into the study. Unfavourable outcome was found with increasing age (62.2 years ± 17.2 vs. 55.7 years ± 12.9; P = 0.07; odds ratio, 1.03; 95 percent confidence interval, 1.00 to 1.07), poor Fisher’s grades (86 percent vs. 58 percent; P = 0.015; odds ratio, 4.50; 95 percent confidence interval, 1.33 to 15.20) and poor WFNS grades (48 percent vs. 14 percent; P = 0.002; odds ratio, 5.76; 95 percent confidence interval, 1.86 to 17.80). A higher distribution of Apolipoprotein E ɛ4 was found amongst those had unfavourable outcome (38 percent vs. 9 percent; P = 0.006; odds ratio, 5.96; 95 percent confidence interval, 1.67 to 21.29). Apolipoprotein E ɛ4 remains to be an independent outcome‐predicting factor (P = 0.003) after adjusted with age, WFNS grading, and Fisher’s grading. Conclusions: Apolipoprotein E ɛ4 was found to be associated with an unfavourable outcome in patients with aneurysmal subarachnoid haemorrhage.
Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. (1994)

The growth-controlling functions of the adenovirus E1A oncoprotein depend on its ability ot interact with a set of cellular proteins. Among these are the retinoblastoma protein, p107, p130, and p300. We have isolated a cDNA encoding full-length human p300 and mapped the chromosomal location of the gene to chromosome 22q13. p300 contains three cysteine- and histidine-rich regions of which the most carboxy-terminal region interacts specifically with E1A. In its center, p300 contains a bromodomain, a hallmark of certain transcriptional coactivators. We have examined the ability of p300 to overcome the repressive effect of E1A on the SV40 enhancer. We show that p300 molecules lacking an intact E1A-binding site can bypass E1A repression and restore to a significant extent the activity of the SV40 enhancer, even in the presence of high levels of E1A protein. These results imply that p300 may function as a transcriptional adaptor protein for certain complex transcriptional regulatory elements.
Senescence Induced by Altered Telomere State, Not Telomere Loss (2002)

Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.
Mechanism of action of the papillomavirus E2 repressor: repression in the absence of DNA binding (1992)

Repression of papillomavirus E2-dependent gene expression was studied by using transient transfections into mouse embryo fibroblast cells. Cotransfection of a gene corresponding to the naturally occurring repressor E2-TR along with the full-length E2 gene resulted in up to 98% repression of E2-dependent reporter gene expression. A series of E2 DNA-binding domain mutants were transferred into the E2-TR form and characterized for their ability to repress E2-dependent transactivation. All mutants which were defective for DNA binding but were dimerization competent repressed E2 transactivation as well or nearly as well as the wild-type repressor. E2 mutants which lacked dimerization activity repressed transactivation poorly or not at all. These results indicate that the E2 repressor can inhibit transcription, in the absence of DNA binding, by forming heterodimers with full-length E2.
Glioma IL13Rα2 Is Associated with Mesenchymal Signature Gene Expression and Poor Patient Prognosis (2013)

A major challenge for successful immunotherapy against glioma is the identification and characterization of validated targets. We have taken a bioinformatics approach towards understanding the biological context of IL-13 receptor α2 (IL13Rα2) expression in brain tumors, and its functional significance for patient survival. Querying multiple gene expression databases, we show that IL13Rα2 expression increases with glioma malignancy grade, and expression for high-grade tumors is bimodal, with approximately 58% of WHO grade IV gliomas over-expressing this receptor. By several measures, IL13Rα2 expression in patient samples and low-passage primary glioma lines most consistently correlates with the expression of signature genes defining mesenchymal subclass tumors and negatively correlates with proneural signature genes as defined by two studies. Positive associations were also noted with proliferative signature genes, whereas no consistent associations were found with either classical or neural signature genes. Probing the potential functional consequences of this mesenchymal association through IPA analysis suggests that IL13Rα2 expression is associated with activation of proinflammatory and immune pathways characteristic of mesenchymal subclass tumors. In addition, survival analyses indicate that IL13Rα2 over-expression is associated with poor patient prognosis, a single gene correlation ranking IL13Rα2 in the top ~1% of total gene expression probes with regard to survival association with WHO IV gliomas. This study better defines the functional consequences of IL13Rα2 expression by demonstrating association with mesenchymal signature gene expression and poor patient prognosis. It thus highlights the utility of IL13Rα2 as a therapeutic target, and helps define patient populations most likely to respond to immunotherapy in present and future clinical trials.
Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin (2015)

The capacity for tissues to repair and regenerate diminishes with age. We sought to determine the age-dependent contribution of native mesenchymal cells and circulating factors on in vivo bone repair. Here we show that exposure to youthful circulation by heterochronic parabiosis reverses the aged fracture repair phenotype and the diminished osteoblastic differentiation capacity of old animals. This rejuvenation effect is recapitulated by engraftment of young haematopoietic cells into old animals. During rejuvenation, β-catenin signalling, a pathway important in osteoblast differentiation, is modulated in the early repair process and required for rejuvenation of the aged phenotype. Temporal reduction of β-catenin signalling during early fracture repair improves bone healing in old mice. Our data indicate that young haematopoietic cells have the capacity to rejuvenate bone repair and this is mediated at least in part through β-catenin, raising the possibility that agents that modulate β-catenin can improve the pace or quality of fracture repair in the ageing population.
징벌적 손해배상제도의 개선방안에 관한 고찰 (2018)

본 서에서는 징벌적 손해배상제도의 활성화의 필요성을 확인하고 그것을 전제로 현행징벌적 손해배상제도를 검토한 결과, 입증책임과 손해배상액 한도의 문제를 확인하였다. 이를 토대로 제안한 개선방안은 다음과 같다. 첫째, 입증책임을 완화할 필요가 있다. 최근 시행된 개정 제조물책임법으로 예를 들자면, 피해자가 제조업자의 부작위까지 입증하도록 과도한 입증책임을...
Mouse‐Human Chimeric Antibody MH171 against the Multidrug Transporter P‐Glycoprotein (1992)

We have developed a mouse-human chimeric antibody MH171, in which the antigen-recognizing variable regions of the mouse monoclonal antibody MRK17 are joined with the constant regions of human IgG1 antibodies. The MRK17 recognizes specifically the multidrug transporter P-glycoprotein and inhibits the growth of human multidrug resistant (MDR) tumor cells in vitro and in the xenograft nude mouse model system. The established chimeric MH171 antibody forms an apparently intact IgG composed of heavy and light chains covalently assembled via disulfide bonds in sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis and is specific to MDR cell lines with a similar affinity to the original mouse MRK17. MH171 also displays strong antibody-dependent cell-mediated cytotoxicity to the target cells in vitro, when human mononuclear cells are used as effector cells. The chimeric antibody against P-glycoprotein, MH171, should be a useful agent in the treatment of human drug-resistant tumors.
Prediction of Impending Hemorrhagic Transformation in Ischemic Stroke Using Magnetic Resonance Imaging in Rats (1998)

Background and Purpose —Hemorrhagic transformation (HT) of ischemic brain tissue may occur in stroke patients either spontaneously or after thrombolysis. A method to assess the risk of HT in ischemic tissue after stroke would improve the safety of thrombolytic therapy. As a means of predicting HT, we investigated the role of contrast-enhanced MRI at acute time points in a rat middle cerebral artery occlusion model with reperfusion. Methods —Intraluminal suture occlusion of the middle cerebral artery was used to produce transient ischemia in male Wistar rats (n=11). Reperfusion was performed by withdrawal of the occluding filament after 2 (n=4), 3 (n=6), or 4 (n=1) hours. MRI studies were performed before and after reperfusion with the use of conventional T1-weighted imaging, with and without gadolinium (Gd-DTPA) contrast agent, and T2-weighted imaging. Follow-up MRI and histological studies were obtained at 24 hours. Results —Petechial hemorrhage occurred by 24 hours in 9 of 11 animals. All animals showed brain swelling and cellular death throughout the ischemic region at 24 hours. A hyperintense region in the preoptic area became visible after Gd-DTPA injection within minutes after reperfusion in animals with subsequent HT. All animals showing acute Gd-DTPA enhancement subsequently developed petechial hemorrhage (or died) by 24 hours. In these animals, statistically significant differences in signal intensity ( P =.0005) between the ipsilateral enhancing region and a homologous contralateral region were detected on post–Gd-DTPA T1-weighted imaging. There was also a statistically significant correlation ( P =.01) between the rate of Gd-DTPA uptake and the size of the enhancing area. Two animals did not enhance with Gd-DTPA and did not exhibit hemorrhage on histological examination or MRI at 24 hours. No abnormalities were seen on precontrast T1-weighted images before and shortly after reperfusion or postcontrast T1-weighted images before reperfusion. Conclusions —The primary finding of this study was the detection of early Gd-DTPA parenchymal enhancement in 82% of the animals after reperfusion. Enhancement was seen before any detectable hemorrhage, suggesting that early endothelial ischemic damage occurs before gross brain infarction and hemorrhage. Thus, we suggest that acute Gd-DTPA enhancement may provide an early prediction of petechial hemorrhage.
Airless Drying: Not just hot wave! (2005)

Drying is often a final unit operation in a chemical or manufacturing industry. Drying a solid means removing relatively small amounts of water or other liquids from the solid to reduce the residual liquid to an acceptably low value. Airless drying was invented by Thomas Stubbing
Immunotherapy in mantle cell lymphoma: Anti‐CD20‐based therapy and beyond (2007)

Mantle cell lymphoma (MCL), an aggressive non-Hodgkin's lymphoma characterized by t(11; 14)(q13; q32) chromosomal translocation and overexpression of cyclin D1, has the worst prognosis among all lymphomas. Recent advances in biology, genetics, and immunology have supported the development of immunotherapy in MCL. Rituximab monotherapy in MCL has limited activity. It is more effective when used in combination with chemotherapy such as R-CHOP, R-hyperCVAD/MTX-Ara-C, or R-FCM as front-line or salvage therapy for mantle cell lymphoma. Maintenance with Rituximab was shown to prolong response duration. Although most results have suggested that combining autologous stem cell transplantation with Rituximab may lead to durable remission, the sample size was not sufficient to declare survival benefit. Anti-CD20 radioimmunoconjugates (RICs) (90)Yttrium-ibritumomab tiuxetan and (131)Iodine-tositumomab have been used in mantle cell lymphoma even when patients are relatively resistant to Rituximab-based therapy. Allogeneic stem cell transplantation is a treatment modality in advanced or relapsed MCL, particularly using reduced-intensity conditioning. MCL may have high response rates and sustained remissions after donor lymphocyte infusion. Dendritic cells (DCs) fused with MCL cells for immunostimulation have preliminarily shown anti-lymphoma effects as well. Idiotype vaccination in MCL patients following Rituximab-containing chemotherapy induced tumor-specific T-cell immunity in the absence of B cells. Other immunotherapy, such as the combination of thalidomide with Rituximab, has shown substantial antitumor activity. A Phase I/II study is ongoing to determine the maximum tolerated dose (MTD) and the efficacy of lenalidomide in combination with Rituximab for relapsed/refractory MCL. This review summarizes the latest and exciting advances in MCL.
Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. (1995)

Alternative splicing of the human glucocorticoid receptor (hGR) pre-mRNA generates two highly homologous isoforms, termed hGR alpha and hGR beta. hGR alpha is a ligand-activated transcription factor which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes by binding to specific glucocorticoid response element (GRE) DNA sequences. In contrast, hGR beta does not bind glucocorticoids and is transcriptionally inactive. We demonstrate here that hGR beta is able to inhibit the effects of hormone-activated hGR alpha on a glucocorticoid-responsive reporter gene in a concentration-dependent manner. [3H]-Dexamethasone binding studies indicate that hGR beta does not alter the affinity of hGR alpha for its hormonal ligand. The presence of hGR beta in nuclear extracts and its ability to bind to a radiolabeled GRE oligonucleotide suggest that its inhibitory effect may be due to competition for GRE target sites. Reverse transcription-PCR analysis shows expression of hGR beta mRNA in multiple human tissues. These results indicate that hGR beta may be a physiologically and pathophysiologically relevant endogenous inhibitor of glucocorticoid action, which may participate in defining the sensitivity of target tissues to glucocorticoids. They also underline the importance of distinguishing between the two receptor isoforms in all future studies of hGR function and the need to revisit old data.
Self-powered electronic skin (2020)

Engineering
New technologies are transforming the way humans and machines interact. Zhao et al. developed a self-powered artificial skin capable of simultaneously converting touch stimuli into electrical signals and visible light in real time. The electrical signals can be used to drive an interactive touch operation platform for easy and intuitive control of consumer electronic devices. Electroluminescent signals provide instant visual feedback to the pressure input. The device uses the triboelectric effect to generate the electrical current, and part of the generated current produces light by exciting embedded luminescence centers. Such surface coverings can operate without an external power supply, which is important for portable or wearable electronics.

Sci. Adv. 10.1126/sciadv.aba4294 (2020).
Characterization and Expression of HmuR, a TonB-Dependent Hemoglobin Receptor of Porphyromonas gingivalis (2000)

The gram-negative pathogen Porphyromonas gingivalis requires hemin for growth. Hemoglobin bound to haptoglobin and hemin complexed to hemopexin can be used as heme sources, indicating that P. gingivalis must have a means to remove the hemin from these host iron-binding proteins. However, the specific mechanisms utilized by P. gingivalis for the extraction of heme from heme-binding proteins and for iron transport are poorly understood. In this study we have determined that a newly identified TonB-dependent hemoglobin-hemin receptor (HmuR) is involved in hemoglobin binding and utilization in P. gingivalis A7436. HmuR shares amino acid homology with TonB-dependent outer membrane receptors of gram-negative bacteria involved in the acquisition of iron from hemin and hemoglobin, including HemR of Yersinia enterocolitica, ShuA of Shigella dysenteriae, HpuB of Neisseria gonorrhoeae and N. meningitidis, HmbR of N. meningitidis, HgbA of Haemophilus ducreyi, and HgpB of H. influenzae. Southern blot analysis confirmed the presence of the hmuR gene and revealed genetic variability in the carboxy terminus of hmuR in P. gingivalis strains 33277, 381, W50, and 53977. We also identified directly upstream of the hmuR gene a gene which we designated hmuY. Upstream of the hmuY start codon, a region with homology to the Fur binding consensus sequence was identified. Reverse transcription-PCR analysis revealed that hmuR and hmuY were cotranscribed and that transcription was negatively regulated by iron. Inactivation of hmuR resulted in a decreased ability of P. gingivalis to bind hemoglobin and to grow with hemoglobin or hemin as sole iron sources. Escherichia coli cells expressing recombinant HmuR were shown to bind hemoglobin and hemin. Furthermore, purified recombinant HmuR was demonstrated to bind hemoglobin. Taken together, these results indicate that HmuR serves as the major TonB-dependent outer membrane receptor involved in the utilization of both hemin and hemoglobin in P. gingivalis.
Antisense Therapeutics: A Promise Waiting to Be Fulfilled (2004)

During the past decade, only one antisense-based therapy has received full Food and Drug Administration (FDA) approval. Vitravene™, developed by Isis Pharmaceuticals, was the first drug based on antisense technology to be successfully commercialized and used in treatment (1). The therapeutic area it is used in is a small niche related to the treatment of preventing blindness in acquired immunodeficiency syndrome (AIDS) patients by inhibiting cytome-galovirus-induced retinitis. The success of Vitravene, however, showed that antisense could be taken all the way through the FDA approval process and provide those patients taking it with a vitally important effect. With Vitravene we saw the first breakthrough in antisense therapy, and, yet, euphoria has turned to disappointment without a second breakthrough. Subsequent trials of Affinitak (Isis), an antisense inhibitor of protein kinase C α, failed to show statistically significant benefits as an antisense therapy for the treatment of non-small cell carcinoma of the lung better than the median survival with control treatments. The results nevertheless proved that antisense was well tolerated and tended toward greater benefit to the survival of patients (p<0.054). The promise of antisense therapy is so attractive that some 20 trials continue.