gebhart/patrepeval huggingface dataset:
Outer Membrane Vesicle Production by Escherichia coli Is Independent of Membrane Instability (2006)

It has been long noted that gram-negative bacteria produce outer membrane vesicles, and recent data demonstrate that vesicles released by pathogenic strains can transmit virulence factors to host cells. However, the mechanism of vesicle release has remained undetermined. This genetic study addresses whether these structures are merely a result of membrane instability or are formed by a more directed process. To elucidate the regulatory mechanisms and physiological basis of vesiculation, we conducted a screen in Escherichia coli to identify gene disruptions that caused vesicle over- or underproduction. Only a few low-vesiculation mutants and no null mutants were recovered, suggesting that vesiculation may be a fundamental characteristic of gram-negative bacterial growth. Gene disruptions were identified that caused differences in vesicle production ranging from a 5-fold decrease to a 200-fold increase relative to wild-type levels. These disruptions included loci governing outer membrane components and peptidoglycan synthesis as well as the sigma(E) cell envelope stress response. Mutations causing vesicle overproduction did not result in upregulation of the ompC gene encoding a major outer membrane protein. Detergent sensitivity, leakiness, and growth characteristics of the novel vesiculation mutant strains did not correlate with vesiculation levels, demonstrating that vesicle production is not predictive of envelope instability.
De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders (2006)

There is immediate potential to enhance success and innovation in drug development by pairing newly emerging approaches in medicinal chemistry and computational biology with knowledge gained from the recent era of high throughput screens and the early years of modern drug discovery when in vivo efficacy was an early "Go/No Go" project management decision. Focused, in-parallel synthetic chemistry platforms, combined with computational analyses serving as decision aids in planning, minimize the total number of compounds synthesized while maximizing the probability of creating bioavailable compounds that sample diverse chemical space. Incorporating a hierarchal strategy that emphasizes early selection of synthesized compounds based on biological or biophysical endpoints presents fewer and more relevant compounds for secondary evaluation of in vivo efficacy using animal screens with disease relevant or clinically translatable endpoints. We summarize here an interdisciplinary approach at the chemistry-biology interface that is used for the rapid discovery of novel lead compounds for neurodegenerative disorders, such as Alzheimer's disease (AD). The chemistry platform uses established chemistries amenable to in-parallel strategies to create synthetic diversifications of the privileged pyridazine chemotype that sample a restricted chemical space. The hierarchal biology platform uses primary screens for in vitro activity and selectivity with the target cell type, and rapid secondary screens for in vivo efficacy and toxicity in animal models with good phenotypic penetrance for disease relevant pathophysiological endpoints or clinically translatable surrogate endpoints. For the AD case study, novel lead compounds were developed in less than two years by a small academic group, and corporate sponsored clinical trials are planned.
19世纪的音乐革命者：柏辽兹、李斯特和瓦格纳 (2003)

我们现在跳到1930年,就是巴黎7月革命的那一年.这样,我们也因此越过了导致形成音乐技巧大提高、不朽之作辈出的几个辉煌时期.正因为有了这几个时期,人们在今天才把国际化了的欧洲音乐与巴赫、亨德尔、莫扎特、海顿、贝多芬和舒伯特的名字联系在了一起.
Characterization of Aspergillus nidulans mutants deficient in cell wall chitin or glucan (1992)

By screening for the osmotically remediable phenotype, mutations in two genes (orlA and orlB) affecting the cell wall chitin content of Aspergillus nidulans were identified. Strains carrying temperature-sensitive alleles of these genes produce conidia which swell excessively and lyse when germinated at restrictive temperatures. Growth under these conditions is remedied by osmotic stabilizers and by N-acetylglucosamine (GlcNAc). Remediation by GlcNAc suggests that the mutations affect early steps in the synthesis of chitin. Temperature and medium shift experiments indicate that the phenotype is the result of decreased synthesis rather than increased chitin degradation and that osmotic stabilizers act to stabilize a defective wall rather than to stabilize the gene product. Two genes, orlC and orlD, which affect cell wall beta-1,3-glucan content were also identified. Walls from strains carrying mutations in these genes exhibit normal amounts of alpha-1,3-glucan and chitin but reduced amounts of beta-1,3-glucan. As for the chitin-deficient mutants, orlC and orlD mutants spontaneously lyse on conventional media but are remedied by osmotic stabilizers. These results indicate that both chitin and beta-1,3-glucan are likely to contribute to the structural rigidity of the cell wall.
Current asthma and respiratory symptoms among pupils in relation to dietary factors and allergens in the school environment (2005)

Previous school studies performed by us in mid-Sweden, showed that most classrooms did not fulfill the ventilation standards. In this study, most of the classrooms fulfilled the ventilation standard, but despite that had widespread allergen contamination. Most previous studies have focused on cat allergen, but our study has shown that also dog and horse allergens can be risk factors for asthma and allergy in schools. As allergens are transported from other environments, mainly the home environment, the main prevention should be to minimize transfer of allergens. This could be achieved by reducing contacts with furry pets and horses, or using different clothes at home and at school (e.g. school uniforms). Increased cleaning in the schools may reduce allergen levels, but the efficiency of this measure must be evaluated in further intervention studies. Finally, our study supports the view that dietary habits among pupils should not be neglected and interaction between dietary factors and indoor allergen exposure needs to be further investigated.
The hidden therapist: evidence for a central role of music in psychedelic therapy (2018)

This study indicates that music plays a central therapeutic function in psychedelic therapy.
Steroid 5alpha-reductase in cultured human fibroblasts. Biochemical and genetic evidence for two distinct enzyme activities. (1976)

<P>Abstract copyright UK Data Service and data collection copyright owner.</P> The&nbsp;<em>Community Life Survey</em>&nbsp;(CLS) is a household survey conducted in England, tracking the latest trends and developments across areas key to encouraging social action and empowering communities, including: volunteering and charitable giving; views about the local area; community cohesion and belonging; community empowerment and participation; influencing local decisions and affairs; and subjective well-being and loneliness. The CLS was first commissioned by the Cabinet Office in 2012. From 2016-17, the Department for Digital, Culture, Media and Sport (DCMS) took over responsibility for publishing results. During 2020, the DCMS also commissioned the<span style="font-style: italic;">&nbsp;Community Life COVID-19 Re-contact Survey</span>&nbsp;(CLRS) (SN 8781) to provide data on how the COVID-19 pandemic has affected volunteering, charitable giving, social cohesion, wellbeing and loneliness in England.<br><br>For the 2023-24 and 2024-25 survey years, DCMS partnered with the Ministry of Housing, Communities and Local Government (MHCLG) to boost the CLS to be able to produce meaningful estimates at Local Authority level. This has enabled data collection at the most granular level since data collection commenced. The questionnaire for 2023-24 was developed collaboratively to adapt to the needs and interests of both DCMS and MHCLG, including some new questions and changes to existing questions, response options and definitions in the 2023-24 and upcoming 2024-25 surveys.<br><br><span style="font-style: italic;">Background<br></span>Up to 2015-16, the survey used a face-to-face methodology. Following thorough testing (experimental online versions of the survey were released for 2013-14, 2014-15 and 2015-16), the CLS moved online from 2016-17 onwards, with an end to the previous face-to-face method. The survey uses a push-to-web methodology (with paper mode for those who are not digitally engaged). The survey informs and directs policy and action in these areas; <ul><li>to provide data of value to all users, including public bodies, external stakeholders and the public; and</li><li>underpin further research and debate on building stronger communities.</li></ul> The CLS incorporates a small number of priority measures from the&nbsp;<span style="font-style: italic;">Citizenship Survey</span>, which ran from 2001-2011, conducted by the then Department for Communities and Local Government. These measures were incorporated in the CLS so that trends in these issues could continue to be tracked over time. (The full&nbsp;<span style="font-style: italic;">Citizenship Survey</span>&nbsp;series is held at the UK Data Archive under GNs 33347 and 33474.) Further information may be found on the GOV.UK&nbsp;<a title="Community Life Survey" href="https://www.gov.uk/government/collections/community-life-survey">Community Life Survey</a>&nbsp;webpage.<br>
Angiogenesis and its inhibitors. (1985)

The hypothesis that solid tumors are angiogenesis-dependent has, in the past decade, generated much new work aimed at understanding the mechanism of angiogenesis itself. Many laboratories in this country and abroad are now studying some aspect of this intriguing problem. Some investigations are focused mainly on tumor angiogenesis, whereas others are centered on angiogenesis that occurs in physiologic situations or that dominates certain non-neoplastic pathologic states. These efforts have brought about [a] the development of bioassays for angiogenesis; [b] the partial purification (and in one case the complete purification) of angiogenic factors from neoplastic and non-neoplastic cells; [c] the development of new polymer technology for the sustained release of these factors and of other macromolecules in vivo; [d] the cloning and long-term culture of capillary endothelial cells; [e] the demonstration of the role of nonendothelial cells, such as mast cells, in modulating angiogenesis; [f] the discovery of angiogenesis inhibitors; and [g] the recent demonstration that certain animal tumors will undergo complete regression when treated by antiangiogenesis alone. The effects of angiogenesis inhibitors provide the most compelling evidence for the role of angiogenesis in tumor growth. That it is now possible not only to inhibit tumor growth but also to eradicate some experimental tumors speaks strongly for a therapeutic approach that may some day be useful in clinical oncology. Conceivably, the original goal to understand the role of angiogenesis in tumor growth will lead to the use of angiogenesis inhibitors in other non-neoplastic diseases.
MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells (2015)

Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing. In the present study, we have explored the biological function of MELK using MELK-T1, a novel and selective small-molecule inhibitor. Strikingly, MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELK-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (CHK2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold.
Effect of active immunization against luteinizing hormone‐releasing hormone on the androgen‐sensitive Dunning R3327‐PAP and androgen‐independent Dunning R3327‐AT2.1 prostate cancer sublines (1997)

BACKGROUND The objective of this study was to determine the effect of active immunization against LHRH on the growth characteristics and histology of subcutaneously implanted tumors of the androgen-sensitive Dunning R3327-PAP and androgen-independent R3327-AT2.1 rat prostate adenocarcinoma sublines. RESULTS We herein demonstrate that 1) active immunization with an LHRH-diphtheria toxoid-conjugate (LHRH-DT) leads to the downregulation of gonadotrophins and testosterone and consequently the atrophy of testosterone-dependent organs such as the testes, prostate, and androgen-sensitive Dunning R3327-PAP tumors, 2) growth inhibition of Dunning R3327-PAP tumors is caused by suppression of cell division rather than by an increase in cell death and is associated with an increase of the tumor stroma content, and 3) volume increase of the androgen-independent Dunning R3327-AT2.1 tumor is slightly but significantly reduced, indicating a local stimulatory LHRH loop with within this tumor cell line. Prostate 32:77–84, 1997. © 1997 Wiley-Liss, Inc.
Internet Multimedia Application Techologies Current Practice and Future. (1996)

Within the zygomatic arch, bilateral osteotomies were performed on 20 adult male New Zealand white rabbits. These were stabilized in an anatomical position with polyglyconate acid plates and screws. At 3, 4, 6, 9, and 12 months, rabbits were killed and their zygomatic complexes removed en bloc. Specimens were serially sectioned for standard histological examination. Although no gross reactions were noted throughout the course of this investigation, histological reactions were brisk. At 3 months, particulate material was surrounded by a foreign body giant cell-type reaction. The quantity of foreign material appeared to decrease by 4 months, at which time the foreign body reaction was partially replaced by fibrous tissue. By 6 months, there was a thick periosteal scar at the osteotomy site with a few islands of persistent foreign material. These were primarily seen in small, irregular vesicular spaces surrounded by a large number of histiocytes with their characteristic foamy-cytoplasm. Although this foreign body reaction had subsided by 12 months, small foci of chronic inflammation still persisted.
Is Slower Early Growth Beneficial for Long-Term Cardiovascular Health? (2004)

FMD was 4% lower in adolescents with the highest compared with the lowest rate of weight gain in the first 2 weeks after birth, a substantial negative effect similar to that for insulin-dependent diabetes mellitus or smoking in adults. Our findings are consistent with the adverse effects of accelerated neonatal growth on long-term cardiovascular health and suggest that postnatal growth patterns could explain the previously reported association between birthweight and later CVD.
Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients (2011)

Current factor IX (FIX) products display a half-life (t(1/2)) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG(1), to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t(1/2) and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716.
Molecular regulation of penicillin biosynthesis in Aspergillus (Emericella) nidulans (2006)

The beta-lactam antibiotic penicillin is produced as end product by only some filamentous fungi, most notably by Aspergillus nidulans and Penicillium chrysogenum. The biosynthesis of this secondary metabolite is catalyzed by three enzymes which are encoded by the following three genes: acvA (pcbAB), ipnA (pcbC) and aat (penDE). The genes are organized into a gene cluster. In A. nidulans, several studies have indicated that the genes are controlled by a complex regulatory network. The wide-domain regulatory protein PACC binds to the intergenic region between acvA and ipnA and, at alkaline pH, increases at least ipnA gene transcription. An additional DNA binding protein (PENR1) was suggested to repress acvA and to activate ipnA and aat expression. Furthermore, three recessive trans-acting mutations have been characterized (prgA1, prgB1, npeE1) which most likely correspond to positively acting regulatory genes of the penicillin biosynthesis genes.
Photochemical gating of heterologous ion channels: Remote control over genetically designated populations of neurons (2003)

Heterologous proteins capable of transducing physical or chemical stimuli into electrical signals can be used to control the function of excitable cells in intact tissues or organisms. Restricted genetically to circumscribed populations of cellular targets, these selectively addressable sources of depolarizing current can supply distributed inputs to neural circuits, stimulate secretion, or regulate force and motility. In an initial demonstration of this principle, we have used elements of a G protein coupled signaling system, the phototransduction cascade of the fruit fly, to sensitize generalist vertebrate neurons to light [Zemelman, B. V., Lee, G. A., Ng, M. & Miesenböck, G. (2002) Neuron 33, 15-22]. We now describe the use of ectopically expressed ligand-gated ion channels as transducers of optical or pharmacological stimuli. When either the capsaicin receptor, TRPV1, the menthol receptor, TRPM8, or the ionotropic purinergic receptor P2X(2) was introduced into hippocampal neurons, the cells responded to pulsed applications of agonist with characteristic sequences of depolarization, spiking, and repolarization. Responses required cognate matches between receptor and agonist, peaked at firing frequencies of approximately 40 Hz, initiated and terminated rapidly, and did not attenuate. Precise dose-response relationships allowed current amplitudes and firing frequencies to be tuned by varying the concentration of ligand. Agonist could be administered either pharmacologically or, in the cases of TRPV1 and P2X(2), optically, through photorelease of the active compounds from the respective "caged" precursors, 4,5-dimethoxy-2-nitrobenzyl-capsaicin and P(3)-[1-(4,5-dimethoxy-2-nitrophenyl)ethyl]-ATP.
A Simian Virus 5 (SV5) P/V Mutant Is Less Cytopathic than Wild-Type SV5 in Human Dendritic Cells and Is a More Effective Activator of Dendritic Cell Maturation and Function (2006)

Human epithelial cells infected with the parainfluenza virus simian virus 5 (SV5) show minimal activation of host cell interferon (IFN), cytokine, and cell death pathways. In contrast, a recombinant SV5 P/V gene mutant (rSV5-P/V-CPI-) overexpresses viral gene products and is a potent inducer of IFN, proinflammatory cytokines, and apoptosis in these cells. In this study, we have compared the outcomes of wild-type (WT) SV5 and rSV5-P/V-CPI- infections of primary human dendritic cells (DC), important antigen-presenting cells for initiating adaptive immune responses. We have tested the hypothesis that a P/V mutant which activates host antiviral responses will be a more potent inducer of DC maturation and function than WT rSV5, which suppresses host cell responses. Infection of peripheral blood mononuclear cell-derived immature DC with WT rSV5 resulted in high levels of viral protein and progeny virus but very little increase in cell surface costimulatory molecules or secretion of IFN and proinflammatory cytokines. In contrast, immature DC infected with the rSV5-P/V-CPI- mutant produced only low levels of viral protein and progeny virus, but these infected cells were induced to secrete IFN-alpha and other cytokines and showed elevated levels of maturation markers. Unexpectedly, DC infected with WT rSV5 showed extensive cytopathic effects and increased levels of active caspase-3, while infection of DC with the P/V mutant was largely noncytopathic. In mixed-culture assays, WT rSV5-infected DC were impaired in the ability to stimulate proliferation of autologous CD4+ T cells, whereas DC infected with the P/V mutant were very effective at activating T-cell proliferation. The addition of a pancaspase inhibitor to DC infected with WT rSV5 reduced cytopathic effects and resulted in higher surface expression levels of maturation markers. Our finding that the SV5 P/V mutant has both a reduced cytopathic effect in human DC compared to WT SV5 and an enhanced ability to induce DC function has implications for the rational design of novel recombinant paramyxovirus vectors based on engineered mutations in the viral P/V gene.
A Study of the Cough Reflex in Idiopathic Pulmonary Fibrosis (2003)

Little is known about the pathogenesis of cough in idiopathic pulmonary fibrosis (IPF). We hypothesized that abnormalities of respiratory tract tachykinin-containing sensory nerves may be implicated. We studied cough response to capsaicin, substance P (SP), and bradykinin in 10 healthy control subjects and 10 patients with IPF. Six patients were tested before and after steroid therapy. Induced sputum cell counts and neurotrophic factor levels were also measured in 13 patients and 13 control subjects. The results show that cough sensitivity to capsaicin was greater in patients (p < 0.01). Neither SP nor bradykinin induced cough in normal subjects. SP and bradykinin induced cough in 7/10 patients (p < 0.002) and 2/10 patients (not significant) with IPF, respectively. Prednisolone caused a reduction in cough sensitivity to capsaicin (p < 0.05) and SP (p < 0.05) in all six patients treated. There were significantly more neutrophils (p = 0.001) and higher levels of nerve growth factor (p < 0.01) and brain-derived neurotrophic factor (p < 0.01) in patient's sputa. These findings suggest functional upregulation of lung sensory neurones in IPF. The cough response to inhaled SP in most patients may reflect disrupted respiratory epithelium. The response to corticosteroids demonstrates that the cough is amenable to therapy.