gebhart/patrepeval huggingface dataset:
Individualized non-invasive brain stimulation engages the subgenual anterior cingulate and amygdala (2018)

Brain stimulation is used clinically to treat a variety of neurological and psychiatric conditions. The mechanisms of the clinical effects of these brain-based therapies are presumably dependent on their effects on brain networks. It has been hypothesized that using individualized brain network maps is an optimal strategy for defining network boundaries and topologies. Traditional non-invasive imaging can determine correlations between structural or functional time series. However, they cannot easily establish hierarchies in communication flow as done in non-human animals using invasive methods. In the present study, we interleaved functional MRI recordings with non-invasive transcranial magnetic stimulation in the attempt to map causal communication between the prefrontal cortex and two subcortical structures thought to contribute to affective dysregulation: the subgenual anterior cingulate cortex (sgACC) and the amygdala. In both cases, we found evidence that these brain areas were engaged when TMS was applied to prefrontal sites determined from each participant's previous fMRI scan. Specifically, after transforming individual participant images to within-scan quantiles of evoked TMS response, we modeled the average quantile response within a given region across stimulation sites and individuals to demonstrate that the targets were differentially influenced by TMS. Furthermore, we found that the sgACC distributed brain network, estimated in a separate cohort, was engaged in response to sgACC focused TMS and was partially separable from the proximal default mode network response. The amygdala, but not its distributed network, responded to TMS. Our findings indicate that individual targeting and brain response measurements usefully capture causal circuit mapping to the sgACC and amygdala in humans, setting the stage for approaches to non-invasively modulate subcortical nodes of distributed brain networks in clinical interventions and mechanistic human neuroscience studies.
Study of information clouding methods to prevent spoilers of sports match (2012)

Seeing the final score of a sports match on the Web often spoils the pleasure of a user who is waiting to watch a recording of this match on TV. This paper proposes four information clouding methods to block spoiling information, and describes implementation of a system using these methods as a browser extension. We then experimentally investigate the usefulness of the methods, taking into account their differences, differences in the variety of content, and differences in the user's interest in sports.
Persistence of Deoxyribonucleic Acid Polymerase I and Its 5′ → 3′ Exonuclease Activity in PolA Mutants of Escherichia coli K12 (1973)

Abstract Partially purified enzyme preparations derived from a strain of Escherichia coli K12 with an amber mutation (polA1) in the DNA polymerase I gene contain approximately 1% as much polymerase I activity as the preparations from wild type strain purified by the same procedure. Two other polymerase I mutants, one temperature-sensitive (polA12) and the other nonsuppressible (polA5), also contain significant levels of polymerase I (12% and 35% of wild type, respectively). In the case of polA12, the polymerase I activity is abnormally thermolabile. The level of polymerase I observed in a given mutant is dependent, in part, on the pH and the template-primer used. Despite their low DNA polymerase I levels, these mutants possess nearly normal amounts of the 5' → 3' exonuclease activity that is known to be part of DNA polymerase I and is separable as a 2.8 S fragment by proteolytic cleavage. In the temperature-sensitive and nonsuppressible mutants, the 5' → 3' exonuclease and polymerase I activities cosediment at approximately 5.4 S just as in the wild type. In contrast, the polymerase I activity in the amber mutant sediments at 5.4 S, but the 5' → 3' exonuclease activity sediments at 2.8 S. These findings suggest that the residual DNA polymerase I activity sedimenting like the wild type enzyme in the polA1 mutants is the result of a low level read-through of the amber mutation, and that the 5' → 3' exonuclease represents the amber peptide, or a proteolytic cleavage product of it.
Incidence rates and treatment of neuropathic pain conditions in the general population ☆ (2008)

Incidence rate estimates of neuropathic pain are scanty and mostly address single types whereas the scope of the disease is wide. We aimed to calculate the incidence rates of neuropathic pain conditions in the Dutch general population and to assess treatment strategies in primary care. The study population included persons registered for at least one year in the Integrated Primary Care Information (IPCI) database between 1996 and 2003. Neuropathic pain was ascertained and classified by systematic review of computerized longitudinal medical records. Incidence rates (IR) were calculated, and the treatment for pain was compared to age and gender matched controls. Among 362,693 persons contributing 1,116,215 person years (PY), we identified 9135 new cases of neuropathic pain (IR: 8.2/1000 PY, 95%CI: 8.0-8.4). Mononeuropathy and carpal tunnel syndrome were the most frequent types with 4.3 and 2.3 cases/1000 PY followed by diabetic peripheral neuropathy and post-herpetic neuralgia at 0.72 and 0.42/1000 PY. Neuropathic pain was 63% more common in women than in men and peaked between the ages 70 and 79. More than 50% of cases received pain medication within 6 months after diagnosis, mostly consisting of NSAIDs or aspirin. Anticonvulsants and tricyclic antidepressants were only used by 4.8 and 4.7% of cases. Neuropathic pain is a rather frequent condition with an annual incidence of almost 1% of the general population and affecting women and middle-aged persons more often. The treatment mostly consisted of regular analgesics suggesting that pharmacological treatment of neuropathic pain is suboptimal.
Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation (2000)

Ecteinascidin 743 (ET-743), a highly promising marine-based antitumor agent presently in phase II clinical trials, has been shown to interfere with the binding of minor-groove-interacting transcription factors, particularly NF-Y, with their cognate promoter elements in vitro. We have shown that NF-Y is a central mediator of activation of transcription of the human P glycoprotein gene (MDR1) by a variety of inducers and that NF-Y functions by recruiting the histone acetyltransferase PCAF to the MDR1 promoter. In the present study, we tested whether ET-743 could block activation of the MDR1 promoter by agents that mediate their effect through the NF-Y/PCAF complex. We report that physiologically relevant concentrations of ET-743 abrogate transcriptional activation of both the endogenous MDR1 gene and MDR1 reporter constructs by the histone deacetylase inhibitors as well as by UV light, with minimal effect on constitutive MDR1 transcription. Notably, this inhibition does not alter the promoter-associated histone hyperacetylation induced by histone deacetylase inhibitors, suggesting an in vivo molecular target downstream of NF-Y/PCAF binding. ET-743 is therefore the prototype for a distinct class of transcription-targeted chemotherapeutic agents and may be an efficacious adjuvant to the treatment of multidrug-resistant tumors.
Estrogen receptor transcription and transactivation Estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer (2000)

Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERalpha and ERbeta, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents.
Production of IL‐10 by melanoma cells: Examination of its role in immunosuppression mediated by melanoma (1994)

Previous studies have shown that IL-10 may modulate immune responses towards the humoral arm by inhibiting production of cytokines involved in cell-mediated responses. In the present studies, we found that mRNA to IL-10 could be demonstrated in 66% of melanoma cell lines by PCR amplification of reverse-transcribed mRNA and in supernatants of the cell lines by ELISA. Release into the supernatants increased approximately 2-fold each day up to 3 days. The MW of 35S-labelled IL-10 secreted by melanoma cells was similar to that reported in previous studies. In the present studies we also examined whether IL-10 may be responsible for some of the immunosuppressive effects of the melanoma cell supernatants observed in previous studies, by testing whether MAbs against IL-10 could reverse the inhibitory effects of these supernatants. Recombinant IL-10 and melanoma supernatants were found to inhibit production of TNF-alpha, IFN-gamma, IL-2 and mixed lymphocyte reactions but reversal of these effects of melanoma supernatants by MAbs against IL-10 was only seen in the case of TNF-alpha production. These results extend the range of cell types known to produce IL-10 and indicate that malignancy of certain cell types may lead to unregulated production of IL-10 that could have the potential to modulate immune responses against the tumor.
Alterations of neurokinin receptors and interstitial cells of Cajal during and after jejunal inflammation induced by Nippostrongylus brasiliensis in the rat (2002)

Substance P (SP) and its receptors NK1 and NK2 are widely expressed in the intestinal wall by neurones, interstitial cells of Cajal (ICC) and smooth muscle cells. Changes in SP and/or its NK receptors have been documented during experimental inflammation in animals or inflammatory bowel diseases in humans, but the data concern the acute phase of the inflammatory process. We determined immunohistochemically whether NK receptors and SP were altered in the muscle coat during jejunal inflammation induced by the nematode Nippostrongylus brasiliensis and whether these alterations persisted when inflammation had spontaneously resolved 30 days postinfection. An ultrastructural analysis was also conducted on ICC, nerves and muscle. At day 14, when inflammation peaked, there was a reduction in NK1 receptors in myenteric neurones and in SP-immunoreactive nerve endings. There were also ultrastructural anomalies in synaptic vesicles and NK2 receptor loss in the circular muscle layer. The SP decrease persisted at day 30, whereas neurones and circular muscle cells re-expressed NK1 and NK2 receptors, respectively. The ICC at the deep muscular plexus, located near to the inflammatory site, underwent alterations leading to their complete loss at day 30. These morphological changes are probably associated with impairment in tachykinergic control of jejunal functions leading to the alterations of motility and sensitivity to distension already described in these animals.
Erratum: High Pressure Behavior ofZrW2O8: Grüneisen Parameter and Thermal Properties [Phys. Rev. Lett. 84, 3879 (2000)] (2000)

The value of the bulk modulus B used in Eq. ( 1) was taken from Ref.[14] as 4.8 3 10 10 Nm 22 .This was pointed out [27] to be inconsistent with that of isothermal compressibility x T (1.38 3 10 22 GPa 21 from Ref. [10]) used in the expression for Grüneisen parameter.If a value of B ͑7.25 3 10 10 Nm 22 ͒ consistent with that of x T is used in Eq. ( 1) one gets a value of thermal expansion coefficient a as 29.9 3 10 26 K 21 , which is in better agreement with the reported value of 2͑11 6 2͒ 3 10 26 K 21 .[27] S. L. Chaplot (private communication).
On sensor management in decentralized data fusion (2005)

A probabilistic framework for decentralized data fusion and sensor management based on the notion of Bayesian information value is presented. Use is made of information as the expected utility of actions within a framework of decentralized decision-theory. Entropy is used as an information metric. Some preliminary results justifying this approach are shown.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Effect of Rapidly Changing River Stage on Uranium Flux through the Hyporheic Zone (2007)

Measurement of ground water/surface water interaction within the hyporheic zone is increasingly recognized as an important aspect of subsurface contaminant fate and transport. Understanding the interaction between ground water and surface water is critical in developing a complete conceptual model of contaminant transport through the hyporheic zone. At the Hanford Site near Richland, Washington, ground water contaminated with uranium discharges to the Columbia River through the hyporheic zone. Ground water flux varies according to changes in hydraulic gradient caused by fluctuating river stage, which changes in response to operation of dams on the Columbia River. Piezometers and continuous water quality monitoring probes were installed in the hyporheic zone to provide long-term, high-frequency measurement of hydraulic gradient and estimated uranium concentrations. Subsequently, the flux of water and uranium was calculated for each half-hour time period over a 15-month study period. In addition, measurement of water levels in the near-shore unconfined aquifer enhanced the understanding of the relationship between river stage, aquifer elevation, and uranium flux. Changing river stage resulted in fluctuating hydraulic gradient within the hyporheic zone. Further, influx of river water caused lower uranium concentrations as a result of dilution. The methods employed in this study provide a better understanding of the interaction between surface and ground water in a situation with a dynamically varying vertical hydraulic gradient and illustrate how the combination of relatively standard methods can be used to derive an accurate estimation of water and contaminant flux through the hyporheic zone.
Phase II study of doxorubicin versus epirubicin in advanced breast cancer. (1986)

Doxorubicin and its epimerized analog epirubicin were tested at a dose of 75 mg/m2 given iv every 3 weeks to 42 patients with advanced breast cancer, 23 of whom were in relapse from prior cyclophosphamide, methotrexate, and 5-FU (CMF) chemotherapy. The median cumulative dose was 540 mg/m2 (range, 225-650) for doxorubicin and 565 mg/m2 (range, 150-600) for epirubicin. Complete plus partial response was documented in 11 of 21 patients (52%) following doxorubicin and in 13 of 21 patients (62%) following epirubicin. The median observation period was 22 months (range, 14-30); the median duration of response and the median survival were superimposable. Doxorubicin and epirubicin exhibited a superior response rate in previously untreated patients [six of eight (75%) vs eight of 11 (73%)] compared to those previously given CMF with or without endocrine therapy [five of 13 (38%) vs five of ten (50%)]. Vomiting, mucositis, and leukopenia were documented less frequently following administration of epirubicin as compared to doxorubicin. Regarding cardiac evaluation, no significant differences were evident between the two drugs. However, a significant fall in the left ventricular ejection fraction was documented in women who received doxorubicin following a cumulative dose greater than 550 mg/m2. Following completion of doxorubicin therapy at cumulative doses of 580 and 562 mg/m2, two women developed left ventricular failure at 6 and 14 months, respectively. Epirubicin appears to be an effective drug for the treatment of breast cancer and, given at equal doses, is less toxic than doxorubicin.
IL-3 and granulocyte-macrophage colony-stimulating factor stimulate two distinct phases of adhesion in human monocytes. (1990)

IL-3 and granulocyte-macrophage CSF are hemopoietic growth factors involved in monocytopoiesis and functional stimulation of circulating blood monocytes. We demonstrate that both cytokines enhance the adhesion of purified human monocytes to cultured human umbilical vein endothelial cells and to plastic surfaces. The stimulation seen was biphasic: an early phase detectable by 10 min, and a late phase seen after 9 h of in vitro culture. IL-3- and granulocyte-macrophage-CSF-stimulated adhesion was seen at concentrations as low as 6 pM, with maximal monocyte adhesion of up to 60% seen at concentrations of 60 pM and above. Both phases of stimulated adhesion were partially inhibited by a monoclonal antibody to CD18, the common beta-chain of the leukocyte functional Ag family of adhesion molecules, but not by an antibody to CD11b, the alpha-chain of MAC-1. However, a difference in the mechanism by which the early and late phases of stimulated adhesion arise could be shown by the use of cycloheximide as an inhibitor of protein synthesis. Although the late phase was totally dependent on de novo protein synthesis, early phase adhesion was not inhibited by cycloheximide, suggesting receptor redistribution or conformational change as the mechanism mediating enhanced adhesion at this time. These findings may be relevant to the pathogenesis of inflammatory disease and may have implications for the clinical use of these cytokines.
Ion‐permeable membrane for on‐chip preconcentration and separation of cancer marker proteins (2011)

Cancer marker proteins have been electrophoretically concentrated and then separated in a microfluidic device. On-chip preconcentration was achieved using an ion-permeable membrane, consisting of acrylamide, N,N'-methylene-bisacrylamide and 2-(acrylamido)-2-methylpropanesulfonate. This negatively charged membrane was photopolymerized in the microdevice near the injection intersection. Anionic proteins were excluded from the porous membrane based on both size and charge, which concentrated target components in the injection intersection prior to separation by microchip capillary electrophoresis (μ-CE). Bovine serum albumin was used in the initial characterization of the system and showed a 40-fold enrichment in the μ-CE peak with 4 min of preconcentration. Adjustment of buffer pH enabled baseline resolution of two cancer biomarkers, α-fetoprotein (AFP) and heat shock protein 90 (HSP90), while fine control over preconcentration time limited peak broadening. Our optimized preconcentration and μ-CE approach was applied to AFP and HSP90, where enrichment factors of >10-fold were achieved with just 1 min of preconcentration. Overall, the process was simple and rapid, providing a useful tool for improving detection in microscale systems.
Estimating The Cost Of New Drug Development: Is It Really $802 Million? (2006)

This paper replicates the drug development cost estimates of Joseph DiMasi and colleagues ("The Price of Innovation"), using their published cost estimates along with information on success rates and durations from a publicly available data set. For drugs entering human clinical trials for the first time between 1989 and 2002, the paper estimated the cost per new drug to be 868 million dollars. However, our estimates vary from around 500 million dollars to more than 2,000 million dollars, depending on the therapy or the developing firm.
[Osteogenesis induced by the combination of growth factor, fibrin glue and coral; towards a substitute of autologous bone graft. An experimental study on the rabbit]. (1994)

A triple mixture of TGF-beta, fibrin glue and natural coral skeleton granules (madreporic calcium carbonate) was tested in a rabbit bilateral cranioplasty model. Three-dimensional CT scan and histomorphometry demonstrated that, at one month and at two months, this association produced significantly more bone tissue than other associations, especially growth factor or coral alone. The rate of mineralization was significantly increased bilaterally in all animals having received TGF-beta. Coral resorption was also accelerated by growth factor and was replaced by histologically normal bone after two months. We emphasize the potentiation of TGF-beta by fibrin glue and natural coral skeleton and its potential application as a bone substitute.
Myelin oligodendrocyte glycoprotein‐induced autoimmune encephalomyelitis is chronic/relapsing in perforin knockout mice, but monophasic in Fas‐ and Fas ligand‐deficient lpr and gld mice (1997)

The expression and action of Fas/Fas ligand (FasL) in multiple sclerosis has been postulated as a major pathway leading to inflammatory demyelination. To formally test this hypothesis, C57BL/6-lpr and -gld mice, which due to gene mutation express Fas and FasL in an inactive form, were immunized with myelin oligodendrocyte glycoprotein peptide(35-55). Whereas in wild-type C57BL/6 mice, experimental autoimmune encephalomyelitis (EAE), was chronic/relapsing, EAE in lpr and gld mice was characterized by a lower incidence of disease and a monophasic course. This contrasts with C57BL/6 perforin knockout mice, which showed the most severe form of EAE of all mouse strains tested, the course being chronic relapsing. The difference noted cannot be attributed to an involvement of FasL in oligodendrocyte damage since oligodendrocytes are insensitive to FasL-mediated cytotoxicity in vitro, and since in the acute phase of EAE gld mice also show CD4+ T cell infiltrates with associated demyelination in brain and spinal cord. Unlike oligodendrocytes, astrocytes were killed by FasL in vitro. It remains to be established whether this latter finding explains the different disease course of lpr and gld mice compared to wild-type and perforin knockout mice.