gebhart/patrepeval huggingface dataset:
Region-based Image Annotation using Asymmetrical Support Vector Machine-based Multiple-Instance Learning (2006)

In region-based image annotation, keywords are usually associated with images instead of individual regions in the training data set. This poses a major challenge for any learning strategy. In this paper, we formulate image annotation as a supervised learning problem under Multiple-Instance Learning (MIL) framework. We present a novel Asymmetrical Support Vector Machine-based MIL algorithm (ASVM-MIL), which extends the conventional Support Vector Machine (SVM) to the MIL setting by introducing asymmetrical loss functions for false positives and false negatives. The proposed ASVM-MIL algorithm is evaluated on both image annotation data sets and the benchmark MUSK data sets.
Activation of a Ca2+‐permeable cation channel by two different inducers of apoptosis in a human prostatic cancer cell line (1999)

1. We have combined patch clamp recording with simultaneous [Ca2+]i measurements in single LNCaP cells (a human prostate cancer cell line), to study the activation of Ca2+-permeable channels by two different inducers of apoptosis, ionomycin and serum deprivation. 2. In perforated patch recording, LNCaP cells had a membrane potential of -40 mV and a resting [Ca2+]i of 90 nM. Application of ionomycin at levels that induced apoptosis in these cells (10 microM) produced a biphasic increase in [Ca2+]i. The first rise in [Ca2+]i was due to release of Ca2+ from internal stores and it was associated with a membrane hyperpolarization to -77 mV. The latter was probably due to the activation of high conductance, Ca2+- and voltage-dependent K+ channels (maxi-K). Conversely, the second rise in [Ca2+]i was always preceded by and strictly associated with membrane depolarization and required external Ca2+. Serum deprivation, another inducer of apoptosis, unmasked a voltage-independent Ca2+ permeability as well. 3. A lower concentration of ionomycin (1 microM) did not induce apoptosis, and neither depolarized LNCaP cells nor produced the biphasic increase in [Ca2+]i. However, the first increment in [Ca2+]i due to release from internal Ca2+ stores was evident at this concentration of ionomycin. 4. Simultaneous recordings of [Ca2+]i and ion channel activity in the cell attached configuration of patch clamp revealed a Ca2+-permeable, Ca2+-independent, non-selective cation channel of 23 pS conductance. This channel was activated only during the second increment in [Ca2+]i induced by ionomycin. The absence of serum activated the 23 pS channel as well, albeit at a lower frequency than with ionomycin. 5. Thus, the 23 pS channel can be activated by two unrelated inducers of apoptosis and it could be another Ca2+ influx mechanism in programmed cell death of LNCaP cells.
Immunotherapies targeting CD38 in Multiple Myeloma (2016)

Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies. In this report, we review the expression pattern of CD38 among normal tissues and in different types of plasma cell dyscrasias including their progenitor cells, minimal residual disease, and circulating tumor cells. We summarize the physiological role of CD38 as well as its role in the pathophysiology of MM and we present the most recent clinical trials using CD38 as a target. In addition, we highlight possible combination immunotherapies incorporating anti-CD38 monoclonal antibodies and we demonstrate alternative immunotherapeutic approaches targeting the same antigen such as CD38-specific chimeric antigen receptor (CAR) T cells.
Trait to gene analysis reveals that allelic variation in three genes determines seed vigour (2016)

Predictable seedling establishment is essential for resource-efficient and cost-effective crop production; it is widely accepted as a critically important trait determining yield and profitability. Seed vigour is essential to this, but its genetic basis is not understood. We used natural variation and fine mapping in the crop Brassica oleracea to show that allelic variation at three loci influence the key vigour trait of rapid germination. Functional analysis in both B. oleracea and the model Arabidopsis identified and demonstrated activity of genes at these loci. Two candidate genes were identified at the principal Speed of Germination QTL (SOG1) in B. oleracea. One gene BoLCVIG2 is a homologue of the alternative-splicing regulator (AtPTB1). The other gene BoLCVIG1 was unknown, but different alleles had different splice forms that were coincident with altered abscisic acid (ABA) sensitivity. We identified a further QTL, Reduced ABscisic Acid 1 (RABA1) that influenced ABA content and provide evidence that this results from the activity of a homologue of the ABA catabolic gene AtCYP707A2 at this locus. Lines containing beneficial alleles of these three genes had greater seed vigour. We propose a mechanism in which both seed ABA content and sensitivity to it determines speed of germination.
Calibrated photoplethysmographic estimation of digital pulse volume and arterial compliance (2007)

Digital pulse volume and arterial compliance have been estimated by using the finger arterial pressure and volume waveforms when performing measurements at rest and during local cold exposure in 17 volunteers. The amplitude-based algorithm determines compliance as a ratio of finger volume and pressure pulses. Cooling was conducted by immersion of the contra-lateral arm in water at 11 degrees C for 2 min. Continuous non-invasive finger blood pressure was measured by the Finapres monitor, while the finger volume pulses were recorded by the UT9201 physiograph, which provides a photoplethysmographic registration of volume changes in a large range of transmural pressures (P(transm)). The photoplethysmographic signal was calibrated by applying a graded modulation to the cuff. The study demonstrated that contra-lateral arm cooling induced a statistically significant (P<0.001) reduction in the digital arterial compliance at P(transm) approximately 0 as well as at P(transm) = 50 mmHg. The median compliance diminished during cooling from 0.67 mm(3 )mmHg(-1) to the level of 55% at P(transm) approximately 0, and from 0.14 mm(3 )mmHg(-1) to the level of 42% at P(transm) = 50 mmHg respectively. The observed changes were mostly due to the reduction in the pulse volume. Digital arterial pressure and volume waveforms recorded by the Finapres monitor combined with a calibrated photoplethysmograph can be used in estimating the absolute values of the dynamic compliance of finger arteries. A quantitative estimation instead of the non-calibrated recording of the digital pulse volume allows shortening the variability and widening the scope of finger arterial compliance measurements.
Transgenic Mice Showing Inflammation-Inducible Overexpression of Granulocyte Macrophage Colony-Stimulating Factor (2004)

We used the promoter of the human C-reactive protein (CRP) gene to drive inflammation-inducible overexpression of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in transgenic mice. Transgenic mice carrying a CRP/GM-CSF fusion gene show a >150-fold increases in circulating levels of GM-CSF within 6 h of intraperitoneal inoculation with 25 microg of lipopolysaccharide. However, some of the transgenic mice also display relatively high basal levels of GM-CSF in the absence of any obvious inflammatory stimulus. Raised basal levels of GM-CSF are associated with a number of pathological changes, including enlarged and histologically abnormal livers and spleens and with increases in the number and activation state of macrophages and granulocytes in the peripheral blood. Despite problems associated with the expression of such a potent pleiotropic cytokine as GM-CSF, the principle of inflammation-inducible expression of chimeric constructs has been shown to be feasible. Inducible expression systems such as that described here could be of potential use in the study of the role of cytokines in health and disease and in the development of disease-resistant strains of livestock.
Imaging small animal whole-body dynamics by single-impulse panoramic photoacoustic computed tomography (2017)

Imaging of small animals, especially rodents provides physiological, pathological, and phenotypical insights into the most relevant milieu—an intact, living system. Currently, non-optical small-animal wholebody imaging approaches lack either spatiotemporal resolution or functional contrasts, whereas pure optical imaging suffers from either shallow penetration (up to ~1 mm) or a poor resolution-to-depth ratio (~1/3). Here, we present a standalone system that breaks all the above limitations. Our system features high spatiotemporal resolution and deep penetration, and can capture anatomical and functional contrasts. We imaged mouse wholebody dynamics in real time with clear sub-organ anatomical and functional details.
Genomic selection in dairy cattle: Integration of DNA testing into breeding programs (2012)

Sires of Males. Sires of males (SM) represent the most elite males that are selected to be sires of the next generation of young bulls.
Regulation of Bone Morphogenetic Protein Activity by Pro Domains and Proprotein Convertases (1999)

Bone morphogenetic proteins (BMPs) are derived from inactive precursor proteins by endoproteolytic cleavage. Here we show that processing of Nodal and Myc-tagged BMP4 is significantly enhanced by SPC1/Furin or SPC4/PACE4, providing direct evidence that regulation of BMP signaling is likely to be controlled by subtilisin-like proprotein convertase (SPC) activities. Nodal processing is dramatically enhanced if two residues adjacent to the precursor cleavage site are substituted with amino acids found at the equivalent positions of Activin, demonstrating that structural constraints at the precursor cleavage site limit the processing efficiency. However, in transfection assays, mature Nodal is undetectable either in culture supernatants or in cell lysates, despite efficient cleavage of the precursor protein, suggesting that mature Nodal is highly unstable. Domain swap experiments support this conclusion since mature BMP4 or Dorsalin are also destabilized when expressed in conjunction with the Nodal pro domain. By contrast, mature Nodal is stabilized by the Dorsalin pro domain, which mediates the formation of stable complexes. Collectively, these data show that the half-life of mature BMPs is greatly influenced by the identity of their pro regions.
Identification of c-fos sequences involved in induction by insulin and phorbol esters. (1988)

We evaluated the mechanism of insulin and phorbol ester induction of the proto-oncogene c-fos in Chinese hamster ovary fibroblasts stably transformed with high levels of genes expressing normal or truncated human insulin receptors. Both insulin and the tumor-promoting phorbol ester phorbol 12-myristate 13-acetate (PMA) induced c-fos mRNA accumulation in cells expressing high numbers of normal human insulin receptors; PMA but not insulin was effective in the cells expressing the mutant receptor. Transient expression studies with plasmid constructions containing c-fos 5'-flanking sequences ligated to the bacterial chloramphenicol acetyltransferase gene indicated that sequences corresponding to the serum response element were required for induction of c-fos transcription by both insulin and PMA. The insulin-sensitive cells contained a nuclear factor, presumably a protein, which bound specifically to this sequence of the c-fos gene; the apparent affinity of this factor to the normal serum response element was not affected by prior treatment of the cells with insulin or PMA. This c-fos binding factor may prove to be important in the regulation of c-fos expression by insulin and activators of protein kinase C.
Development of oral immunomodulatory agents in the management of multiple sclerosis (2011)

The emergence of oral disease-modifying therapies in multiple sclerosis (MS) will have a significant impact on the evolving scenario of immunomodulatory treatments in MS where current therapies are all injectable. Reducing relapses in trials translates for individuals with MS into a therapeutic aim of stopping future events. Thus the possible absence of any perceived benefits to the individual together with the long disease course, variable outcome, and a younger age group affected in MS makes side effects the major issue. The use of disease-modifying therapies as a whole needs to be placed in the context of a widening therapeutic indication where the use of these therapies is being justified at an increasingly early stage and in pre-MS syndromes such as clinically isolated and radiologically isolated syndromes where no fixed disability is likely to have accumulated. The five oral therapies discussed (cladribine, fingolimod, laquinimod, BG-12, and teriflunomide) have just completed Phase III studies and some have just been licensed. New oral drugs for MS need to be placed within this evolving marketplace where ease of delivery together with efficacy and side effects needs to be balanced against the known issues but also the known long-term safety of standard injectables.
Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ) (2001)

Glucose homeostasis depends on insulin responsiveness in target tissues, most importantly, muscle and liver. The critical initial steps in insulin action include phosphorylation of scaffolding proteins and activation of phosphatidylinositol 3-kinase. These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. We show that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle. These data establish Akt2 as an essential gene in the maintenance of normal glucose homeostasis.
IL‐10 and TGF‐β cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy (2003)

Abstract The regulation of normal and allergic immune responses to airborne allergens in the mucosa is still poorly understood, and the mechanism of specific immunotherapy (SIT) in normalizing the allergic response to such allergens is currently not clear. Accordingly, we have investigated the immunoregulatory mechanism of both normal and allergic responses to the major house‐dust mite (HDM) and birch pollen allergens — Dermatophagoides pteroynyssinus (Der p)1 and Bet v 1, respectively — as well as the immunologic basis of SIT to HDM in rhinitis and asthma patients. In normal immunity to HDM and birch pollen, an allergen‐specific peripheral T cell suppression to Der p 1 and Bet v 1 was observed. The deviated immune response was characterized by suppressed proliferative T celland Th1 (IFN‐γ) and Th2 (IL‐5, IL‐13) cytokine responses, and increased IL‐10 and TGF‐β secretion by allergen‐specific T cells. Neutralization of cytokine activity showed that T cell suppression was induced by IL‐10 and TGF‐β during SIT and in normal immunity to the mucosal allergens. In addition, SIT induced an antigen‐specific suppressive activity in CD4 + CD25 + T cells of allergic individuals. Together, these results demonstrate a deviation towards a regulatory/suppressor T cell response during SIT and in normal immunity as a key event for the healthy immune response to mucosal antigens.
Decentralized cognitive mac for dynamic spectrum access (2005)

We consider the problem of opportunistic dynamic spectrum access (DSA) in an ad hoc network in which unlicensed secondary users communicate through channels not used by the primary users. Decentralized cognitive medium access control protocols are presented that allow secondary users to recognize spectrum opportunity and transmit based on a partial observation of the instantaneous spectrum availability. Under a framework of partially observable Markov decision process (POMDP), we derive optimal and suboptimal decentralized strategies for the secondary users to decide which channel(s) to sense and access for the maximization of the overall network throughput
How to Construct Polar Codes (2011)

A method for efficiently constructing polar codes is presented and analyzed. Although polar codes are explicitly defined, straightforward construction is intractable since the resulting polar bit-channels have an output alphabet that grows exponentially with he code length. Thus the core problem that needs to be solved is that of faithfully approximating a bit-channel with an intractably large alphabet by another channel having a manageable alphabet size. We devise two approximation methods which "sandwich" the original bit-channel between a degraded and an upgraded version thereof. Both approximations can be efficiently computed, and turn out to be extremely close in practice. We also provide theoretical analysis of our construction algorithms, proving that for any fixed $ε&gt; 0$ and all sufficiently large code lengths $n$, polar codes whose rate is within $ε$ of channel capacity can be constructed in time and space that are both linear in $n$.
A Monoclonal Anti-Human IL-6 Receptor Antibody Inhibits the Proliferation of Human Myeloma Cells (1993)

A monoclonal antibody (UV4) against the human IL-6 receptor (hIL-6R) was generated by immunizing BALB/c mice with both a human myeloma cell line (U266) and a murine cell line (M12.4/R) transfected with the hIL-6R cDNA. Flow cytometric analysis demonstrated that UV 4 stains the hIL-6R+ cell lines U266 and U937, but not the hIL-6R- cell lines Daudi and K562. Competitive inhibition assays demonstrated that preincubation of U266 cells with UV4 inhibited the binding of a phycoerythrin (PE)-IL-6 conjugate to the hIL-6R and also inhibited the proliferative activity of IL-6 on the IL-6-dependent human myeloma cell lines ILKM2 and ILKM3. In contrast, UV4 did not interfere with the proliferation of the hIL-6R- Burkitt's lymphoma cell line, Daudi. Direct sandwich radioimmunoassays further confirmed that the UV4 bound to the same molecule as the goat anti-hIL-6R antibody. These results suggest that both UV4 and human IL-6 bind to the same or adjacent epitopes on the hIL-6R. This monoclonal antibody should facilitate studies of the structure-function relationship of IL-6R and may be useful for the treatment of IL-6-dependent diseases such as multiple myeloma.
Determinants within an 18-Amino-Acid U1A Autoregulatory Domain That Uncouple Cooperative RNA Binding, Inhibition of Polyadenylation, and Homodimerization (2003)

The human U1 snRNP-specific U1A protein autoregulates its own production by binding to and inhibiting the polyadenylation of its own pre-mRNA. Previous work demonstrated that a short sequence of U1A protein is essential for autoregulation and contains three distinct activities, which are (i) cooperative binding of two U1A proteins to a 50-nucleotide region of U1A pre-mRNA called polyadenylation-inhibitory element RNA, (ii) formation of a novel homodimerization surface, and (iii) inhibition of polyadenylation by inhibition of poly(A) polymerase (PAP). In this study, we purified and analyzed 11 substitution mutant proteins, each having one or two residues in this region mutated. In 5 of the 11 mutant proteins, we found that particular amino acids associate with one activity but not another, indicating that they can be uncoupled. Surprisingly, in three mutant proteins, these activities were improved upon, suggesting that U1A autoregulation is selected for suboptimal inhibitory efficiency. The effects of these mutations on autoregulatory activity in vivo were also determined. Only U1A and U170K are known to regulate nuclear polyadenylation by PAP inhibition; thus, these results will aid in determining how widespread this type of regulation is. Our molecular dissection of the consequences of conformational changes within an RNP complex presents a powerful example to those studying more complicated pre-mRNA-regulatory systems.
Biafungin (CD101), a Novel Echinocandin, Displays a Long Half-life in the Chimpanzee, Suggesting a Once-Weekly IV Dosing Option (2014)

Background: The echinocandins are an important class of antifungal agents, but are administered once daily by intravenous (IV) infusion. An echinocandin that could be administered once weekly could facilitate earlier hospital discharges and could expand usage to indications where daily infusions are impractical. Biafungin is a highly stable echinocandin for once-weekly IV administration. The compound was found to have a spectrum of activity and potency comparable to other echinocandins. In chimpanzees single dose pharmacokinetics of IV and orally administered biafungin were compared to IV anidulafungin, which has the longest half-life (T1/2) of the approved echinocandins. Methods: The pharmacokinetics of biafungin and anidulafungin were compared in Pan troglodytes. Six healthy adult female chimpanzees (three groups of two) received a single dose of either IV biafungin (1.0 mg/kg, 1 h infusion), oral biafungin (10 mg/kg, bolus gavage), or IV anidulafungin (1.0 mg/kg, 1 h infusion). Blood draws were collected over 22 days in animals receiving biafungin and over 10 days for anidulafungin. Quantifications of biafungin and anidulafungin were performed using qualified LC/MS/MS and LC/MS methods, respectively. Pharmacokinetic parameters were calculated using noncompartmental analyses. Results: After IV administration, the T1/2 and clearance for biafungin in the chimpanzee were 81 h and 3.41 mL/h/kg, whereas for anidulafungin the observed values were 30 h and 25.2 mL/h/kg, respectively. The oral bioavailability of biafungin was 4.5%, but exposures were high (AUC0-inf of ~137,000 ng*h/mL) and persisted after a single dose. The apparent T1/2 after oral administration was longer than after IV administration (99 h vs 81 h). The Tmax after oral administration occurred late (24 h). Conclusions: Biafungin has a T1/2 nearly 3-fold longer and a clearance over 7-fold slower than those for anidulafungin in the chimpanzee. Despite a low oral bioavailability, slow clearance leads to high AUCs after a single oral dose. These results suggest that biafungin could potentially be administered in patients once weekly as an IV infusion, enabling earlier hospital discharges and expansion of use to situations where daily infusion is impractical.
Effect of low density lipoprotein receptor deficiency on the metabolism of apolipoprotein B-100 in blood plasma. Kinetic studies in normal and Watanabe heritable hyperlipidemic rabbits. (1987)

The kinetics of apolipoprotein (apo) B-100 in particles containing apo E (B,E particles) or lacking apo E (B particles) were studied in Watanabe heritable hyperlipidemic (WHHL) rabbits deficient in low density lipoprotein (LDL) receptors, and compared with those of normal rabbits after injection of radioiodinated very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and LDL. In both groups results of kinetic modeling were consistent with the hypothesis that all apo B enters the plasma in VLDL, mainly as B,E particles, followed by delipidation and partial conversion to IDL and LDL, with concomitant conversion of some B,E particles to B particles. In WHHL rabbits, production of VLDL apo B was reduced by 40%, but LDL production was increased threefold. Defective removal of B,E and B particles in all three lipoprotein classes, coupled with preserved processes of delipidation, can account for the observed increases in the concentration of apo B (threefold in VLDL, fivefold in IDL, and twenty-twofold in LDL) in WHHL rabbits.