gebhart/patrepeval huggingface dataset:
Essential genes (2005)

Understanding the biology of C. elegans relies on identification and analysis of essential genes, genes required for growth to a fertile adult. Approaches for identifying essential genes include several types of classical forward genetic screens, genome-wide RNA interference screens and systematic targeted gene knockout. Based on most estimates made from screening results thus far, from 15-30% of C. elegans genes appear to be essential. Genetic redundancy masks some essential functions and pleiotropy of many essential genes poses a challenge for a full understanding of their functions. Temperature sensitive mutations are valuable tools for studies of essential genes, but our ability to analyze essential genes would benefit from development of new tools for conditional inactivation or activation of specific genes.
Stability, quaternary structure, and folding of internal, external, and core‐glycosylated invertase from yeast (1992)

The role of carbohydrate chains for the structure, function, stability, and folding of glycoproteins has been investigated using invertase as a model. The protein is encoded by several different genes, and its carbohydrate moiety is heterogeneous. Both properties complicate physicochemical comparisons. Here we used the temperature-sensitive sec18 secretion mutant of yeast with a single invertase gene (SUC2). This mutant produces the carbohydrate-free internal invertase, the core-glycosylated form, and, at the permissive temperature, the fully glycosylated external enzyme, all with identical protein moieties. The core-glycosylated enzyme resembles the nascent glycoprotein chain that folds in the endoplasmic reticulum. Therefore, it may be considered a model for the in vivo folding of glycoproteins. In addition, because of its uniform glycosylation, it can be used to investigate the state of association of native invertase. Glycosylation is found to stabilize the protein with respect to thermal denaturation and chaotropic solvent components; the stabilizing effect does not differ for the external and the core-glycosylated forms. Unlike the internal enzyme, the glycosylated forms are protected from aggregation. Native internal invertase is a dimer (115 kDa) whereas the core-glycosylated enzyme is a mixture of dimers, tetramers, and octamers. This implies that core-glycosylation is necessary for oligomerization to tetramers and octamers. Dimerization is required and sufficient to generate enzymatic activity; further association does not alter the specific activity of core-glycosylated invertase, suggesting that the active sites of invertase are not affected by the association of the dimeric units. Reconstitution of the glycosylated and nonglycosylated forms of the enzyme after preceding guanidine denaturation depends on protein concentration. The maximum yield (approximately 80%) is obtained at pH 6-8 and protein concentrations < or = 4 micrograms/mL for the nonglycosylated and < or = 40 for the glycosylated forms of the enzyme. The lower stability of the internal enzyme is reflected by a narrower pH range of reactivation and enhanced aggregation. As indicated by the sigmoidal reactivation kinetics at low protein concentration both folding and association are rate-determining.
Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth (2009)

The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.
A new coronavirus associated with human respiratory disease in China (2020)

Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health<sup>1-3</sup>. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing<sup>4</sup> of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China<sup>5</sup>. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice (1994)

We have found a new spontaneous autosomal recessive mutation in mice that causes a systemic absence of lymph nodes and Peyer's patches. The name "alymphoplasia", with the gene symbol "aly", is proposed for this mutant. The spleen of aly/aly mice is devoid of well-defined lymphoid follicles, and the thymus does not show a clear cortical-medullary distinction. The mutant homozygotes are deficient in both humoral and cell-mediated immune functions, and are highly susceptible to infections. They have a reduced level of IgM and severely depressed levels of IgG and IgA in their sera, and do not reject allogeneic skin grafts. However, they have mature T and B cells as determined from their cell surface antigens. The results of bone marrow transplantation experiments suggest a mesenchymal disorder as a possible cause of the lack of lymph nodes and of immunodeficiency in the aly mouse. The aly mutant mouse may be a useful animal model of primary immunodeficiency, as are the nu (nude) and scid (severe combined immunodeficiency) mice.
Temperature-Sensitive Mutants of p16CDKN2 Associated with Familial Melanoma (1996)

Altered expression or function of the p16CDKN2 tumor suppressor gene on chromosome 9p21 occurs in a wide range of human tumors, and mutations in the gene have been shown to segregate with familial predisposition to malignant melanoma. We have used a variety of assays to examine the functional properties of tumor-associated alleles, including eight premature termination mutants, eight missense mutants, and three isoforms of p16 initiated at different amino-terminal methionine codons. The amino- and carboxy-terminal domains of the protein, outside the ankyrin-like repeats, appeared to be dispensable, but the majority of the premature termination mutations led to loss of function. Of the missense mutations tested, four displayed clear loss of function whereas two behaved like the wild type under all conditions tested. The remaining two mutations, a G-to-W mutation at position 101 (Gl01W) and V126D, both of which are associated with familial melanoma, were found to be temperature sensitive for binding to Cdk4 and Cdk6 in vitro, for inhibiting cyclin D1-Cdk4 in a reconstituted pRb-kinase assay, and for increasing the proportion of G1-phase cells following transfection. These findings clarify previous disparities and argue strongly that p16CDKN2 is a bona fide tumor suppressor associated with familial melanoma.
Automatic Switching at the Edmonton Television Studios (1966)

The Edmonton CBC television studios were installed in 1962 with the accent on unattended and automatic operation using a minimum of staff. Present facilities include a 2-camera studio, a single remotely controlled camera studio, two videotape recorders, two telecines and two mobile units. The single operator master control position has now been automated using the “Chronolog” system. The advantages (and disadvantages) of this system in a television operation of this size are discussed in the light of two years of experience with it.
A review of gas sensors employed in electronic nose applications (2004)

This paper reviews the range of sensors used in electronic nose (e‐nose) systems to date. It outlines the operating principles and fabrication methods of each sensor type as well as the applications in which the different sensors have been utilised. It also outlines the advantages and disadvantages of each sensor for application in a cost‐effective low‐power handheld e‐nose system.
Guidebook to the homeobox genes (1994)

Preface 1. A history of the homeobox 2. The homeobox in cell differentiation and evolution 3. A comprehensive classification of homeobox genes Short descriptions of each homeobox gene References
Subcutaneous Capillary Filtrate Collector for Measurement of Blood Glucose (1992)

The capillary filtrate collector (CFC) is a device that creates an ultrafiltrate at 50-100 microliters/h from subcutaneous capillaries, and carries this filtrate out of the body for chemical analysis. From inside out, components include three looped hollow fiber ultrafiltration membranes, a polytetrafluoroethylene (PTFE) cuff, polyurethane tubing, a "Y" connector leading to a sampling port, a hub, and a needle placed into a 5 ml vacutainer tube. Animal studies have demonstrated that the CFC filtrate glucose level is exactly that of blood at the time the filtrate is created. The authors have performed clinical trials to determine the correlation of blood glucose and CFC glucose levels, and the time delay between contemporary samples. Seven diabetic patients wore the CFC device, tubing, and vacutainer tube for 1 month. In home monitored diabetic patients, fingerstick glucose measurements were performed at the usual daily schedule. The vacutainer was then evacuated, and this average sample analyzed and compared with the average of prior blood glucose levels. An optical device then was applied to measure the linear velocity of CFC fluid through external tubing, and predict the time for fluid to pass from fibers to the sampling port (average, 25 min). Capillary filtrate collector samples drawn at this time had glucose concentrations that generally correlated with blood levels. In diabetic patients on hemodialysis, the vacutainer was evacuated at the start of each treatment, and CFC and blood samples were drawn every 20 min during the treatment. Comparison of glucose-versus-time curves indicated a reasonable correlation between blood and CFC samples, with a delay related to flow rate (which declined 50% during dialysis).(ABSTRACT TRUNCATED AT 250 WORDS)
Brain function in Duchenne muscular dystrophy (2002)

Duchenne muscular dystrophy (DMD) is the second most commonly occurring genetically inherited disease in humans. It is an X-linked condition that affects approximately one in 3300 live male births. It is caused by the absence or disruption of the protein dystrophin, which is found in a variety of tissues, most notably skeletal muscle and neurones in particular regions of the CNS. Clinically DMD is characterized by a severe pathology of the skeletal musculature that results in the premature death of the individual. An important aspect of DMD that has received less attention is the role played by the absence or disruption of dystrophin on CNS function. In this review we concentrate on insights into this role gained from investigation of boys with DMD and the genetically most relevant animal model of DMD, the dystrophin-deficient mdx mouse. Behavioural studies have shown that DMD boys have a cognitive impairment and a lower IQ (average 85), whilst the mdx mice display an impairment in passive avoidance reflex and in short-term memory. In DMD boys, there is evidence of disordered CNS architecture, abnormalities in dendrites and loss of neurones, all associated with neurones that normally express dystrophin. In the mdx mouse, there have been reports of a 50% decrease in neurone number and neural shrinkage in regions of the cerebral cortex and brainstem. Histological evidence shows that the density of GABA(A) channel clusters is reduced in mdx Purkinje cells and hippocampal CA1 neurones. At the biochemical level, in DMD boys the bioenergetics of the CNS is abnormal and there is an increase in the levels of choline-containing compounds, indicative of CNS pathology. The mdx mice also display abnormal bioenergetics, with an increased level of inorganic phosphate and increased levels of choline-containing compounds. Functionally, DMD boys have EEG abnormalities and there is some preliminary evidence that synaptic function is affected adversely by the absence of dystrophin. Electrophysiological studies of mdx mice have shown that hippocampal neurones have an increased susceptibility to hypoxia. These recent findings on the role of dystrophin in the CNS have implications for the clinical management of boys with DMD.
Toward Fully Synthetic N‐Linked Glycoproteins (2003)

Substantial quantities of fully synthetic, homogeneous, N-linked glycopeptides may be accessed by a highly convergent and flexible protocol. Only four transformations are required to generate naturally linked glycopeptides in high yield. Amination of a free glycan is followed by acylation with an asparagine residue of a peptide and Fmoc deprotection; native chemical ligation completes the puzzle to afford N-linked glycopeptides (see scheme). Fmoc=9-fluorenylmethoxycarbonyl.
Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline (2010)

We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and, in some men in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected by measurement of free or bioavailable testosterone level, using validated assays. We recommend testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. We recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer such as African-Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score above 19, or uncontrolled or poorly controlled heart failure. When testosterone therapy is instituted, we suggest aiming at achieving testosterone levels during treatment in the mid-normal range with any of the approved formulations, chosen on the basis of the patient's preference, consideration of pharmacokinetics, treatment burden, and cost. Men receiving testosterone therapy should be monitored using a standardized plan.
Gray-box extraction of execution graphs for anomaly detection (2004)

Many host-based anomaly detection systems monitor a process by observing the system calls it makes, and comparing these calls to a model of behavior for the program that the process should be executing. In this paper we introduce a new model of system call behavior, called an <i>execution graph</i>. The execution graph is the first such model that both requires no static analysis of the program source or binary, and conforms to the control flow graph of the program. When used as the model in an anomaly detection system monitoring system calls, it offers two strong properties: (i) it accepts only system call sequences that are consistent with the control flow graph of the program; (ii) it is maximal given a set of training data, meaning that any extensions to the execution graph could permit some intrusions to go undetected. In this paper, we formalize and prove these claims. We additionally evaluate the performance of our anomaly detection technique.
The Bacterial Second Messenger cdiGMP Exhibits Promising Activity as a Mucosal Adjuvant (2007)

The development of mucosal adjuvants is still a critical need in vaccinology. In the present work, we show that bis(3',5')-cyclic dimeric GMP (cdiGMP), a second messenger that modulates cell surface properties of several microorganisms, exerts potent activity as a mucosal adjuvant. BALB/c mice were immunized intranasally with the model antigen beta-galactosidase (beta-Gal) coadministered with cdiGMP. Animals receiving cdiGMP as an adjuvant showed significantly higher anti-beta-Gal immunoglobulin G (IgG) titers in sera than controls (i.e., 512-fold [P < 0.05]). Coadministration of cdiGMP also stimulated efficient beta-Gal-specific secretory IgA production in the lung (P < 0.016) and vagina (P < 0.036). Cellular immune responses were observed in response to both the beta-Gal protein and a peptide encompassing its major histocompatibility complex class I-restricted epitope. The IgG1-to-IgG2a ratio of anti-beta-Gal antibodies and the observed profiles of secreted cytokines suggest that a dominant Th1 response pattern is promoted by mucosal coadministration of cdiGMP. Finally, the use of cdiGMP as a mucosal adjuvant also led to the stimulation of in vivo cytotoxic T-lymphocyte responses in C57BL/6 mice intranasally immunized with ovalbumin and cdiGMP (up to 30% of specific lysis). The results obtained indicate that cdiGMP is a promising tool for the development of mucosal vaccines.
Mapping of sensory responses to epidural stimulation of the intraspinal neural structures in man (1993)

A database is presented of sensory responses to electrical stimulation of the dorsal neural structures at various spine levels in 106 subjects subjected to epidural spinal cord stimulation. All patients were implanted for chronic pain management and were able to perceive stimulation in the area of pain. All patients entered in this study were able to reliably report their stimulation pattern. Several patients were implanted with more than one electrode array. The electrode arrays were placed in the dorsal epidural space at levels between C-1 and L-1. The structures that were likely involved include the dorsal roots, dorsal root entry zone, dorsal horn, and dorsal columns. At the present time, exact characterization of the structure being stimulated is possible only in limited instances. Various body areas are presented with the correspondent spine levels where implanted electrodes generate paresthesias. Areas that are relatively easy targets for stimulation are the median aspect of the hand, the abdominal wall, the anterior aspect of the thigh, and the foot. Some areas are particularly difficult to cover with stimulation-induced paresthesias; these include the C-2 distribution, the neck, the low back, and the perineum.
Specific sequestering agents for the actinides. 21. Synthesis and initial biological testing of octadentate mixed catecholate-hydroxypyridinonate ligands (1993)

The linear octadentate ligand 3,4,3-LIHOPO, which contains four 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) groups, is the most effective agent for in vivo chelation of Pu(IV) yet prepared. However, its clinical potential is limited by acute toxicity of the free ligand (but not Fe3+ complex) at high dosage. The high acidity of HOPO ligands and the much lower acidity of catechol (CAM) ligands suggested that mixed octadentate (CAM-HOPO) ligands containing one or two 1,2-HOPO and three (or two) catechol (CAM) groups might be as effective for Pu removal [fully eight-coordinated Pu(IV) complexes formed at pH > or = 6] and less toxic than 3,4,3-LIHOPO. Treatment of spermine with 3-(2,3-dimethoxybenzoyl)thiazol-idine-2-thione (1) (molar ratio 2:1) gave 1,14-bis(2,3-dimethoxybenzoyl)-1,5,10,14-tetraazatetradecane (2, DiCAM-spermine) in 80% yield. Addition of 2 to a 2-fold excess of the reaction product of 1-hydroxy-2-pyridone-6-carboxylic acid (HOPO-C) and 1,1'-carbonyldiimidazole (CDI) in N,N-dimethylformamide (DMF) and deprotection with BBr3 gave 1,14-bis(2,3-dihydroxybenzoyl)-5,10-bis(1-hydroxy-2-pyridon-6-oyl) -1,5,10,14-tetraaza-tetradecane [3, 3,4,3-LI(diCAM-diHOPO)] in 5% yield. Addition of 2 to an equimolar amount of the reaction product of HOPO-C and CDI in N,N-dimethylacetamide (DMAA), purification of the hexadentate intermediate, subsequent treatment with an equimolar amount of 2,3-dimethoxybenzoyl chloride (DMB), and deprotection with BBr3 gave 1,5,14-tris(2,3-dihydroxybenzoyl)-10-(1-hydroxy-2-pyridon-6-oyl)-1 ,5,10,14- tetraazatetradecane [4, 3,4,3-LI(triCAM-HOPO)] in 5% yield. Ligands were administered to mice [30 mumol kg-1 ip at 1 h or orally at 3 min after iv injection of plutonium(IV)-238 citrate, kill at 24 h]. Plutonium excretion after injection of either CAM-HOPO ligand was 700% of that for 24-h Pu-injected controls, 140% of that for mice given the tetracatecholate analogue 3,4,3-LICAM (significantly more, p < 0.01), but only 80% of that promoted by 3,4,3-LIHOPO (significantly less). Orally administered 3,4,3-LI-(diCAM-diHOPO) promoted significantly more Pu excretion than an equimolar amount of CaNa3DTPA. Potency of the CAM-HOPO ligands for in vivo chelation of Pu(IV) resembled that of structurally hexadentate tris-(hydroxypyridinonate) and tris(sulfocatecholate) ligands and functionally hexadentate tetrakis-(sulfocatecholate) and tetrakis(carboxycatecholate) ligands. The Pu complexes of the CAM-HOPO ligands are to some degree unstable at pH < 7.4, as judged by Pu residues in kidneys in excess of 24-h Pu-injected controls. Synthetic yields were insufficient for chemical investigations or evaluation of acute toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Conceptual and empirical developments of marketing channel conflict (1989)

Managers regularly have to struggle with conflict within the marketing channel and it is therefore important that marketing managers should have an understanding of conflict and its meaning in the channel setting. This paper attempts to provide a background to this understanding by reviewing the conceptual and empirical developments in the field of marketing channel conflict. These developments are drawn together into an integrated model of current research into channel conflict.