gebhart/patrepeval huggingface dataset:
Chronoregulation by Asparagine Deamidation (2007)

Every asparagine in every protein undergoes nonenzymatic deamidation to aspartate or isoaspartate at a rate determined by the surrounding protein structure and cellular environment. Under physiologic conditions, the deamidation half-life of individual asparagines in proteins is proposed to range from less than a day to several centuries. More than 200 proteins have been shown to undergo deamidation to a meaningful degree, and modeling predicts that hundreds more undergo deamidation at rates that have the potential to be of biological consequence. Because deamidation converts an asparagine into an aspartate or isoaspartate, it introduces a negative charge into a protein and results in the isomerization of a residue. Therefore, deamidation has the potential to change protein function. Additionally, deamidation is thought to render some proteins more susceptible to degradation. In most instances in which asparagine deamidation has been identified in vivo, it is involved in pathology. Hence, deamidation has been viewed primarily as a form of protein damage. However, the pervasiveness and evolutionary persistence of these unstable asparagines suggest that they may have a beneficial role. Notably, the change of even a single neighboring amino acid can have a marked effect on the rate of deamidation of an asparagine. Therefore, the underlying rate of deamidation of any asparagine is genetically programmable. This characteristic, combined with the wide range of deamidation rates that can be programmed, imparts to asparagines the potential to serve as molecular timers that regulate protein function and stability.
Management of keloids and hypertrophic scars: current and emerging options (2013)

In the context of growing aesthetic awareness, a rising number of patients feel disappointed with their scars and are frequently seeking help for functional and aesthetic improvement. However, excessive scarring following surgery or trauma remains difficult to improve despite a plethora of advocated treatment strategies as frequently observed in daily clinical routine. It is thus still preferable to prevent scarring by minimizing risk factors as much as possible. Hence, it remains crucial for the physician to be aware of basic knowledge of healing mechanisms and skin anatomy, as well as an appreciation of suture material and wound closure techniques to minimize the risk of postoperative scarring. Next to existing, well known prophylactic and therapeutic strategies for the improvement of excessive scarring, this article discusses emerging techniques such as intralesional cryotherapy, intralesional 5-fluorouracil, interferon, and bleomycin. Some of them have been successfully tested in well-designed trials and already have extended or may extend the current spectrum of excessive scar treatment in the near future. Innovative options such as imiquimod 5% cream, photodynamic therapy, or botulinum toxin A may also be of certain importance; however, the data currently available is too contradictory for definite recommendations.
Development of a 3D real time gesture recognition methodology for virtual environment control (2008)

In this paper, we propose a real time 3D gesture recognition system that relies on the state based approach. The novelty of this work is the introduction of probabilistic neural networks (PNNs) to characterize the uncertain boundaries of each state. The 3D gestures are modeled as a sequence of states in a configuration space; the number of states and their spatial parameters are calculated by dynamic k-means clustering on the training data of the gesture without temporal information. Gesture recognition is performed using a simple Finite State Machine (FSM), where, each state transition depends only on the output of its corresponding PNN and optionally on its time restrictions (minimum and maximum time permitted in the state). If a recognizer reaches its final state, then it could be said that a gesture is recognized. The approach is illustrated with the implementation of a real time system that recognizes the semantic meaning of seven basic gestures of the Indian Dance, the description of the system and the technologies used, it will be described in detail in the paper.
Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma (2016)

The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DON's therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DON's amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.
Prolonged changes in excitability of pyramidal tract neurones in the cat: a post‐synaptic mechanism. (1979)

1. Prolonged changes in the excitability of cortical neurones can be produced by altering their firing rates for brief periods. In the anaesthetized cat, increased firing of pyramidal tract cells induced by trains of antidromic conditioning shocks led to increases in cell excitability, as measured by the size of the mass response at the medullary pyramid to test shocks applied to the cortical surface. We have shown in two ways that post-synaptic mechanisms could be responsible. 2. In one experimental design, MgCl2 solution (1 mole/l.) was applied to the cortical surface in order to block synaptic activity throughout the cortical depth. Following antidromic conditioning trains, cell excitability was increased; the size of the mass response was up to 30% larger than the control values. This persisted undiminished for up to 3 hr. 3. In the second experimental design, synaptic activity was not blocked, but we compared the effects of antidromic plus synaptic activation of pyramidal tract cells with the effects of synaptic activation alone. Antidromic plus synaptic activation was obtained by applying conditioning trains to the pyramidal tract at the medulla ipsilateral to the cortical test shock; prolonged increases in the ipsilateral response to the test shock were produced. Synaptic activation alone was obtained by the same conditioning trains, but in those cells whose axons projected into the contralateral pyramidal tract; prolonged increases in the contralateral response to the cortical test shock were never seen. In many instances prolonged decreases in excitability were found. 4. We conclude that prolonged increases in excitability of pyramidal tract cells can occur in the absence of any synaptic input, demonstrating that the underlying mechanism is post-synaptic; this does not preclude the action of synaptic mechanisms when synaptic transmission is not blocked.
A Proline-Rich Motif (PPPY) in the Gag Polyprotein of Mason-Pfizer Monkey Virus Plays a Maturation-Independent Role in Virion Release (1998)

Virus assembly represents one of the last steps in the retrovirus life cycle. During this process, Gag polyproteins assemble at specific sites within the cell to form viral capsids and induce membrane extrusion (viral budding) either as assembly progresses (type C virus) or following formation of a complete capsid (type B and type D viruses). Finally, the membrane must undergo a fusion event to pinch off the particle in order to release a complete enveloped virion. Structural elements within the MA region of the Gag polyprotein define the route taken to the plasma membrane and direct the process of virus budding. Results presented here suggest that a distinct region of Gag is necessary for virus release. The pp24 and pp16 proteins of the type D retrovirus Mason-Pfizer monkey virus (M-PMV) are phosphoproteins that are encoded in the gag gene of the virus. The pp16 protein is a C-terminally located cleavage product of pp24 and contains a proline-rich motif (PPPY) that is conserved among the Gag proteins of a wide variety of retroviruses. By performing a functional analysis of this coding region with deletion mutants, we have shown that the pp16 protein is dispensable for capsid assembly but essential for virion release. Moreover, additional experiments indicated that the virus release function of pp16 was abolished by the deletion of only the PPPY motif and could be restored when this motif alone was reinserted into a Gag polyprotein lacking the entire pp16 domain. Single-amino-acid substitutions for any of the residues within this motif confer a similar virion release-defective phenotype. It is unlikely that the function of the proline-rich motif is simply to inhibit premature activation of protease, since the PPPY deletion blocked virion release in the context of a protease-defective provirus. These results demonstrate that in type D retroviruses a PPPY motif plays a key role in a late stage of virus budding that is independent of and occurs prior to virion maturation.
Culinary trompe-l'oeil: A new concept in coating (2012)

In the course of any creative innovation, the visual connection is a constant that, even unconsciously, influences the work. The present paper reveals the development of formulas and recipes that arise in order to realize what, in principle, is no more than an exercise in visual replication of a product that is foreign to a given culture. After the execution of this imitation, with hindsight one perceives a culinary object that is literally an edible stone—all this by means of various stages of games of perception that seem to alternate between mineral and vegetable. The point of departure for such a strategy was our initial research in formulating edible coatings. This in turn led to a culinary formula for replicating a tunta or Andean potato. The technical development of this new culinary object, here serves as a test case for the theoretical basis of this paper. To the extent that the process of this development to its culmination successfully achieves the imitation of an Andean potato, this process reveals a new culinary category that creates an object that retains the same sensory qualities of the potato, but with the outward aspect of a stone gathered from a river bed—to this end, the process modifies the composition of the coating by incorporating various colorings. On the one hand, the aim is to imitate an ingredient that is inherently edible; on the other, the idea is to surpass that imitation by investing the ingredient with apparent qualities of objects not fit for human consumption: river stones. The experiment focusses primarily on the development of a mixture of kaolin and lactose dissolved in water. The application of a formula that mainly comprises these elements opens the possibility to transcend the basic trompe l'oeil exercise in illusion with a new idea of food coating. That is to say that the coating does not merely transform the appearance of the product; but also, in a manner that coincides with the completion of cooking, retains the humidity of its content. It is also a fact that, at the same time, it manifests one of the few cases of retaining a crunchy surface while hot—since it is rare in any traditional recipe that crunchiness and humidity could be compatible with such a texture.
The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease (2007)

Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)-12 [signalling through signal transduction and activator of transcription (STAT)-4] skews towards Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth factor (TGF)-beta towards Treg and IL-6 and TGF-beta towards Th17. The committed cells are characterized by expression of specific transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORgammat for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)-gamma and IL-17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1-dependent have been demonstrated subsequently to have a non-redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen-induced arthritis. In contrast, Tregs have anti-inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL-17 and Treg biology and expand on this hypothesis.
Analysis of Tyrosine-O-Sulfation (2009)

Tyrosine O-sulfation was first described about 50 years ago as a post-translational modification of fibrinogen (1). In the following thirty years it was considered to be a rare modification affecting only a few proteins and peptides. However, in the beginning of the 1980s tyrosine (Tyr) sulfation was shown to be a common modification and since then an increasing number of proteins have been identified as sulfated. The target proteins belong to the classes of secretory, plasma membrane, and lysosomal proteins, which reflects the intracellular localization of the enzymes catalyzing Tyr sulfation, the tyrosylprotein sulfotrans-ferases (TPSTs). TPSTs are type II integral membrane glycoproteins that reside in the trans Golgi network and use adenosine 3′-phosphate 5′-phosphosulfate (PAPS) as a co-substrate and sulfate donor. In higher organisms, 2 enzymes have been identified and cloned and they appear to be ubiquitously expressed in tissues (2–4). Moreover, homologous genes are present in lower eukaryotes as well as in the nematode Caenorhabditis elegans, fruit fly, and zebrafish. Both TPST-1 and TPST-2 knock-out mice models have been established and both display distinct phenotypes. The TPST-1 knock out mice are slightly smaller than wild-type mice and the female produces smaller litters (5). The TPST-2 knockout mouse has delayed growth but reaches normal weight at 10 wk. Strikingly, the TPST-2 knock-out male is infertile (6). The biological function of Tyr sulfation is modulation of protein-protein interactions. For instance, Tyr sulfation is necessary for binding of the peptide hormone cholecystokinin (CCK) to the CCK-1 receptor (7); it is critical for interactions between p-selectin and PSGL-1 (P-Selectin Glycoprotein Ligand-l) (8); between hirudin and thrombin (9); and it modulates the ability of HIV -1 virus to enter cells via the chemokin receptor CCR5 and CD4 (10). In addition, sulfation has been reported to modulate proteolytic processing (11) and secretion rates of secretory proteins (12). From these functions, it follows that it is not only important to detect Tyr sulfation, but also to identify the sulfation site to establish effects on the activity on the protein. Attempts have been made to determine a consensus site for tyrosine sulfation and generate algorithms that predict sulfation sites (13–15), one of these is the “sulfinator,” which is available at www.expasy.org. However, it is known that the sulfinator at best gives an indication of possible sulfation sites, and it has been shown that nontypical structures, which are not identified by the sulfinator, can be sulfated (16,17).
AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer (2015)

AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).
Circulating Methylated SEPT9 DNA in Plasma Is a Biomarker for Colorectal Cancer (2009)

Circulating methylated SEPT9 DNA, as measured in the new (m)SEPT9 assay, is a valuable biomarker for minimally invasive detection of colorectal cancer. The new assay is amenable to automation and standardized use in the clinical laboratory.
Light-Mediated Spatial Control via Photolabile Fluorescently Quenched Peptide Cassettes (2010)

Light-regulatable compounds are finding increasing utility as spatial and temporal probes of biological behavior. An independent measure of successful light-induced structural change is possible when alteration (e.g., activation, deactivation, etc.) of the bioprobe can be directly linked to a fluorescent readout. We have identified a series of photolabile fluorescently quenched cassettes that display extraordinarily large fluorescence enhancements upon photolysis. A pair of cassettes has been inserted into mitochondrial localization sequences to assess an organelle-targeted light-mediated release strategy for controlling biological activity. The peptide constructs are readily absorbed by mitochondria and subsequently can be cleaved in a light-dependent fashion as assessed by the predicted changes in absorbance and fluorescence.
Culture in vitro of isolated guinea pig megakaryocytes: recovery, survival, morphologic changes, and maturation (1977)

Isolated guinea pig megakaryocytes were maintained in liquid cultures for up to 4 days. Megakaryocytes were incubated in siliconized glass vials in Dulbecco's Modified Eagle Medium with 5%-10% guinea pig serum and 2.3% bovine serum albumin. Cultured megakaryocytes did not adhere to glass vials and were almost entirely recovered by aspiration. No reproduction or cell division of megakaryocytes occurred. A small decline in viability occurred promptly on placing the freshly isolated cells in culture medium and could be attributed to reexposure to calcium. On incubation there was little further cell death. Up to 2 days in culture the megakaryocytes remained morphologically intact and appeared similar to megakaryocytes in situ. Megakaryocytes matured in culture with a loss of cytoplasmic basophilia, an increase in granule content, and progressive changes in nuclear configuration. The most mature megakaryocytes developed pseudopod formation but large-scale platelet liberation was not seen. The ability to culture megakaryocytes in vitro will allow more extensive biochemical and physiologic studies of this cell than previously possible.
PSEUDOMONAS AERUGINOSA INFECTION IN CYSTIC FIBROSIS: (1977)

P. aeruginosa strains originating from the respiratory tract of patients with cystic fibrosis (CF) and patients with other diseases (non-CF) were analysed with regard to their sensitivity to the bactericidal activity of human serum. P. aeruginosa strains isolated from CF patients were more sensitive than strains from non-CF patients to the bactericidal activity of normal human serum. The bactericidal activity was heatlabile. As regards the sensitivity to normal human serum, mucoid and non-mucoid variants were not found to differ. Strains originating from chronically infected CF patients with many precipitins against these bacteria did not differ with respect to serum sensitivity from strains originating from intermittently colonized CF patients without P. aeruginosa precipitins. Compared with normal sera, CF sera showed similar or higher bactericidal activity against a panel of P. aeruginosa strains. In this respect, any difference between CF sera with precipitins and CF sera without precipitins against P. aeurginosa was not found. Sera from three CF patients chronically infected with P. aeruginosa, and with many precipitins against these bacteria, showed a selective inability in bactericidal activity against the patients' own P. aeruginosa isolate possibly reflecting the presence of "bactericidal blocking" antibodies.
Optimizing economic outcomes in antibiotic therapy of patients with acute bacterial exacerbations of chronic bronchitis (2000)

The social, medical and economic effects of acute bacterial exacerbations of chronic bronchitis on individual patients and the resource implications of this disease for the healthcare sector are considerable. Optimizing the selection of patients who should receive antibiotics according to stringent clinical criteria is the first step in promoting good clinical practice and cost-effectiveness. Antibiotic efficacy is then the major driver of cost, especially when it reduces the need for hospitalization. Resistance to first-line antibiotics can be expected to increase the risk of treatment failure. Other drivers of cost include non-compliance, which predisposes to therapeutic failure, and the selection of resistant strains. Treatment regimens of short duration, once-daily dosing and good tolerability are determinants of good compliance and cost savings. The expenses of first-line antibiotics typically account for only a small proportion of the overall costs of healthcare and the cheapest antibiotics are not necessarily the most cost-effective. The clinical success rate of first-line therapy is the primary determinant of the overall expenditure on healthcare because of the high costs associated with treatment failure, especially if it leads to hospitalization. Factors such as poor patient compliance and high antibiotic resistance rates, which undermine the clinical efficacies of first-line therapy, will increase the overall costs of treatment.
Telmisartan Plus HCTZ vs. Amlodipine Plus HCTZ in Older Patients With Systolic Hypertension: Results From a Large Ambulatory Blood Pressure Monitoring Study (2006)

Systolic hypertension often requires combination therapy. Few data exist comparing angiotensin receptor blocker plus diuretic therapy with other combinations in older patients. In a prospective, randomized, open-label, blinded-end point trial, patients (> or =60 years of age) with predominantly systolic hypertension received telmisartan 40-80 mg or amlodipine 5-10 mg for 8 weeks, before the addition of hydrochlorothiazide (HCTZ) 12.5 mg for a further 6 weeks. Twenty-four-hour ambulatory blood pressure monitoring showed that telmisartan plus HCTZ (n=448) and amlodipine plus HCTZ (n=424) changed systolic blood pressure for the last 6 hours of the dosing interval by -18.3 and -17.4 mm Hg, respectively (p=0.2520). Over the 24-hour period, telmisartan plus HCTZ was superior (-19.3 and -17.2 mm Hg, respectively; p=0.001) and provided higher systolic control rates (65.9% and 58.3%, respectively; p=0.0175). Adverse events (41.2% and 53.7%, respectively) and discontinuations (5.0% and 11.3%, respectively) were lower (p<0.0001) with telmisartan than with amlodipine, mainly due to peripheral edema (1.2% and 24.3%, respectively).