gebhart/patrepeval huggingface dataset:
2-Amino-2-deoxyisochorismate Is a Key Intermediate in Bacillus subtilis p-Aminobenzoic Acid Biosynthesis (2009)

Chorismate is an important and central metabolite branching off to the biosyntheses of aromatic amino acids and p-aminobenzoic acid (pABA), a component of the vitamin folic acid. Here we report on a novel variation of a unified catalytic mechanism in Bacillus subtilis pABA biosynthesis that includes the formation of a new intermediate, 2-amino-2-deoxyisochorismate (ADIC), thus significantly differing from the mechanism in Escherichia coli. In B. subtilis, chorismate is converted to ADIC, which is catalyzed by aminodeoxychorismate synthase (ADCS). In a second step, ADIC is converted to aminodeoxychorismate (ADC) by addition of ammonia to C4, also catalyzed by ADCS. The third step is the aminodeoxychorismate lyase-catalyzed elimination of pyruvate from ADC. To our knowledge, B. subtilis aminodeoxychorismate synthase is the first enzyme exhibiting ADIC synthase activity in primary metabolism. We further provide evidence that pABA biosynthesis via ADIC might be a common mechanism for several other microorganisms.
Motility and Chemotaxis in Agrobacterium tumefaciens Surface Attachment and Biofilm Formation (2007)

Bacterial motility mechanisms, including swimming, swarming, and twitching, are known to have important roles in biofilm formation, including colonization and the subsequent expansion into mature structured surface communities. Directed motility requires chemotaxis functions that are conserved among many bacterial species. The biofilm-forming plant pathogen Agrobacterium tumefaciens drives swimming motility by utilizing a small group of flagella localized to a single pole or the subpolar region of the cell. There is no evidence for twitching or swarming motility in A. tumefaciens. Site-specific deletion mutations that resulted in either aflagellate, flagellated but nonmotile, or flagellated but nonchemotactic A. tumefaciens derivatives were examined for biofilm formation under static and flowing conditions. Nonmotile mutants were significantly deficient in biofilm formation under static conditions. Under flowing conditions, however, the aflagellate mutant rapidly formed aberrantly dense, tall biofilms. In contrast, a nonmotile mutant with unpowered flagella was clearly debilitated for biofilm formation relative to the wild type. A nontumbling chemotaxis mutant was only weakly affected with regard to biofilm formation under nonflowing conditions but was notably compromised in flow, generating less adherent biomass than the wild type, with a more dispersed cellular arrangement. Extragenic suppressor mutants of the chemotaxis-impaired, straight-swimming phenotype were readily isolated from motility agar plates. These mutants regained tumbling at a frequency similar to that of the wild type. Despite this phenotype, biofilm formation by the suppressor mutants in static cultures was significantly deficient. Under flowing conditions, a representative suppressor mutant manifested a phenotype similar to yet distinct from that of its nonchemotactic parent.
An Improved Method for Three-dimensional Reconstruction of Protein Expression Patterns in Intact Mouse and Chicken Embryos and Organs (2007)

We have developed a wholemount immunofluorescence protocol for the simultaneous detection of up to three proteins in mouse and chicken embryos. Combined with Murray's clearing reagent (BABB) and microscope objectives with long working ranges and high numerical apertures mounted on a confocal microscope, cellular resolution can be obtained in depths offering the possibility of examining expression patterns in entire organs or embryos. Three-dimensional projections of the optical confocal sections can be computed with computer software allowing rotation around any axis. The protocol is robust and we find that most antibodies working on tissue sections also work with this protocol. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
One‐step syntheses of macrocyclic compounds: A short review (2001)

Abstract Macrocyclic ligands have been prepared by various one‐step cyclooligomerization processes. This short review covers one‐step cyclization reactions involving the formation of four to twenty or more new covalent bonds. The new macrocycles reviewed include cyclophanes, biscrown ethers, cryptands, macrolides, cage compounds, calixarenes, homocalixarenes, cucubiturils, and supercryptands all prepared by one‐step syntheses.
Activation and stabilization of human tryptophan hydroxylase 2 by phosphorylation and 14-3-3 binding (2008)

TPH (tryptophan hydroxylase) catalyses the rate-limiting step in the synthesis of serotonin, and exists in two isoforms: TPH1, mainly found in peripheral tissues and the pineal body, and TPH2, a neuronal form. In the present study human TPH2 was expressed in Escherichia coli and in HEK (human embryonic kidney)-293 cells and phosphorylated using several different mammalian protein kinases. TPH2 was rapidly phosphorylated to a stoichiometry of 2 mol of phosphate/mol of subunit by PKA (protein kinase A), but only to a stoichiometry of 0.2 by Ca(2+)/calmodulin dependent protein kinase II. Both kinases phosphorylated Ser(19), but PKA also phosphorylated Ser(104), as determined by MS, phosphospecific antibodies and site-directed mutagenesis of several possible phosphorylation sites, i.e. Ser(19), Ser(99), Ser(104) and Ser(306). On average, purified TPH2 WT (wild-type) was activated by 30% after PKA phosphorylation and studies of the mutant enzymes showed that enzyme activation was mainly due to phosphorylation at Ser(19). This site was phosphorylated to a stoichiometry of up to 50% in HEK-293 cells expressing TPH2, and the enzyme activity and phosphorylation stoichiometry was further increased upon treatment with forskolin. Purified PKA-phosphorylated TPH2 bound to the 14-3-3 proteins gamma, epsilon and BMH1 with high affinity, causing a further increase in enzyme stability and activity. This indicates that 14-3-3 proteins could play a role in consolidating and strengthening the effects of phosphorylation on TPH2 and that they may be important for the regulation of serotonin function in the nervous system.
The role of adherens junctions and VE-cadherin in the control of vascular permeability (2008)

Endothelial cells control the passage of plasma constituents and circulating cells from blood to the underlying tissues. This specialized function is lost or impaired in several pathological conditions - including inflammation, sepsis, ischemia and diabetes - which leads to severe, and sometimes fatal, organ dysfunction. Endothelial permeability is regulated in part by the dynamic opening and closure of cell-cell adherens junctions (AJs). In endothelial cells, AJs are largely composed of vascular endothelial cadherin (VE-cadherin), an endothelium-specific member of the cadherin family of adhesion proteins that binds, via its cytoplasmic domain, to several protein partners, including p120, beta-catenin and plakoglobin. Endogenous pathways that increase vascular permeability affect the function and organization of VE-cadherin and other proteins at AJs in diverse ways. For instance, several factors, including vascular endothelial growth factor (VEGF), induce the tyrosine phosphorylation of VE-cadherin, which accompanies an increase in vascular permeability and leukocyte diapedesis; in addition, the internalization and cleavage of VE-cadherin can cause AJs to be dismantled. From the knowledge of how AJ organization can be modulated, it is possible to formulate several pharmacological strategies to control the barrier function of the endothelium. We discuss the possible use of inhibitors of SRC and other kinases, of agents that increase cAMP levels, and of inhibitors of lytic enzymes as pharmacological tools for decreasing endothelial permeability.
Regularities in the two-photon spectra of polysubstituted benzenes (1982)

The regularities in the two-photon 1Lb ← 1A spectrum of polysubstituted benzenes have been studied. Orientation intensity rules are derived which predict the relative two-photon intensities for mono:ortho:meta:para:1,2,3:1,3,5:1,2,4 homosubstitution to be 1:3:1:0:4:0:1, as opposed to the one-photon rule 1:1:1:4:0:0:3. The TP 1Lb spectrum for polysubstituted fluoro- and methyl-benzenes are reported and are in good agreement with these rules. In particular, the theory shows that even in the ortho case where the excited state has A1 symmetry and in the case of Cs symmetry (e.g., 1,2,4 trisubstitution) only the symmetric tensor component, which contributes to the higher symmetry molecules, is nonzero. This prediction is confirmed by polarization experiments. For para-heterosubstitution, the theory requires the two-photon spectrum to be enhanced when the substituents are opposite in their electron donating properties. In contrast, the one-photon spectrum is enhanced when both substituents are either donating or withdrawing.
Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion (2009)

Oxidative stress can render platelets functionally less active by shedding key adhesion receptors via the activation of p38. This suggests that oxidative injury of platelets may attenuate their function.
Leveraging Disease Progression Learning for Medical Image Recognition (2018)

Unlike natural images, medical images often have intrinsic characteristics that can be leveraged for neural network learning. For example, images that belong to different stages of a disease may continuously follow a certain progression pattern. In this paper, we propose a novel method that leverages disease progression learning for medical image recognition. In our method, sequences of images ordered by disease stages are learned by a neural network that consists of a shared vision model for feature extraction and a long short-term memory network for the learning of stage sequences. Auxiliary vision outputs are also included to capture stage features that tend to be discrete along the disease progression. Our proposed method is evaluated on a public diabetic retinopathy dataset, and achieves about 3.3% improvement in disease staging accuracy, compared to the baseline method that does not use disease progression learning.
SOM230 Inhibits Insulin-Like Growth Factor-I Action in Mammary Gland Development by Pituitary Independent Mechanism: Mediated through Somatostatin Subtype Receptor 3? (2005)

Somatostatin analogs (SAs) treat acromegaly by lowering pituitary GH secretion, which, in turn, lowers systemic IGF-I. The profound systemic effect is often greater than expected in the face of only partial GH suppression. Here we report that the SA SOM230 can also act by a nonpituitary-mediated inhibition of IGF-I action. SOM230 inhibited mammary development in intact and hypophysectomized female rats, a process requiring IGF-I. IGF-I overcame this inhibition. SOM230 also inhibited other actions of IGF-I (inhibition of apoptosis, phosphorylation of insulin receptor substrate-1, and cell division). SOM230 did not reduce IGF-I mRNA abundance in mammary gland but did stimulate IGF binding protein 5 (IGFBP5). IGFBP5 was 3.75 times higher in mammary epithelium of SOM230 than in placebo animals (P < 0.001). Administration of IGFBP-5 also inhibited GH-induced mammary development (P < 0.001). Measurement of sstr(1-5) (somatostatin subtype receptor) by real-time RT-PCR revealed that the mammary glands had an abundance of sstr(3) and lower amounts of sstr(4) and sstr(5) but no sstr(1) or sstr(2.) That mammary development was also inhibited to a lesser degree than SOM230 by octreotide, whose main action is through sstr(2), strongly suggests that sstr(3) is at least in part mediating the effects of the SAs. We conclude that 1) SAs inhibit IGF-I action in the mammary gland through a novel nonpituitary mechanism; 2) IGFBP-5, here shown to inhibit pubertal mammary development, might mediate the effect; and 3) Measurement of available sstr receptors in the mammary gland suggests that sstr(3) mediates the SA activity, but sstr(5) is also a possible mediator.
BONE-GRAFTING AND BONE-GRAFT SUBSTITUTES (2002)

Christopher G. Finkemeier, MD; Department of Orthopaedic Surgery, University of California Davis Medical Center, 4860 Y Street, Suite 3800, Sacramento, CA 95817
Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome (2012)

The 8p11 myeloproliferative syndrome is a rare, aggressive myeloproliferative neoplasm characterized by constitutively active FGFR1 fusion proteins that arise from specific chromosomal translocations and which drive aberrant proliferation. Although FGFR1 inhibitors have shown in vitro activity against FGFR1 fusions, none are in use clinically and there is a need to assess additional compounds as potential therapy. Here we use cell lines and primary cells to investigate ponatinib (AP24534). Ponatinib-treated Ba/F3 cells transformed by ZMYM2-FGFR1 and BCR-FGFR1 and the FGFR1OP2-FGFR1 positive KG1A cell line showed reduced proliferation and decreased survival when compared to control cells. Inhibition induced apoptosis and reduced phosphorylation of the FGFR1 fusion proteins and substrates. Ponatinib-treated cells from 8p11 myeloproliferative syndrome patients (n=5) showed reduced colony growth compared to controls. In one evaluable patient, ponatinib specifically reduced numbers of FGFR1-fusion gene positive colonies. Ponatinib, therefore, shows considerable promise for the treatment of patients with 8p11 myeloproliferative syndrome.
Immunization with Amyloid-β Attenuates Inclusion Body Myositis-Like Myopathology and Motor Impairment in a Transgenic Mouse Model (2009)

Inclusion body myositis (IBM), the most common muscle disease to afflict the elderly, causes slow but progressive degeneration of skeletal muscle and ultimately paralysis. Hallmark pathological features include T-cell mediated inflammatory infiltrates and aberrant accumulations of proteins, including amyloid-beta (Abeta), tau, ubiquitinated-proteins, apolipoprotein E, and alpha-synuclein in skeletal muscle. A large body of work indicates that aberrant Abeta accumulation contributes to the myodegeneration. Here, we investigated whether active immunization to promote clearance of Abeta from affected skeletal muscle fibers mitigates the IBM-like myopathological features as well as motor impairment in a transgenic mouse model. We report that active immunization markedly reduces intracellular Abeta deposits and attenuates the motor impairment compared with untreated mice. Results from our current study indicate that Abeta oligomers contribute to the myopathy process as they were significantly reduced in the affected skeletal muscle from immunized mice. In addition, the anti-Abeta antibodies produced in the immunized mice blocked the toxicity of the Abeta oligomers in vitro, providing a possible key mechanism for the functional recovery. These findings provide support for the hypothesis that Abeta is one of the key pathogenic components in IBM pathology and subsequent skeletal muscle degeneration.
Mycoplasmal Infections in Chronic Illnesses: Fibromyalgia and Chronic Fatigue Syndromes, Gulf War Illness, HIV-AIDS and Rheumatoid Arthritis (1999)

Invasive bacterial infections are associated with several acute and chronic illnesses, including: aerodigestive diseases such as Asthma, Pneumonia, Inflammatory Bowel Disease; rheumatoid diseases, such as Rheumatoid Arthritis (RA); immunosuppression diseases such as HIV-AIDS; Genitourinary Infections and chronic fatigue illnesses such as Chronic Fatigue Syndrome (CFS), Fibromyalgia Syndrome (FMS) and Gulf War Illnesses (GWI). It is now apparent that such infections could be (a) causative, (b) cofactors or (c) opportunistic agents in a variety of chronic illnesses. Using Forensic Polymerase Chain Reaction we have looked for the presence of one class of invasive infection (mycoplasmal infections) inside blood leukocyte samples from patients with CFS (Myalgic Encephalomyelitis ), FMS, RA and GWI. There was a significant difference between symptomatic CFS, FMS, GWI and RA patients with positive mycoplasmal infections of any species (45-63%) and healthy positive controls (~9%) (P<0.001). This difference was even greater when specific species (M. fermentans, M. hominis, M. penetrans, M. pneumoniae) were detected. Except for GWI, most patients had multiple mycoplasmal infections (more than one species of mycoplasma). Patients with different diagnoses but overlapping signs and symptoms often have mycoplasmal infections, and such mycoplasma-positive patients generally respond to multiple cycles of particular antibiotics (doxycycline, minocycline, ciprofloxacin, azithromycin and clarithromycin). Multiple cycles of these antibiotics plus nutritional support appear to be necessary for successful treatment. In addition, immune enhancement and other supplements appear to help these patients regain their health. Other chronic infections may also be involved to various degrees with or without mycoplasmal infections in causing patient morbidity in various chronic illnesses.
Regulation of Alternative Splicing by Reversible Protein Phosphorylation (2007)

The vast majority of human protein-coding genes are subject to alternative splicing, which allows the generation of more than one protein isoform from a single gene. Cells can change alternative splicing patterns in response to a signal, which creates protein variants with different biological properties. The selection of alternative splice sites is governed by the dynamic formation of protein complexes on the processed pre-mRNA. A unique set of these splicing regulatory proteins assembles on different pre-mRNAs, generating a "splicing" or "messenger ribonucleoprotein code" that determines exon recognition. By influencing protein/protein and protein/RNA interactions, reversible protein phosphorylation modulates the assembly of regulatory proteins on pre-mRNA and therefore contributes to the splicing code. Studies of the serine/arginine-rich protein class of regulators identified different kinases and protein phosphatase 1 as the molecules that control reversible phosphorylation, which controls not only splice site selection, but also the localization of serine/arginine-rich proteins and mRNA export. The involvement of protein phosphatase 1 explains why second messengers like cAMP and ceramide that control the activity of this phosphatase influence alternative splicing. The emerging mechanistic links between splicing regulatory proteins and known signal transduction pathways now allow in detail the understanding how cellular signals modulate gene expression by influencing alternative splicing. This knowledge can be applied to human diseases that are caused by the selection of wrong splice sites.
The Sodium-Hydrogen Exchanger: From Molecule to its Role in Disease (2003)

1: Regulation of Intracellular pH in Mammalian Cells. 1. Introduction. 2. Intracellular Compartmentalization Of pH. 3. Cytoplasmic pH. 4. Intracellular Buffers. 5. Measurement Of pHi During Acid-Base Loading. 6. Transport Systems That Regulate pHi. 2: Molecular and Functional Diversity of Mammalian Na+/H+ Exchangers. 1. Introduction. 2. Genetic Heterogeneity. 3. Conclusion. 3: Two Functional Regulatory Factors of Na+/H+ Exchangers: The Proton and aHP. 1. Introduction. 2. The Proton. 3. CHP. 4. Conclusion. 4: Regulation of Expression of the Na+/H+ Exchanger in the Myocardium and Other Tissues. 1. Introduction. 2. Na+/H+ Exchanger Expression Varies In Response To The Environment. 3. Transcriptional Regulation Of The Na+/H+ Exchanger Gene. 4. Conclusion. 5: Na-H Exchange Function in Colonic Epithelial Cells. 1. Introduction. 2. Apical Membrane NHEs. 3. Basolateral Membrane NHEs. 6: NhaA Na+/H+Antiporter. Structure, Mechanism and Function in Homestasis of Na+ and pH. 1. Introduction. 2. The Response to Na+ Occurs At The Transcription Level. 3. The Ecological Importance Of The Antiporters In The Enteric Bacteria Escherichia coli And Vibrio cholerae. 4. The NhaA Protein. 5. Relationship Between Function And Structure Of NhaA. 6. Dynamics Of NhaA. 7. Dynamics In 3D Of The pH Induced Conformational Changes Of NhaA. 8. Conclusion. 7: The Use of Transgenic Animal Models to Study Na+/H+ Exchange. 1. Introduction. 2. Transgenic Studies On The NHE1 Isoform Of The Na+/H+ Exchanger. 3. Transgenic Studies On The NHE2 And NHE3 Isoform Of Na+/H+ Exchanger. 4. Pitfalls In Transgenic Studies. 5. Conclusion. 8: pH-Regulatory Mechanisms in the Mammalian Oocyte and Early Embryo. 1. Introduction. 2. Oocyte And Embryo Development. 3. Expression Of Na+/H+ Exchanger (NHE) And Anion Exchanger (AE) Isoforms In Mammalian PI Embryos. 4. Activity Of pHi-Regulatory Mechanism In PI Embryos. 5. pHiRegulatory Mechanisms During Meiosis And Fertilization. 6. Conclusion. 9: Na+/H+ Exchanger Activation by Myocardial Stretch. 1. Introduction. 2. Mechanism Of Stretch-Induced Increase Of The NHE Activity. 3. Mechanical Counterpart Of Stretch-Induced Increase Of The NHE Activity. 10: The Paradoxical Role of Na+/H+ Exchanger in the Diabetic Heart. 1. Introduction. 2. Depressed Na+/H+ Exchanger (NHE) Activity In Insulin-Deficient (TYPE I) Diabetes And Associated Increased Resistance Of Diabetic Hearts To Ischemia And Reperfusion Injury. 3. NHE In Non-Insulin-Dependent (TYPE 2) Diabetes. 4. Conclusion. 11: Role of Na-H Exchanger in Vascular Remodelling in
Economic aspects of diabetic foot care in a multidisciplinary setting: a review (2006)

Diabetic foot problems are frequent and are associated with high costs. A multidisciplinary approach to diabetic foot problems has proved to be cost saving with regard to cost of treatment itself. Nevertheless, it remained unclear if these savings could offset the overall costs involved in implementing this kind of approach. The few studies that address this issue specifically all show an acceptable cost-effectiveness, but often the profit will be evident after some years only, because long-term costs are involved. Based on these data, policymakers should foresee sufficient reimbursement for preventive and early curative measures, and not only for 'salvage manoeuvres'.
Cytokine appearance in human endotoxemia and primate bacteremia. (1988)

The results of recent work have demonstrated that endotoxin elicits the production of several immunopeptide cytokines that likely mediate the development of septic shock. Bolus injection of endotoxin (20 units per kilogram of body weight) to four volunteers resulted in peak serum cachetin/tumor necrosis factor (TNF) levels of 358 +/- 166 picograms per milliliter within 90 minutes after challenge (p less than 0.05 versus base line) and peak serum interleukin-1 levels of 2.14 +/- 0.89 units per milliliter within two hours after challenge. By contrast, the infusion of a lethal dose of live Escherichia coli to four baboons revealed peak serum cachectin/TNF levels of 20,500 +/- 9,890 picograms per milliliter within 90 minutes after bacteria were given (p less than 0.05 versus base line) and peak interleukin-1 levels of 14.2 +/- 10.1 units per milliliter three hours after bacterial challenge. No detectable monokine levels were observed in either model six hours after challenge. Interferon-gamma levels reached a peak of 2.67 +/- 1.66 nanograms per milliliter in baboon sera at eight hours after bacterial infusion and was no longer detectable by 12 hours. Interferon-gamma was not detected in the sera of humans. These results suggest that the transient release of cachectin/TNF, followed by interleukin-1 and interferon-gamma, may participate in the cascade of events noted in overwhelming bacterial invasion.
Infection-Triggered Anorexia Nervosa in Children: Clinical Description of Four Cases (2000)

There may be a link between infectious disease and some cases of AN, which raises the possibility of new treatment.