A survey on deep learning in medical image analysis

Signaling Recognition Events with Fluorescent Sensors and Switches.

A general all-atom force field for atomistic simulation of common organic molecules, inorganic small molecules, and polymers was developed using state-of-the-art ab initio and empirical parametrization techniques. The valence parameters and atomic partial charges were derived by fitting to ab initio data, and the van der Waals (vdW) parameters were derived by conducting MD simulations of molecular liquids and fitting the simulated cohesive energies and equilibrium densities to experimental data. The combined parametrization procedure significantly improves the quality of a general force field. Validation studies based on large number of isolated molecules, molecular liquids and molecular crystals, representing 28 molecular classes, show that the present force field enables accurate and simultaneous prediction of structural, conformational, vibrational, and thermophysical properties for a broad range of molecules in isolation and in condensed phases. Detailed results of the parametrization and validation f...

COMPASS: An ab Initio Force-Field Optimized for Condensed-Phase ApplicationsOverview with Details on Alkane and Benzene Compounds

The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ER alpha or ER beta protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ER alpha or ER beta complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid. Saturation ligand-binding analysis of human ER alpha and ER beta protein revealed a single binding component for [3H]-17beta-estradiol (E2) with high affinity [dissociation constant (Kd) = 0.05 - 0.1 nM]. All environmental estrogenic chemicals [polychlorinated hydroxybiphenyls, dichlorodiphenyltrichloroethane (DDT) and derivatives, alkylphenols, bisphenol A, methoxychlor and chlordecone] compete with E2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities (RBA) are at least 1000-fold lower than that of E2. Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E2 for binding to ER beta than to ER alpha. Estrogenic chemicals, as for instance nonylphenol, bisphenol A, o, p'-DDT and 2',4',6'-trichloro-4-biphenylol stimulate the transcriptional activity of ER alpha and ER beta at concentrations of 100-1000 nM. Phytoestrogens, including genistein, coumestrol and zearalenone stimulate the transcriptional activity of both ER subtypes at concentrations of 1-10 nM. The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E2 >> zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin > formononetin = ipriflavone = quercetin = chrysin for ER alpha and E2 >> genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ER beta. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ER alpha and a mixed agonist-antagonist for ER beta. In summary, while the estrogenic potency of industrial-derived estrogenic chemicals is very limited, the estrogenic potency of phytoestrogens is significant, especially for ER beta, and they may trigger many of the biological responses that are evoked by the physiological estrogens.

/pdf/interaction-of-estrogenic-chemicals-and-phytoestrogens-with-j0qbzn4u7e.pdf

Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.

Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17beta-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 A, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addition, each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.

Molecular basis of agonism and antagonism in the oestrogen receptor.

Two 2,3-diphenylindene and -indenone systems, with potential fluorescent and photofluorogenic properties, were prepared and studied as ligands for the estrogen receptor. The indene systems were prepared by Friedel-Crafts cyclization of appropriate alpha-benzyl desoxybenzoin systems, and the indenones either by oxidation of the indenes, by cyclization of alpha-benzoyl desoxybenzoins, or by acylium ion attack on tolan. Crystallographic analysis of the 2,3-diphenylindene and -indenone systems shows the phenyl substituents twisted out of the plane of the indene/indenone systems, with both torsional angles greater in the indenone than indene system; the phenyl attachment to the five-membered ring allows these systems to be considerably more planar than the related 1,2-diphenyl-3,4-dihydronaphthalene and the triarylethylene nonsteroidal estrogens. In contrast to the diphenyldihydronaphthalenes, the diarylindene and -indenone systems undergo photocyclization to phenanthrenes inefficiently. The estrogen receptor binding affinity of these systems is reasonably high (9-59% relative to estradiol), with the indenone systems having higher affinity than the indenes; additional hydroxyl substitution raises the affinity of the indenes but lowers that of the indenones. These trends can be rationalized by considering differences in molecular volumes or surface areas (related to torsional angles) and specific polar interactions.

2,3-Diarylindenes and 2,3-Diarylindenones: Synthesis, Molecular Structure, Photochemistry, Estrogen Receptor Binding Affinity, and Comparisons with Related Triarylethylenes.

2‐Arylindenes and 2‐Arylindenones: Synthesis of Probes to Study the Binding Orientation of Unsymmetrical Nonsteroidal Ligands to the Estrogen Receptor.

Abstract Background Hepatotoxicity secondary to therapy for Mycobacterium tuberculosis (MTB) is a common complication that may lead to treatment interruption. N-Acetylcysteine (NAC) exerts a hepatoprotective effect by repleting glutathione stores and enhancing the cellular antioxidant defense mechanism. NAC has been found to be protective against liver toxicity in animals treated for MTB infection. Randomized controlled trials have shown that its use in humans also decreases the risk of hepatotoxicity associated with anti-MTB treatment but there is minimal data regarding its utility for treatment of liver toxicity. Methods Patients who received NAC from January 2012 to March 2018 for prophylaxis and treatment of increasing liver function tests (LFTs) while on isoniazid (INH) were included. A retrospective review of the medical record system was performed. Results Nineteen patients were included. Eight received NAC for treatment. The average age was 49 years. Seventy percent of patients were male. The mean BMI was 25. Five patients had underlying liver cirrhosis and two had hepatic steatosis. Eleven patients had Hepatitis C (HCV) and one had active Hepatitis B infection. Ten patients had MTB pulmonary infection, thee had latent TB infection, two meningitis, and three had disseminated disease. One patient was treated for atypical mycobacterial infection. The dose of NAC used was 600 mg oral twice daily and the duration was variable. The prophylaxis group had stable LFTs during treatment, except for two patients whose enzymes increased more than three times the upper limit of normal. These two patients had underlying HCV and liver cirrhosis. Only one required discontinuation of INH. This group received NAC for an average of 47 days. The treatment group had a favorable trend of liver enzymes after NAC initiation, with levels significantly improving by day 14 (Figures 1 and 2). Three patients did not require discontinuation of antibiotics. INH was stopped prior to NAC initiation in four patients. No side effects of NAC were documented in any patient. Conclusion NAC is a safe and effective measure to prevent and treat hepatotoxicity secondary to INH therapy. More studies are needed to determine its optimal dose and duration for this indication. Figure 1. Figure 2. Disclosures All authors: No reported disclosures.

/pdf/802-use-of-n-acetylcysteine-for-prevention-and-treatment-of-3dq6sbdfp7.pdf

802. Use of N-Acetylcysteine for Prevention and Treatment of Isoniazid Induced Liver Injury During Treatment of Mycobacterial Infections

Infection with members of the order Rickettsiales (the genera Rickettsia, Anaplasma, Orientia, and Ehrlichia) is known to cause hemophagocytic lymphohistiocytosis (HLH). The literature is scant on flea-borne typhus (FBT) being implicated in this process. We present a case of autopsy-proven HLH caused by FBT in a 71-year-old diabetic female who was initially suspected of having diabetic ketoacidosis who rapidly suffered decompensated multi-organ failure. Although she was suspected of having FBT and HLH pre-mortem, due to her rapid progression to multi-organ failure, she was transitioned to comfort care by her family five days after admission. A literature search yielded five other cases of HLH secondary to FBT, which are analyzed in this review. The literature on HLH occurring with infection due to other members of the order Rickettsiales is also surveyed.

/pdf/flea-borne-typhus-causing-hemophagocytic-lymphohistiocytosis-h3n53lgm.pdf

Gregory M. Anstead

Papers

2,3-Diarylindenes and 2,3-Diarylindenones: Synthesis, Molecular Structure, Photochemistry, Estrogen Receptor Binding Affinity, and Comparisons with Related Triarylethylenes.

2‐Arylindenes and 2‐Arylindenones: Synthesis of Probes to Study the Binding Orientation of Unsymmetrical Nonsteroidal Ligands to the Estrogen Receptor.

802. Use of N-Acetylcysteine for Prevention and Treatment of Isoniazid Induced Liver Injury During Treatment of Mycobacterial Infections

Flea-Borne Typhus Causing Hemophagocytic Lymphohistiocytosis: An Autopsy Case

The diagnosis of endemic mycoses