484 research outputs found
QH-singularity of partially ordered spaces
No full textEach partial order generates a transitive quasi-uniformity. In this article we will study the properties of quasi-uniformities that are defined by a partial order and are QH-singular.Accepted author manuscriptAnalysi
Post-translational formylglycine modification of bacterial sulfatases by the radical S-adenosylmethionine protein AtsB
No full textFang QH, Peng JH, Dierks T. Post-translational formylglycine modification of bacterial sulfatases by the radical S-adenosylmethionine protein AtsB. JOURNAL OF BIOLOGICAL CHEMISTRY. 2004;279(15):14570-14578.C-alpha-Formylglycine (FGly) is the catalytic residue of sulfatases. FGly is generated by post-translational modification of a cysteine ( prokaryotes and eukaryotes) or serine ( prokaryotes) located in a conserved (C/S) XPXR motif. AtsB of Klebsiella pneumoniae is directly involved in FGly generation from serine. AtsB is predicted to belong to the newly discovered radical S-adenosylmethionine (SAM) superfamily. By in vivo and in vitro studies we show that SAM is the critical co-factor for formation of a functional AtsB . SAM . sulfatase complex and for FGly formation by AtsB. The SAM-binding site of AtsB involves (83)GGE(85) and possibly also a juxtaposed FeS center coordinated by Cys(39) and Cys(42), as indicated by alanine scanning mutagenesis. Mutation of these and other conserved cysteines as well as treatment with metal chelators fully impaired FGly formation, indicating that all three predicted FeS centers are crucial for AtsB function. It is concluded that AtsB oxidizes serine to FGly by a radical mechanism that is initiated through reductive cleavage of SAM, thereby generating the highly oxidizing deoxyadenosyl radical, which abstracts a hydrogen from the serine-CbetaH2-OH side chain
Posttranslational modification of serine to formylglycine in bacterial sulfatases - Recognition of the modification motif by the iron-sulfur protein AtsB
No full textMarquordt C, Fang QH, Will E, Peng JH, Figura von K, Dierks T. Posttranslational modification of serine to formylglycine in bacterial sulfatases - Recognition of the modification motif by the iron-sulfur protein AtsB. JOURNAL OF BIOLOGICAL CHEMISTRY. 2003;278(4):2212-2218.Calpha-formylglycine is the catalytic residue of sulfatases. Formylglycine is generated by posttranslational modification of a cysteine (pro- and eukaryotes) or serine (pro-karyotes) located in a conserved (C/S)XPXR motif. The modifying enzymes are unknown. AtsB, an iron-sulfur protein, is strictly required for modification of Se-72 in the periplasmic sulfatase AtsA of Klebsiella pneumoniae. Here we show W that AtsB is a cytosolic protein acting on newly synthesized serine-type sulfatases, (ii) that AtsB-mediated FGly formation is dependent on AtsA's signal peptide, and (iii) that the cytosolic cysteine-type sulfatase of Pseudomonas aeruginosa can be converted into a substrate of AtsB if the cysteine is substituted by serine and a signal peptide is added. Thus, formylglycine formation in serine-type sulfatases depends both on AtsB and on the presence of a signal peptide, and AtsB can act on sulfatases of other species. AtsB physically interacts with AtsA in a Ser(72)-dependent manner, as shown in yeast two-hybrid and GST pulldown experiments. This strongly suggests that AtsB is the serine-modifying enzyme and that AtsB relies on a cytosolic function of the sulfatase's signal peptide
The Activity of QH II 66 and It’s Analogs in Medulloblastoma, Melanoma and Non-small Cell Lung Cancer Cell Lines.
No full textGABAARs (gamma-aminobutyric acid type A receptors) are transmembrane pentameric ligand-gated chloride ion channels that respond to GABA, the central nervous system's principal inhibitory neurotransmitter (CNS). The benzodiazepines (BZDs) bind between the GABAAR α+γ2-subunits at their extracellular interface. The binding of ligands to distinct subunits of GABAA receptors, notably the α1-6β2/3γ2 ion channels, can have a wide range of effects on brain activities. The sedative, ataxic, amnesic, anticonvulsant, and addictive actions of GABAARs' α1-subtype selective ion channels should be avoided, except for the anticonvulsant and anxiolytic effects, while creating ligands for this BZ allosteric modulatory site. Many studies have linked the α2/3-containing GABAARs to anxiolytic, anticonvulsant, and antinociceptive properties. Muscle relaxation may be mediated by interaction of α3 subtypes at higher doses. GABAARs that include the α5 subtype are known to play a role in cognition, learning, and memory. GABA activity disruption at α5 GABAAR subtypes plays a role in the pathophysiology of CNS illnesses such schizophrenia, major depressive disorder (MDD), bipolar disorder, and some anxiety disorders such as OCD.Medulloblastoma is the most common pediatric brain tumor. There are four subgroups of medulloblastoma: WNT, SHH, Group 3 and Group 4. Group 3 has the highest morbidity rate, relapse and metastasis rate. The standard treatment of medulloblastoma includes surgical removal of the tumor followed by radiation and chemotherapy which cause unwanted side effects such hearing impairment, permanent damage to the endocrine system and neurocognitive functions and secondary tumors. Better treatments of medulloblastoma are needed. In group 3 medulloblastoma tumors they show a high expression of GABRA5 receptors, which is the α5 subunit of ligand gated ionotropic γ-aminobutyric acid type A receptors. In recent times, there is a lot of evidence published on the role of ion channel activity on brain cancer progression. Collaborating with Dr. Sengupta’s research group at Emory University it was shown that by using positive allosteric modulators of GABRA5 such as benzodiazepines like KRM-II-08 and QH-II-66 the cell viability of group 3 medulloblastoma can be impaired in vivo and in vitro with better specificity and potency than the standard of care treatments in the clinic. In this research several analogues of KRM-II-08 were designed, synthesized, and assayed and the most potent analogue binds with native tumor receptors with EC50 and IC50 values of ~0.8 micromolar. As a result of this binding, there is a 2 x 10⁹ ions.sec-1 chloride flux which morphologically evokes mitochondrial membrane depolarization, nuclei distention, and cellular blebbing. This is correlated with the localization of pro-apoptotic Bcl-2-associated death promoter (BAD) protein. Thus, this potent, non-toxic benzodiazepine may serve as an efficient anti-cancer drug for group 3 type medulloblastoma. This study was published in 2019. Melanoma is the deadliest form of skin cancer. More than 100,000 people are expected to be diagnosed in the USA in 2021. Current treatment with radiotherapy and immune checkpoint inhibitors does not show significant improvement in patients. Therapy combined with QH-II-66, radiation, and an immune checkpoint inhibitor shows improved results in controlling the metastasis by lowering the mass of the tumor. By gene expression analysis it was seen that these cancer cells show high expression of GABAA receptors, includes α5 GABAA subunits. Electrophysiology shows these receptors are functional. This sensitization to melanoma cells is benzodiazepine exclusive and does not impair normal cells. In a syngeneic mouse model of melanoma QH-II-66 showed increase in the depolarization in mitochondria which initiates programmed cell death of cancer cells. Combined therapy with QH II 66 and radiation show even better results. Lymphocyte and CD8+T cell counts were also increased after the treatment. Large-scale synthesis here was developed for QH II 66. It was important to point out the related benzodiazepine was either very weak or not active at all in these cancers. Thus, this potent, non-toxic benzodiazepine may serve as an efficient anti-cancer drug for melanoma. This study produced one publication in 2021 and two patent application submission in 2022. After these studies a large scale synthesis was required. An efficient large scale synthetic route was developed for KRM II 08 and QH II 66. In the new route there was a 40% overall yield for QH II 66 and a 35% overall yield for KRM II 08. It was achieved by purification of steps by a crystallization process. This synthetic route helped reduce the time and money, as well as made the procedure more efficient to synthesize these two compounds. More than 30 grams of each of these two compounds were synthesized during this study. These two-lead compounds were also tested in H1792 lung cancer cell lines. Both compounds were active in H1792 lung cancer cell lines. At least 20 analogues were synthesized and analyzed on H1792 cancer cell lines in collaboration of Dr. Krummel’s and Dr. Sengupta’s lab at University of Cincinnati. A new novel compound TA II 73 was discovered during this process which was two times more efficacious than the previous lead compound QH II 66 in H1792 non-small cell lung cancer cell lines, melanoma cell lines and glioblastoma cell lines. This TA II 73 developed a whole new series of anticancer benzodiazepines which have a 2’CH3 in the pendent phenyl ring. TA II 73 is non sedative on the rotorod assay at 40 mg/Kg dose. During this process the synthetic route for TA II 73 was also improved. Experiment also showed that it is also active in LN 18 cell line which was derived from glioblastoma cancer patients. There are important consequences of the development of the anticancer drugs contained in a privileged benzodiazepine skeleton. QH II 66, KRM II 08, TA II 73 and many other anticancer drugs have gone through the blood brain barrier in 20 to 30 minutes, as opposed to many anticancer drugs which do not have to be injected directly into the brain. While QH II 66 and analogs greatly enhance the anticancer activity of radiation and/or immune checkpoint inhibitor when they are given together, the combination of all three is even more potent, synergistically in mouse cancer models. In addition, these anticancer compounds are non-toxic for normal cells. Furthermore, the anxiolytic activity and slight sedative activity of these agents will be important to patients who are undergoing dual or combination therapy because some stress will be decreased. It is felt, especially in combination therapy, anticancer drugs developed here will have clinical significance.2024-06-0
Seismicity pattern changes prior to large earthquakes - An approach of the RTL algorithm
No full textA statistical method, which is called the Region-Time-Length (RTL) algorithm and takes into account information such as magnitude, occurrence time and place of earthquakes, was applied to earthquake data to investigate seismicity pattern changes prior to large earthquakes. Based on the RTL algorithm and some newly developed parameters such as the Q-parameter (average of the RTL values over some time window) and S-parameter (an index of seismic activation), I quantified both the temporal and spatial characteristics of seismicity pattern changes in various tectonic regions. The results indicated that seismic quiescence anomalies generally started a few years before the occurrence of the earthquakes and lasted from 1 to 2.5 years. The duration of the subsequent stage of seismic activation generally lasted several months. The linear dimension of the quiescence zone reached a few hundred kilometers (several times the rupture dimension of the mainshock), while the activation zone was generally in order of several tens of kilometers (comparable to the rupture dimension). An earthquake is most likely to occur once the relevant source region has passed through the quiescence and activation stages. Close investigation of possible artifacts due to the selection of model parameters and the changes of seismological networks are important in identifying real seismicity changes from man-made ones. Further stochastic testing using random earthquake catalogs was also done and it supports that the anomalies revealed in my works are significant. Besides studying on seismicity changes before large earthquakes, I also performed the first test of the above statistical method for investigating seismicity changes of earthquake swarms. It indicated that an increased RTL parameter would be a new potentially useful index for the risk alarm of earthquake swarms.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000225540800011&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Geosciences, MultidisciplinaryMeteorology & Atmospheric SciencesOceanographySCI(E)26ARTICLE3469-4911
Estimation of Partial Linear Error-in-Variables Models with Validation Data
No full textAbstractConsider the partial linear models of the formY=Xτβ+g(T)+e, where thep-variate explanatoryXis erroneously measured, and bothTand the responseYare measured exactly. LetXbe the surrogate variable forXwith measurement error. Let the primary data set be that containing independent observations on (Y,X,T) and the validation data set be that containing independent observations on (X,X,T), where the exact observations onXmay be obtained by some expensive or difficult procedures for only a small subset of subjects enrolled in the study. In this paper, without specifying any structure equation and the distribution assumption ofXgivenX, a semiparametric method with the primary data is employed to obtain the estimators ofβandg(·) based on the least-squares criterion with the help of validation data. The proposed estimators are proved to be strongly consistent. The asymptotic representation and the asymptotic normality of the estimator ofβare derived, respectively. The rate of the weak consistency of the estimator ofg(·) is also obtained
A comparison of Landau-Ginzburg models for odd-dimensional Quadrics
No full textIn [Rie08], the second author defined a Landau-Ginzburg model for homogeneous spaces G/P, as a regular function on an affine subvariety of the Langlands dual group. In this paper, we reformulate this LG model (X^, W_t) in the case of the odd-dimensional quadric, as a rational function on a Langlands dual projective space, in the spirit of work by R. Marsh and the second author for type A Grassmannians and by both authors for Lagrangian Grassmannians. We also compare this LG model with the one obtained independently by Gorbounov and Smirnov, and we use this comparison to deduce part of a conjecture of the second author for odd-dimensional quadrics
Recommended from our members
Search for top quark decays t → qH with H → γγ using the ATLAS detector
No full textA search is performed for flavour-changing neutral currents in the decay of a top quark to an up-type (c, u) quark and a Higgs boson, where the Higgs boson decays to two photons. The proton-proton collision data set used corresponds to 4.7 fb-1 at √ = 7TeV and 20.3fb-1 at √ = 8TeV collected by the ATLAS experiment at the LHC. Top quark pair events are searched for in which one top quark decays to qH and the other decays to bW. Both the hadronic and the leptonic decay modes of the W boson are used. No significant signal is observed and an upper limit is set on the t → qH branching ratio of 0.79 at the 95% confidence level. The corresponding limit on the tqH coupling combination λtcH2 + λtuH2 is 0.17. © 2014 The Author(s)
Changes in terrestrial ecosystem since 30 Ma in East Asia: Stable isotope evidence from black carbon in the South China Sea
No full textSEARCHING FOR EVIDENCE OF EARLY RICE AGRICULTURE AT PREHISTORIC SITES IN CHINA THROUGH PHYTOLITH ANALYSIS - AN EXAMPLE FROM CENTRAL CHINA
No full textAn exploratory phytolith analysis is applied at an archaeological site in central China to search for evidence of rice agriculture. Three key phytolith morpho-types are used in the identification of rice at the generic level (Oryza). They are common in the cultural layers of the site studied. Since this locale is far outside the natural distribution of wild rice, it is suggested that the rice is cultivated. The results indicate that phytolith analysis provides a useful technique in the elucidation of rice origins and dispersion.Plant SciencesPaleontologySCI(E)0NOTE3-4481-4858
- …
