Stem cells fuel bitter ethical divisions.
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Bioethics↗
Biomedical subjects
M Gross
Publications and source records attributed to M Gross.
Highly functionalized dimeric tetraethynylethenes and expanded radialenes: strong evidence for macrocyclic cross-conjugation.
A selection of dimeric tetraethynylethenes (TEEs) and perethynylated expanded radialenes, containing different donor/acceptor substitution patterns, have been prepared and fully characterized. The first X-ray crystal structure of an expanded [6]radialene, with twelve peripheral 3,5-di(tert-butyl)phenyl substituents, is presented. This macrocycle, the all-carbon core of which is isomeric with fullerene C60, adopts a non-planar, "chair-like" conformation. Also a TEE dimer, carrying N,N-dimethylaniline donor substituents, has been subjected to an X-ray crystallographic analysis. The electronic properties were studied by UV/Vis spectroscopy and electrochemistry, providing fundamental insight into mechanisms of pi-electron delocalization in the acyclic and macrocyclic chromophores. Donor or donor-acceptor-substituted dimeric TEE derivatives show very strong absorptions extending over the entire UV/Vis region; their longest wavelength absorption bands have high charge-transfer character. Macrocyclic cross-conjugation in the expanded radialenes becomes increasingly efficient with increasing donor-acceptor polarization. A dual, strongly solvent-polarity-dependent fluorescence was observed for a tetrakis(N,N-dimethylaniline)-substituted dimeric TEE; this interesting emission behavior is explained by the twisted intramolecular charge-transfer (TICT) state model. Donor-substituted expanded radialenes display huge resonance-enhanced third-order nonlinear optical coefficients.
Journal Article↗
The utilization of classical spin Monte Carlo methods to simulate the magnetic behavior of extended three-dimensional cubic networks incorporating M(II) ions with an S = 5/2 ground state spin.
The numerical simulations of the magnetic properties of extended three-dimensional networks containing M(II) ions with an S = 5/2 ground-state spin have been carried out within the framework of the isotropic Heisenberg model. Analytical expressions fitting the numerical simulations for the primitive cubic, diamond, together with (10-3) cubic networks have all been derived. With these empirical formulas in hands, we can now extract the interaction between the magnetic ions from the experimental data for these networks. In the case of the primitive cubic network, these expressions are directly compared with those from the high-temperature expansions of the partition function. A fit of the experimental data for three complexes, namely [(N(CH(3))(4)][Mn(N(3))] 1, [Mn(CN(4))](n)() 2, and [Fe(II)(bipy)(3)][Mn(II)(2)(ox)(3)] 3, has been carried out. The best fits were those obtained using the following parameters, J = -3.5 cm(-)(1), g = 2.01 (1); J = -8.3 cm(-)(1), g = 1.95 (2); and J = -2.0 cm(-)(1), g = 1.95 (3).
Journal Article↗
New efforts develop therapeutic antibodies.
Since the development of monoclonal antibodies twenty-five years ago, researchers and biotech companies have been looking to develop therapeutic uses for them. Michael Gross looks at some of the latest efforts.
Animals↗
Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease.
BACKGROUND: We studied whether lipid-lowering therapy with atorvastatin (target LDL cholesterol [LDL-C] <100 mg/dL) compared with a moderate treatment regimen that used other lipid-lowering drugs led to a lesser progression of atherosclerosis and to different changes in plaque echogenicity in patients with coronary artery disease. METHODS AND RESULTS: This study was a 12-month, open-label, randomized, multicenter trial, which used serial 3D intracoronary ultrasound to calculate plaque volume and plaque echogenicity. After transcatheter therapy, 131 patients were randomized (atorvastatin n=65, usual care n=66). The target plaque had to be a minor lesion (ie, a diameter stenosis of <50% on angiography). After 12 months, mean LDL-C was reduced from 155 to 86 mg/dL in the atorvastatin group and from 166 to 140 mg/dL in the usual care group. Mean absolute plaque volume showed a larger increase in the usual care group compared with the atorvastatin group (usual care 9.6+/-28.1 mm(3), atorvastatin 1.2+/-30.4 mm(3); P=0.191). The hyperechogenicity index of the plaque increased to a larger extent for the atorvastatin group than for the usual care group, with a significant treatment effect for the percent change (atorvastatin 42.2%, usual care 10.1%; P=0.021). CONCLUSIONS: One year of lipid-lowering therapy to <100 mg/dL LDL-C most likely led to a slowdown of plaque growth of minor lesions. The significantly larger increase in plaque hyperechogenicity is most likely due to a change in plaque composition.
Anticholesteremic Agents↗
Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells.
Androgen signaling influences the development and growth of prostate carcinoma. The transcriptional activity of androgen receptor (AR) is regulated by positive or negative transcriptional cofactors. We report here that PIAS1, PIAS3, and PIASy of the protein inhibitor of activated STAT (PIAS) family, which are expressed in human prostate, display distinct effects on AR-mediated gene activation in prostate cancer cells. While PIAS1 and PIAS3 enhance the transcriptional activity of AR, PIASy acts as a potent inhibitor of AR in prostate cancer cells. The effects of PIAS proteins on AR are competitive. PIASy binds to AR but does not affect the DNA binding activity of AR. An NH2-terminal LXXLL signature motif of PIASy, although not required for PIASy-AR interaction, is essential for the transrepression activity of PIASy. Our results identify PIASy as a transcriptional corepressor of AR and suggest that different PIAS proteins have distinct effects on AR signaling in prostate cancer cells.
Amino Acid Sequence↗
Putting cells together again.
Computational biologists are trying to combine the pieces of knowledge about the cell to develop a bigger picture. Such a 'virtual cell' is proving useful for the simulation of cellular processes, reports Michael Gross.
Animals↗
Caught in the trio trap? Potential selection bias inherent to association studies using parent-offspring trios.
During the last years, the validity of classic case control studies in psychiatric genetic research has been increasingly under question due to the risk of population stratification problems inherent to this type of association study. By consequence, the application of family-based association studies using parent-offspring trios has been strongly advocated. Recently, however, in a study comparing clinical characteristics between index patients from parent-offspring trios and singleton patients with bipolar affective disorder, the question was raised whether a systematic neglect of case control association studies could lead to a selection bias of susceptibility genes. In a similar approach, we compared demographic and clinical characteristics of 122 singleton bipolar patients with those of 54 bipolar patients derived from parent-offspring trios. The singleton patients did not only present with a higher age of onset, but also with a higher frequency of suicidal behavior and a higher familial loading for suicidality. These findings suggest that the genetic mechanism for disease might be different between trio-based and classic case control samples, where patients are examined whose parents are not available for genetic studies. Thus, giving up case control designs for the sake of family-based association studies could be at the risk of selecting against several genetically determined factors.
Adult↗
Identification of a novel human islet amyloid polypeptide beta-sheet domain and factors influencing fibrillogenesis.
Human islet amyloid polypeptide (hIAPP) accumulates as pancreatic amyloid in type 2 diabetes and readily forms fibrils in vitro. Investigations into the mechanism of hIAPP fibril formation have focused largely on residues 20 to 29, which are considered to comprise a primary amyloidogenic domain. In rodents, proline substitutions within this region and the subsequent beta-sheet disruption, prevents fibril formation. An additional amyloidogenic fragment within the C-terminal sequence, residues 30 to 37, has been identified recently. We have extended these observations by examining a series of overlapping peptide fragments from the human and rodent sequences. Using protein spectroscopy (CD/FTIR), electron microscopy and X-ray diffraction, a previously unrecognised amyloidogenic domain was localised within residues 8 to 20. Synthetic peptides corresponding to this region exhibited a transition from random coil to beta-sheet conformation and assembled into fibrils having a typical amyloid-like morphology. The comparable rat 8-20 sequence, which contains a single His18Arg substitution, was also capable of assembling into amyloid-like fibrils. Examination of peptide fragments corresponding to residues 1 to 13 revealed that the immediate N-terminal region is likely to have only a modulating influence on fibril formation or conformational conversion. The contributions of charged residues as they relate to the amyloid-forming 8-20 sequence were also investigated using IAPP fragments and by assessing the effects of pH and counterions. The identification of these principal amyloidogenic sequences and the effects of associated factors provide details on the IAPP aggregation pathway and structure of the peptide in its fibrillar state.
Amino Acid Sequence↗
Substance use among men who have sex with men: comparison with a national household survey.
OBJECTIVE: Compare substance use among men who have sex with men (MSM) at high risk for HIV infection to a nationally representative sample of heterosexual men. METHODS: Compare data from surveys of 3,212 MSM recruited for participation in a Vaccine Preparedness Study (VPS) with an age-standardized group of 2481 single, urban-dwelling men from the 1995 National Household Survey on Drug Abuse (NHSDA). RESULTS: Except for alcohol, relative risk (RR [95% confidence interval (CI)]) for use of any substance was higher in the VPS than the National Household Survey on Drug Abuse (NHSDA) (3.64 [3.01-4.42]). Drugs with the highest relative risks were "poppers" (21.6 [15.2-30.8]), sedatives (6.98 [2.46-19.8]), hallucinogens (6.14 [4.61-8.17]), tranquilizers (4.99 [2.96-8.42]), and stimulants (4.47 [3.58-5.58]). RR was higher for weekly use of poppers (33.5 [12.5-89.6]), stimulants (2.75 [1.79-4.22]), marijuana (2.37 [1.93-2.92]), and cocaine (2.24 [1.32-3.79]); and for daily use of marijuana (1.49 [1.08-2.05]). CONCLUSIONS: Participants in the VPS used more substances than a group of age-standardized, single, urban-dwelling men from the NHSDA. In view of previous data showing that substance use can be associated with unprotected sex, assessing substance use among MSM at high risk for HIV infection is an important component of risk reduction efforts.
Adolescent↗
Magnetic boost for structural studies.
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Nuclear Magnetic Resonance, Biomolecular↗
Race quickens for the first human clone.
The dazzling creation of Dolly, the cloned sheep, led many states to legislate against the possibility of using similar technology to create human clones. But for some, this prize is proving too tempting to ignore. Michael Gross reports.
Animals↗
Are US populations appropriate for trials of human immunodeficiency virus vaccine? The HIVNET Vaccine Preparedness Study.
Questions exist about whether testing of preventive human immunodeficiency virus (HIV)-1 vaccines, which will require rapid recruitment and retention of cohorts with high HIV-1 seroincidence, is feasible in the United States. A prospective cohort study was conducted in 1995-1997 among 4,892 persons at high risk for HIV infection in nine US cities. At 18 months, with an 88% retention rate, 90 incident HIV-1 infections were observed (1.31/100 person-years (PY), 95% confidence interval (CI): 1.06, 1.61). HIV-1 seroincidence rates varied significantly by baseline eligibility criteria--1.55/100 PY among men who had sex with men, 0.38/100 PY among male intravenous drug users, 1.24/100 PY among female intravenous drug users, and 1.13/100 PY among women at heterosexual risk-and by enrollment site, from 0.48/100 PY to 2.18/100 PY. HIV-1 incidence was highest among those men who had sex with men who reported unprotected anal intercourse (2.01/100 PY, 95% CI: 1.54, 2.63), participants who were definitely willing to enroll in an HIV vaccine trial (1.96/100 PY, 95% CI: 1.41, 2.73), and women who used crack cocaine (1.62/100 PY, 95% CI: 0.92, 2.85). Therefore, cohorts with HIV-1 seroincidence rates appropriate for HIV-1 vaccine trials can be recruited, enrolled, and retained.
AIDS Vaccines↗
Hereditary non-polyposis colorectal cancer (HNPCC): new germline mutation (190-191 del AA) in the human MLH1 gene and review of clinical guidelines for surveillance of affected families.
Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common genetic diseases comprising at least 5-6% of all colorectal cancers. It is characterized by early onset and mostly right-sided tumors (proximal to the splenic flexure). Molecular analyses are useful methods for diagnosis in index patients and for the detection of risk persons in affected families. A 37-year-old female patient whose family history fulfilled the criteria for hereditary non-polyposis colorectal cancer (HNPCC) was studied using PCR and DNA sequencing for the detection of mutations in the mismatch repair genes hMSH2 and hMLH1. Additionally, literature was reviewed (MEDLINE research until 2000) concerning clinical guidelines for surveillance in HNPCC families. A new deletion of two adenosine nucleotides (190-191 del AA) at codon 64 in exon 2 of the hMLH1 gene was found. The frameshift led to a stop codon at amino acid position 75. This mutation is considered to be disease causing in the development of the colorectal cancer of this family. Six publications with detailed recommendations for the surveillance of risk persons were found in the literature. Following their guidelines, colonoscopy is recommended from 20-30 years on for members of a family who fulfills either the Amsterdam criteria or the Bethesda criteria in combination with a detection of microsatellite instability. Female risk persons should be investigated gynecologically, including a transvaginal ultrasound examination, from 25-35 years on for the early detection of endometrial or ovarian cancer. Recommendations for gastroscopy, abdominal ultrasound examination and urine analysis are not given in all publications. Genetic counseling is recommended from 18 years on for all members of affected families.
Adaptor Proteins, Signal Transducing↗
A transcriptional corepressor of Stat1 with an essential LXXLL signature motif.
Interferon (IFN) treatment induces tyrosine phosphorylation and nuclear translocation of Stat1 (signal transducer and activator of transcription) to activate or repress transcription. We report here that a member of the protein inhibitor of activated STAT family, PIASy, is a transcriptional corepressor of Stat1. IFN treatment triggers the in vivo interaction of Stat1 with PIASy, which represses Stat1-mediated gene activation without blocking the DNA binding activity of Stat1. An LXXLL coregulator signature motif located near the NH(2) terminus of PIASy, although not involved in the PIASy-Stat1 interaction, is required for the transrepression activity of PIASy. Our studies identify PIASy as a transcriptional corepressor of Stat1 and suggest that different PIAS proteins may repress STAT-mediated gene activation through distinct mechanisms.
Amino Acid Motifs↗
Twists and turns in protein folding.
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Computational Biology↗
DHPLC mutation analysis of the hereditary nonpolyposis colon cancer (HNPCC) genes hMLH1 and hMSH2.
Denaturing high-performance liquid chromatography (DHPLC) is an efficient method for detection of mutations involving a single or few numbers of nucleotides, and it has been successfully used for mutation detection in disease-related genes. Colorectal cancer is one of the most common cancers, and mutations in the genes for hereditary nonpolyposis colon cancer (HNPCC), hMLH1 and hMSH2, also involve mainly point mutations. Sequence analysis is supposed to be a screening method with high sensitivity; however, it is time-consuming and expensive. We therefore decided to test sensitivity and reproducibility of DHPLC for 71 sequence variants in hMLH1 and hMSH2 initially found by sequence analysis in DNA samples of German HNPCC patients. DHPLC conditions of the PCR products were based on the melting pattern of the wild-type sequence of the corresponding PCR fragments. All but one of the 71 mutations was detected using DHPLC (sensitivity of 97%). Running time per sample averaged only 7 min, and the system is highly automated. Thus DHPLC is a rapid and sensitive method for the detection of hMLH1 and hMSH2 sequence variants.
Adaptor Proteins, Signal Transducing↗
Hyponatraemia as a complication of colonoscopy.
A case of colonoscopy-induced hyponatraemic encephalopathy led us to study the risk of hyponatraemia after gastrointestinal endoscopy. We assessed 40 patients before and after colonoscopy. 20 gastroscopy patients served as controls. Our findings show a high incidence (7.5%) of hyponatraemia after colonoscopy, in association with raised serum concentrations of arginine vasopressin. Physicians should be aware of this complication, since it may contribute to psychological and neurological symptoms after colonoscopy.
Arginine Vasopressin↗