109 research outputs found
Learning effective amino acid interactions through iterative stochastic techniques
The prediction of the three-dimensional structures of the native state of
proteins from the sequences of their amino acids is one of the most important
challenges in molecular biology. An essential ingredient to solve this problem
within coarse-grained models is the task of deducing effective interaction
potentials between the amino acids. Over the years several techniques have been
developed to extract potentials that are able to discriminate satisfactorily
between the native and non-native folds of a pre-assigned protein sequence. In
general, when these potentials are used in actual dynamical folding
simulations, they lead to a drift of the native structure outside the
quasi-native basin. In this study, we present and validate an approach to
overcome this difficulty. By exploiting several numerical and analytical tools
we set up a rigorous iterative scheme to extract potentials satisfying a
pre-requisite of any viable potential: the stabilization of proteins within
their native basin (less than 3-4 \AA cRMS). The scheme is flexible and is
demonstrated to be applicable to a variety of parametrizations of the energy
function and provides, in each case, the optimal potentials.Comment: Revtex 17 pages, 10 eps figures. Proteins: Structure, Function and
Genetics (in press
Impact of estradiol variability and progesterone on mood in perimenopausal women with depressive symptoms
OBJECTIVE: To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology.
DESIGN AND INTERVENTION: Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models.
SETTING: Academic medical center.
PATIENTS: Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Asberg Depression Rating Scale [MADRS] score 15.5 +/- 5.3).
RESULTS: During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (beta= 0.11, 95% confidence interval [95%CI] [0.04 to 0.18, p=0.001]; beta= -2.62 [95%CI -4.52 to -0.71, p=0.007], respectively), after accounting for higher BMI, lifetime history of depression, and stressful life events.
CONCLUSIONS: Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone
Diversity in Functional Organization of Class I and Class II Biotin Protein Ligase
The cell envelope of Mycobacterium tuberculosis
(M.tuberculosis) is composed of a variety of lipids
including mycolic acids, sulpholipids, lipoarabinomannans, etc., which impart
rigidity crucial for its survival and pathogenesis. Acyl CoA carboxylase (ACC)
provides malonyl-CoA and methylmalonyl-CoA, committed precursors for fatty acid
and essential for mycolic acid synthesis respectively. Biotin Protein Ligase
(BPL/BirA) activates apo-biotin carboxyl carrier protein (BCCP) by biotinylating
it to an active holo-BCCP. A minimal peptide (Schatz), an efficient substrate
for Escherichia coli BirA, failed to serve as substrate for
M. tuberculosis Biotin Protein Ligase
(MtBPL). MtBPL specifically biotinylates
homologous BCCP domain, MtBCCP87, but not
EcBCCP87. This is a unique feature of
MtBPL as EcBirA lacks such a stringent
substrate specificity. This feature is also reflected in the lack of
self/promiscuous biotinylation by MtBPL. The N-terminus/HTH
domain of EcBirA has the self-biotinable lysine residue that is
inhibited in the presence of Schatz peptide, a peptide designed to act as a
universal acceptor for EcBirA. This suggests that when biotin
is limiting, EcBirA preferentially catalyzes, biotinylation of
BCCP over self-biotinylation. R118G mutant of EcBirA showed
enhanced self and promiscuous biotinylation but its homologue, R69A
MtBPL did not exhibit these properties. The catalytic
domain of MtBPL was characterized further by limited
proteolysis. Holo-MtBPL is protected from proteolysis by
biotinyl-5′ AMP, an intermediate of MtBPL catalyzed
reaction. In contrast, apo-MtBPL is completely digested by
trypsin within 20 min of co-incubation. Substrate selectivity and inability to
promote self biotinylation are exquisite features of MtBPL and
are a consequence of the unique molecular mechanism of an enzyme adapted for the
high turnover of fatty acid biosynthesis
Faithful chaperones
This review describes the properties of some rare eukaryotic chaperones that each assist in the folding of only one target protein. In particular, we describe (1) the tubulin cofactors, (2) p47, which assists in the folding of collagen, (3) α-hemoglobin stabilizing protein (AHSP), (4) the adenovirus L4-100 K protein, which is a chaperone of the major structural viral protein, hexon, and (5) HYPK, the huntingtin-interacting protein. These various-sized proteins (102–1,190 amino acids long) are all involved in the folding of oligomeric polypeptides but are otherwise functionally unique, as they each assist only one particular client. This raises a question regarding the biosynthetic cost of the high-level production of such chaperones. As the clients of faithful chaperones are all abundant proteins that are essential cellular or viral components, it is conceivable that this necessary metabolic expenditure withstood evolutionary pressure to minimize biosynthetic costs. Nevertheless, the complexity of the folding pathways in which these chaperones are involved results in error-prone processes. Several human disorders associated with these chaperones are discussed
Meta-synthesis and comparative meta-analysis of education research findings: some risks and benefits
Profiling a customer base through a sample survey: a data mining approach for business solution
Functional MRI of Dynamic 3D Visual Object Recognition
The pattern of visual motion perceived during observer self-movement contributes to sense of direction and visuospatial orientation.GVSfunctionalneuro-imagin
Headaches And Diplopia Secondary To Ipilimumab Treatment For Stage III Melanoma
Diplopia and headaches is an ominous sign for intracranial spread in patients with malignancy. However, it is important for clinicians to review chemotherapy medications as a potential cause of symptoms
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