Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of sequence signature defining functional specificity and structural stability in helix‐loop‐helix proteins

Specific functional properties of many proteins directing developmental responses via transcriptional regulation are orchestrated by their characteristic helix‐loop‐helix (HLH) structural motif. The entire HLH motif in all these proteins assumes a common conformation irrespective of their individual biological effects. The motif controls the affinity of HLH proteins for homo‐ or heterodimerization, permitting mixing and matching of regulatory factors, and thereby expanding the functional repertoire. Systematic analysis of molecular contacts at the dimer interface using the models built for the functional dimers combined with the pattern of conserved/nonconserved residues within different categories of HLH proteins helped in understanding the differential role played by different residues at the dimer interface for expressing corresponding functions. The residues associated with the self and partner interactions were identified, and the signature residues contributing toward dimeric stability and functional specificity were defined. It is evident that most of the residues involved in self interactions are common among all the HLH proteins. However, while certain residues involved in partner interactions are common among all the HLH proteins, certain others are common within a category, and still others vary widely defining specificity signature at different levels. Proteins 2001;42:471–480. © 2001 Wiley‐Liss, Inc.
Disease‐specific patterns of locus coeruleus cell loss

Computer visualization techniques were used to map and to quantitatively reconstruct the entire locus coeruleus, including the nucleus subcoeruleus, to compare the topographic patterns of cell loss in postmortem brains from patients with Parkinson's disease, Alzheimer's disease, and Down syndrome. There was comparable cell loss in all three diseases (approximately 60%) compared with aged normal subjects, and there was a significant loss of nucleus subcoeruleus cells specifically in patients with Parkinson's disease (63%). There was a significant positive correlation between the magnitude of locus coeruleus cell loss and the duration of Alzheimer's disease, but no such correlation was found for Parkinson's disease. In patients with Parkinson's disease, there was comparable cell loss throughout the rostral‐caudal extent of the nucleus; however, in patients with Alzheimer's disease and Down syndrome, the greatest cell loss always occurred within the rostral portion of the nucleus, with a relative sparing of caudal cells. These data are consistent with the hypothesis that cell loss in Parkinson's disease is the result of a pathological process that attacks the catecholaminergic cells of the locus coeruleus and the subcoeruleus in general; in Alzheimer's disease and Down syndrome, however, the pathological process only affects the rostral, cortical‐projecting locus coeruleus cells and spares the caudal, noncortical‐projecting cells.
Vasoactive intestinal peptide stimulates bone resorption via a cyclic adenosine 3',5'-monophosphate-dependent mechanism.

Vasoactive intestinal peptide (VIP) stimulated bone resorption in mouse calvaria in organ culture. The effect was dose dependent between 0.01–1.0 fig VIP/ml (3–300 nM). Stimulation over a period of 48 h was greater when the peptide was added in four staggered doses than if the same total dose was added at time zero. VIP-stimulated bone resorption was as great as that produced by two other polypeptides, epidermal growth factor and platelet-derived growth factor, which we have previously found to act via a prostaglandin (PG)-mediated mechanism. However, unlike these polypeptides, the action of VIP on bone was not blocked by inhibitors of PG synthesis, such as indomethacin or cortisol. RIA of bone culture medium showed no increase in the concentration of PGE2 in the presence of maximum stimulatory concentrations of VIP. VIP rapidly enhanced (<1 h) the production of cAMP by calvaria 8- to 13-fold. Increases in cAMP accumulation were potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine, and is.
Calcium Signal-induced Cofilin Dephosphorylation Is Mediated by Slingshot via Calcineurin*

Cofilin, an essential regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 and reactivated by dephosphorylation. Although cofilin undergoes dephosphorylation in response to extracellular stimuli that elevate intracellular Ca2+ concentrations, signaling mechanisms mediating Ca2+-induced cofilin dephosphorylation have remained unknown. We investigated the role of Slingshot (SSH) 1L, a member of a SSH family of protein phosphatases, in mediating Ca2+-induced cofilin dephosphorylation. The Ca2+ ionophore A23187 and Ca2+-mobilizing agonists, ATP and histamine, induced SSH1L activation and cofilin dephosphorylation in cultured cells. A23187- or histamine-induced SSH1L activation and cofilin dephosphorylation were blocked by calcineurin inhibitors or a dominant-negative form of calcineurin, indicating that calcineurin mediates Ca2+-induced SSH1L activation and cofilin dephosphorylation. Importantly, knockdown of SSH1L expression by RNA interference abolished A23187- or calcineurin-induced cofilin dephosphorylation. Furthermore, calcineurin dephosphorylated SSH1L and increased the cofilin-phosphatase activity of SSH1L in cell-free assays. Based on these findings, we suggest that Ca2+-induced cofilin dephosphorylation is mediated by calcineurin-dependent activation of SSH1L.
Differential Hypoxic Regulation of Hypoxia-Inducible Factors 1α and 2α

The hypoxia-inducible transcription factors (HIF) 1α and HIF-2α play a critical role in cellular response to hypoxia. Elevated HIF-α expression correlates with poor patient survival in a large number of cancers. Recent evidence suggests that HIF-2α appears to be preferentially expressed in neuronal tumor cells that exhibit cancer stem cell characteristics. These observations suggest that expression of HIF-1α and HIF-2α is differentially regulated in the hypoxic tumor microenvironment. However, the underlying mechanisms remain to be fully investigated. In this study, we investigated the transcriptional regulation of HIF-1α and HIF-2α under different physiologically relevant hypoxic conditions. We found that transcription of HIF-2α was consistently increased by hypoxia, whereas transcription of HIF-1α showed variable levels of repression. Mechanistically, differential regulation of HIF-α transcription involved hypoxia-induced changes in acetylation of core histones H3 and H4 associated with the proximal promoters of the HIF-1α or HIF-2α gene. We also found that, although highly stable under acute hypoxia, HIF-1α and HIF-2α proteins become destabilized under chronic hypoxia. Our results have thus provided new mechanistic insights into the differential regulation of HIF-1α and HIF-2α by the hypoxic tumor microenvironment. These findings also suggest an important role of HIF-2α in the regulation of tumor progression under chronic hypoxia. Mol Cancer Res; 9(6); 757–65. ©2011 AACR.
Comparison of intraocular pressure profiles during cataract surgery by phacoemulsification and extracapsular cataract extraction.

BACKGROUND AND OBJECTIVE In view of reports of fluctuations in intraocular pressure (IOP) during phacoemulsification, real-time IOP during small-incision, manual extracapsular cataract extraction (ECCE) and phacoemulsification was measured to determine the effect of anterior chamber maintainer infusion on intraoperative IOP dynamics. PATIENTS AND METHODS A comparative study of IOP during cataract surgery was conducted by these two methods in 29 patients. An anterior chamber maintainer infused balanced salt solution continuously into the eye throughout ECCE. The anterior chamber maintainer was open in 7 cases throughout phacoemulsification and switched off during phacoemulsification in 7 cases. RESULTS IOP measurements during small-incision ECCE were physiologic (range, 5 to 20 mm Hg) during most of the operation and coincided with the value of hydrostatic pressure established by the height of the anterior chamber maintainer infusion bottle. During phacoemulsification without concomitant anterior chamber maintainer, IOP was positive (> 2 to 3 mm Hg) as long as the phacoemulsification infusion line was activated (position 1). Moving to position 0 caused hypotony. Occlusion breaks occasionally caused wide fluctuations in IOP. Concomitant anterior chamber maintainer and phacoemulsification infusion did not prevent surges, but may account for the lower range of fluctuation. The anterior chamber maintainer also maintained a positive IOP at position 0 during phacoemulsification. CONCLUSIONS An anterior chamber maintainer in conjunction with a self-sealing incision can maintain stable physiologic IOP during small-incision ECCE. The IOP fluctuations during phacoemulsification, especially during occlusion breaks, can be attenuated by an anterior chamber maintainer.
Are the correlates of cigarette smoking initiation different for black and white adolescents?

BACKGROUND Studies of adolescent smoking suggest that the causes of smoking initiation may differ for Blacks and Whites. METHODS Correlates of smoking initiation were examined among 1,277 nonsmokers, ages 12-14, who completed questionnaires in their homes. The analyses examined relationships between smoking initiation and 11 explanatory variables using logistic regression with the combined sample and with Black and White samples. RESULTS Over two years, 24 percent of Whites and 14 percent of Blacks started to smoke. Whites were more likely to start smoking at age 12 and Blacks at age 14. Having a best friend who smoked increased the odds of initiating smoking over twofold for Whites but had no effect on the odds of smoking for Blacks. CONCLUSIONS Whites initiate smoking earlier than Blacks and are more likely to be influenced by friend behavior.
Adaptive MMSE receiver with beamforming for DS/CDMA systems

The minimum mean-squared error (MMSE) receiver is a linear filter which can suppress multiple access interference (MAI) effectively in direct-sequence code-division multiple-access (CDMA) communications. An antenna array is also an efficient scheme for suppressing MAI and improving the system performance. In this letter, we consider an adaptive MMSE receiver in conjunction with beamforming in CDMA systems employing an antenna array. The proposed structure is featured as a low complexity receiver, which adapts the MMSE filter coefficients and the beamforming weights simultaneously. However, it does require the channel state information and the direction of arrival (DOA) of the desired user signal. As a result, we propose two adaptation methods to perform joint channel estimation and signal detection without any training sequence. It is demonstrated that the two proposed methods achieve similar bit-error-rate performance. More importantly, their performance degradation compared with the case with perfect channel information is small.
The Kinetic Mechanism of the SufC ATPase

Protein products of the suf operon are involved in iron-sulfur metabolism. SufC is an ATPase that can interact with SufB in the absence of nucleotide. We have studied the transient kinetics of the SufC ATPase mechanism using the fluorescent ATP analogue, 2′(3′)-O-N-methylanthraniloyl-ATP (mantATP). mantATP initially binds to SufC weakly. A conformational change of the SufC·mantATP complex then occurs followed by the very slow cleavage of mantATP to mantADP and the rapid release of Pi. In the presence of SufB, the cleavage step is accelerated and the release of mantADP is inhibited. Both of these effects promote the formation of a SufC·mantADP complex. In the absence and presence of SufB, mantADP remains more tightly bound to SufC than mantATP. These studies provide a basis for how the SufB and -C proteins interact in the processes involved in regulating iron-sulfur transfer.
Levosimendan in Off-Pump Coronary Artery Bypass: A Four-Times Masked Controlled Study

We tested the hypothesis that levosimendan produced beneficial hemodynamic effects during and after off-pump coronary artery bypass grafting in patients with good preoperative left ventricular function. Levosimendan at low dose (12 μg/kg), high dose (24 μg/kg), or placebo were administered in thirty-one patients in a randomized and four-times masked controlled study. Heart rate was not significantly different between experimental groups. Significant increases in cardiac output and left ventricular ejection fraction occurred after high-dose (P < 0.001; P = 0.006) and low-dose levosimendan (P = 0.001; P = 0.002). Both doses of levosimendan produced significant increased stroke volume and decreased systemic vascular resistance. Mean arterial pressure, pulmonary capillary wedge pressure, and left ventricular end-systolic volume were not significantly different between groups. The low-dose levosimendan produced better hemodynamic response than high-dose and may be preferable in patients undergoing off-pump coronary artery bypass grafting.
Cooperation between soluble factors and integrin‐mediated cell anchorage in the control of cell growth and differentiation

Recently it has become clear that integrins and other adhesive receptors play an important role in the control of cell growth and differentiation. In various cell types, anchorage to the extracellular matrix via integrins strongly influences the ability of the cell to respond to soluble mitogens or to differentiation factors. Thus adhesive receptors must generate signals that influence cell behavior. Some of the pathways of adhesion receptor signaling are now beginning to be worked out, but there is still much to learn. In particular, the mechanistic basis for the cooperation between anchorage signals and signals from soluble growth and differentiation factors remains ill‐defined. This review will examine some of the current information linking adhesion receptors to control of mitogenesis and differentiation.
Accuracy of patient recall of opportunistic smoking cessation advice in general practice.

OBJECTIVE: To determine the accuracy of patient recall of a question about smoking in a specified consultation in general practice; the accuracy of smokers' recall of advice to stop smoking; and predictors of accurate recall. DESIGN: Analysis of 1075 audiotapes was compared blind with matching patient questionnaires administered after the consultation to calculate sensitivity and specificity for patient recall as a dichotomous variable. Predictors of recall were determined by logistic regression. SETTING: General practitioner training practices, New South Wales, Australia. SUBJECTS: Thirty-four trainees and consecutive samples of their patients 16-65 years of age. RESULTS: Patient recall of a question about smoking had a high false positive rate of 21% but a sensitivity of 93%. Smokers over-reported advice to stop smoking (specificity 82%; sensitivity 92%). Predictors of accuracy of a question about smoking included patient sex (women 1.58 times more likely than men to be accurate); smoking status (smokers 1.7 times as likely as non-smokers to be accurate); and interval since consultation (those who completed their questionnaires within a week were 1.84 times more likely to be accurate). CONCLUSIONS: Patient recall is systematically biased towards over-reporting of a question about smoking status and, among smokers, of advice to quit. Although we recommend its continued application in health services evaluation, findings should be interpreted with caution, particularly if subjects are male or the interval between recall of smoking cessation advice and the occasion of service in which it might have occurred is considerably delayed.
Regulation of Human Myometrial Contractility During Pregnancy and Labour: Are Calcium Homeostatic Pathways Important?

If we are to develop new strategies for the treatment and management of preterm and dysfunctional term labour, it is imperative that we improve current understanding of the control of human uterine activity. Despite many studies of animal pregnancy, there is a paucity of knowledge relating to the complex control of human myometrium during pregnancy. It is hypothesized that human myometrium is relatively quiescent during the majority of pregnancy and that as term approaches there is cascade of molecular events that prepare the uterus for labour. This review will consider the cellular mechanisms involved in the regulation of human myometrial activity and the modulation of these by hormonal and mechanical signals. In particular, the contribution of calcium homeostatic pathways to the control of human myometrial contractility during gestation will be discussed.
An investigation of the effects of endometriosis on the proteome of human eutopic endometrium: A heterogeneous tissue with a complex disease

The pathogenesis of endometriosis includes the proliferation of heterogeneous endometrial cells and their invasion into ectopic sites within the peritoneal cavity. This may be due to abnormalities of the eutopic endometrium itself, predisposing the cells to survive and implant ectopically. We investigated the applicability of 2‐DE gels and peptide mass mapping to identify candidate endometrial proteins with a role in endometriosis. Despite the heterogeneous nature of endometrium, our results show that combining the analysis of 2‐DE gels and peptide mass mapping yields consistent data. We identified dysregulated proteins in women with endometriosis which included: (i) molecular chaperones including heat shock protein 90 and annexin A2, (ii) proteins involved in cellular redox state, such as peroxiredoxin 2, (iii) proteins involved in protein and DNA formation/breakdown, including ribonucleoside‐diphosphate reductase, prohibitin and prolyl 4‐hydroxylase, and (iv) secreted proteins, such as apolipoprotein A1. These proteins have functions which suggest that they could play a role in the pathogenesis of endometriosis. This study demonstrated that 2‐DE gel analysis and mass spectroscopic protein identification are suitable for the identification of proteins with candidate associations with endometriosis. These techniques should be used on a larger scale to identify endometriosis‐related proteins, thus improving the understanding of this complex disease.
Dual GABAA receptor‐mediated inhibition in rat presympathetic paraventricular nucleus neurons

The inhibitory neurotransmitter GABA plays a key role in the modulation of paraventricular nucleus (PVN) neuronal excitability and sympathoexcitatory outflow, under both physiological and pathological conditions. In addition to mediating conventional synaptic transmission (phasic inhibition), GABAA receptors of distinct biophysical, molecular and pharmacological properties have been recently found to underlie a slower, persistent form of inhibition (tonic inhibition). Whether the ‘tonic’ inhibitory modality is present in presympathetic PVN neurons, and what its role is in modulating their activity is at present unknown. Here, we combined tract‐tracing techniques with patch‐clamp electrophysiology to address these questions. Recordings obtained from PVN‐RVLM (rostral ventrolateral medulla) projecting neurons show that besides blocking GABAA‐mediated inhibitory postsynaptic currents (IPSCs, Iphasic), the GABAA receptor blockers bicuculline and picrotoxin caused an outward shift in the holding current (Itonic). Conversely, the high affinity GABAA blocker gabazine blocked Iphasic without affecting Itonic. THIP, a GABAA receptor agonist that preferentially activates δ‐ over γ‐containing receptors, enhanced the magnitude of Itonic. Our results also indicate that during conditions of strong and/or synchronous synaptic activity, Itonic may be activated by spillover of synaptically released GABA. Blockade of Itonic induced membrane depolarization, increased firing activity, and enhanced the input–output function of PVN‐RVLM neurons. Altogether, our results support the presence of a persistent GABAA‐mediated inhibitory modality in presympathetic PVN neurons, which plays a major role in modulating their excitability and firing activity.
Strenuous physical activity and breast cancer risk in African-American women.

OBJECTIVES Some studies of white women suggest that exercise reduces the incidence of breast cancer. There are no data on black women. We assessed the relationship between strenuous physical activity and prevalent breast cancer among participants in the Black Women's Health Study. METHODS Data on strenuous recreational physical activity at various ages and other factors were collected in 1995 by mail questionnaire from 64,524 United States black women aged 21 to 69 years. The 704 women who reported breast cancer (cases) were matched on age and on menopausal status at the time of the breast cancer diagnosis with 1408 women who did not report breast cancer (controls). Odds ratios for levels of physical activity at various ages were derived from conditional logistic regression with control for potential confounding factors. RESULTS Odds ratios for > or =7 h per week relative to < 1 were significantly reduced for strenuous activity at age 21 for breast cancer overall and premenopausal breast cancer, at age 30 for breast cancer overall, and at age 40 for postmenopausal breast cancer. There was no evidence of a reduction associated with exercise in high school. CONCLUSIONS The findings of the present study suggest that strenuous physical activity in early adulthood is associated with a reduced risk of breast cancer in African-American women.
Population based study of fatigue and psychological distress

Abstract Abstract Objectives: To determine the prevalence of fatigue in the general population and the factors associated with fatigue. Design: Postal survey. Setting: Six general practices in southern England. Subjects: 31 651 men and women aged 18-45 years registered with the practices. Main outcome measures: Responses to the 12 item general health questionnaire and a fatigue questionnaire which included self reported measures of duration, severity, and causes of fatigue. Results - 15 283 valid questionnaires were returned, giving a response rate of 48.3%, (64% after adjustment for inaccuracies in the practice registers). 2798 (18.3%) of respondents reported substantial fatigue lasting six months or longer. Fatigue and psychological morbidity were moderately correlated (r=0.62). Women were more likely to complain of fatigue than men, even after adjustment for psychological distress. The commonest cited reasons for fatigue were psychosocial (40% of patients). Of 2798 patients with excessive tiredness, only 38 (1.4%) attributed this to the chronic fatigue syndrome. Conclusion: Fatigue is distributed as a continuous variable in the community and is closely associated with psychological morbidity.