Miracle-dz/UniFAR-FTUs huggingface dataset:
Benzo[b]tryptanthrin Inhibits MDR1, Topoisomerase Activity, and Reverses Adriamycin Resistance in Breast Cancer Cells

Tryptanthrin is an indoloquinazoline alkaloid isolated from indigo. Tryptanthrin and its benzo‐annulated derivative, benzo[b]tryptanthrin, inhibit both topoisomerases I (topo I) and II (topo II) and cause cytotoxicity in several human cancer cell lines. From diverse assessment methods, including cleavage complex stabilization, comet, DNA unwinding/intercalation, topo II ATPase inhibition, ATP competition for topo II, and wound‐healing assays, we determined that the mode of action of benzo[b]tryptanthrin is as a DNA non‐intercalative and ATP‐competitive topo I and II dual catalytic inhibitor. Benzo[b]tryptanthrin induced apoptosis through the cleavage of caspase‐3 and PARP in HCT15 colon cancer cells. Additionally, benzo[b]tryptanthrin reversed adriamycin resistance by down‐regulation of multidrug resistance protein 1 (MDR1) in adriamycin‐resistant MCF7 breast cancer cells (MCF7adr) with more potent inhibitory activity than tryptanthrin. Taken together, derivatization by benzo‐annulation of tryptanthrin ameliorated the MDR‐reversing effect of tryptanthrin and may pave the way to the discovery of a novel potent adjuvant agent for chemotherapy.
Influence of patient literacy on the effectiveness of a primary care-based diabetes disease management program.

CONTEXT Low literacy is an important barrier for patients with diabetes, but interventions to address low literacy have not been well examined. OBJECTIVE To examine the role of literacy on the effectiveness of a comprehensive disease management program for patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS Analysis of the influence of literacy on glycemic control and systolic blood pressure using data from a randomized controlled trial (conducted from February 2001 through April 2003) of a comprehensive diabetes management program. Participants were 217 patients aged 18 years or older with type 2 diabetes and poor glycemic control (glycosylated hemoglobin [HbA1c] levels > or =8.0%) and presenting to a US academic general internal medicine practice. INTERVENTIONS All communication to patients was individualized and delivered to enhance comprehension among patients with low literacy. Intervention patients received intensive disease management from a multidisciplinary team. Control patients received an initial management session and continued with usual care. MAIN OUTCOME MEASURES Achievement of goal HbA1c levels and systolic blood pressure at 12-month follow-up for control and intervention patients stratified by literacy status. RESULTS Complete 12-month data were available for 193 patients (89%). Among patients with low literacy, intervention patients were more likely than control patients to achieve goal HbA1c levels (< or =7.0%) (42% vs 15%, respectively; adjusted odds ratio [OR], 4.6; 95% confidence interval [CI], 1.3 to 17.2; P = .02). Patients with higher literacy had similar odds of achieving goal HbA1c levels regardless of intervention status (24% vs 23%; adjusted OR, 1.0; 95% CI, 0.4 to 2.5; P = .98). Improvements in systolic blood pressure were similar by literacy status. CONCLUSIONS Literacy may be an important factor for predicting who will benefit from an intervention for diabetes management. A diabetes disease management program that addresses literacy may be particularly beneficial for patients with low literacy, and increasing access to such a program could help reduce health disparities.
The effect of air puff stress on c‐Fos expression in rat hypothalamus and brainstem: central circuitry mediating sympathoexcitation and baroreflex resetting

Psychological stress evokes increases in sympathetic activity and blood pressure, which are due at least in part to an upward resetting of the baroreceptor‐sympathetic reflex. In this study we determined whether sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM), which have a critical role in the reflex control of sympathetic activity, are activated during air puff stress, a moderate psychological stressor. Secondly, we identified neurons that are activated by air puff stress and that also project to the nucleus tractus solitarius (NTS), a key site for modulation of the baroreceptor reflex. Air puff stress resulted in increased c‐Fos expression in several hypothalamic and brainstem nuclei, including the paraventricular nucleus (PVN), dorsomedial hypothalamus, perifornical area (PeF), periaqueductal gray (PAG), NTS and rostral ventromedial medulla, but not in the RVLM region that contains sympathetic premotor neurons. In contrast, neurons in this RVLM region, including catecholamine‐synthesizing neurons, did express c‐Fos following induced hypotension, which reflexly activates RVLM sympathetic premotor neurons. The highest proportion of NTS‐projecting neurons that were double‐labelled with c‐Fos after air puff stress was in the ventrolateral PAG (29.3 ± 5.5%), with smaller but still significant proportions of double‐labelled NTS‐projecting neurons in the PVN and PeF (6.5 ± 1.8 and 6.4 ± 1.7%, respectively). The results suggest that the increased sympathetic activity during psychological stress is not driven primarily by RVLM sympathetic premotor neurons, and that neurons in the PVN, PeF and ventrolateral PAG may contribute to the resetting of the baroreceptor‐sympathetic reflex that is associated with psychological stress.
The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults

Objective To assess the association of MRI white matter hyperintensities (WMHI) with cognitive performance, cerebral structure, and cerebral metabolism in 51 healthy individuals aged 19 to 91 years without cerebrovascular risk factors. Background Abnormal white matter signals have been associated with brain atrophy, reduced cerebral blood flow, focal neurologic signs, gait disorder, and poorer neuropsychological test performance. Most studies of WMHI, however, include subjects with hypertension or other identifiable causes of cerebrovascular disease that may have an independent effect on brain structure and function. To assess brain changes associated with WMHI independent of cerebrovascular risk factors, we determined WMHI volume, brain volume, cerebral metabolism, and cognitive performance for a group of subjects free of medical illness. Regional cerebral metabolism and cognitive domains were also assessed to evaluate the possible role of frontal lobe dysfunction in subjects with WMHI. Design Cross-sectional study of 51 very healthy subjects aged 19 to 91 years. Methods WMHI, brain, and CSF volumes were determined by MRI segmentation. Neuropsychological tests were employed to assess multiple cognitive domains. Brain metabolism was determined from 18-fluoro-2-deoxy-d-glucose PET. Multivariate relations were tested with stepwise linear regression. Models included the potential confounders of age and education where appropriate. Results The distribution of WMHI volume was bimodal, with five subjects having WMHI volumes beyond three SDs from the normally distributed population. A WMHI volume of greater than 0.5% of intracranial volume was considered abnormal. Within the multivariate models, WMHI volumes were significantly predictive of increased ventricular volume, reduced brain volume, and reduced cognitive scores. Subjects with greater than 0.5% WMHI volume also had significantly lower frontal lobe metabolism, significantly higher systolic blood pressure, significantly larger ventricular volume, and significantly lower scores on frontal lobe-mediated neuropsychological tests than age-matched controls. Conclusion WMHI volume is associated with structural and functional brain changes even within a group of very healthy individuals. WMHI is associated with poorer frontal lobe cognitive function and, when severe, is accompanied by significantly reduced frontal lobe metabolism. Subjects with large WMHI volumes have significantly higher systolic blood pressure, brain atrophy, reduced cerebral metabolism, and lower scores on tests of frontal lobe function than age-matched controls. Large amounts of WMHI are, therefore, pathologic and may be related to elevated systolic blood pressure even when it is within the normal age-related range.
Robust Extraction of Respiratory Activity From PPG Signals Using Modified MSPCA

The pulse oximeter's photoplethysmographic (PPG) signals can be well utilized for extracting the vital respiratory activity, in addition to saturation and heart rate estimations, avoiding the usage of additional sensor for recording respiratory signal, in turn reducing the number of sensors connected to the patient's body for recording vital signals. In this paper, we present a robust algorithm called modified multi scale principal component analysis (MMSPCA), for extraction of respiratory activity embedded in the PPG signals. The PPG signals are more commonly corrupted by motion artifacts (MA) due to voluntary or involuntary movements of the patients, making it difficult for the algorithms to extract respiratory signals. The problem of extracting respiratory signals from PPGs in the presence of MA is addressed for the first time in this paper. The problem gets aggravated when PPGs are severely afflicted with MAs in situations such as the MA frequency band (usually below 0.2 Hz) overlapping on to the band of respiratory frequencies (0.2-0.4 Hz). In the presented algorithm, the kurtosis and energy contribution levels (ECL) of approximate and detail coefficients are calculated for each wavelet sub-band matrix, generating a modified wavelet sub-band matrix. This makes the presented algorithm based on MMSPCA more robust in the sense that it is made motion resistant by suitably modifying the MSPCA. Functioning of the proposed algorithm is tested on the data recorded from 15 healthy subjects. Each data set consists of intentionally created possible MA noises, viz., vertical, horizontal, waving, and pressing MAs with different breathing patterns. The method is also applied on the recordings available with MIMIC database of Physionet archive. The statistical and error analysis, performed to test the efficacy of the presented MMSPCA algorithm, revealed a very good acceptance for derived respiratory signal, when compared with the originally recorded respiratory signals using classical method. The MMSPCA method clearly outperformed the conventional MSPCA-based method in the presence of MA.
Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa

Background This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. Objectives The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. Methods 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. Results No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. Conclusions The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women. Trial Registration ClinicalTrials.gov NCT01071174
The effects of mivacurium‐induced neuromuscular block on Bispectral Index and Cerebral State Index in children under propofol anesthesia – a prospective randomized clinical trial

Background: In adults anesthetized with propofol, muscle relaxants may decrease the Bispectral Index (BIS). The aim of this prospective randomized trial was to detect the influence of a muscle relaxant bolus on the BIS and the Cerebral State Index (CSI) in children under propofol anesthesia.
Migrants’ Intention to Move or Stay in their Initial Destination

The objective of this article is to find out why immigrants intend to stay in or leave their initial destination. The insight into such factors could help develop policy measures to deal with potential out-migration, especially from the regions that view international migration as a solution to their demographic and economic difficulties. The study uses multinomial logistic regression to estimate the strength of association between migrants' intention to move and immigration category, human capital, economic and social factors. The data come from the Longitudinal Survey of Immigrants to Australia. The findings show that different groups of migrants have different propensities to move or stay in their initial destination. Employer-sponsored migrants are even less likely to intend to relocate than family class. Highly educated and skilled migrants tend to be more likely to express the intention to move or have doubts. Satisfactory employment has a positive impact on retention.
Feeder‐Free Monolayer Cultures of Human Embryonic Stem Cells Express an Epithelial Plasma Membrane Protein Profile

Human embryonic stem cells (hESCs) are often cocultured on mitotically inactive fibroblast feeder cells to maintain their undifferentiated state. Under these growth conditions, hESCs form multilayered colonies of morphologically heterogeneous cells surrounded by flattened mesenchymal cells. In contrast, hESCs grown in feeder cell‐conditioned medium on Matrigel instead tend to grow as monolayers with uniform morphology. Using mass spectrometry and immunofluorescence microscopy, we showed that hESCs under these conditions primarily express proteins belonging to epithelium‐related cell‐cell adhesion complexes, including adherens junctions, tight junctions, desmosomes, and gap junctions. This indicates that monolayers of hESCs cultured under feeder‐free conditions retain a homogeneous epithelial phenotype similar to that of the upper central cell layer of colonies maintained on feeder cells. Notably, feeder‐free hESCs also coexpressed vimentin, which is usually associated with mesenchyme, suggesting that these cells may have undergone epithelium‐to‐mesenchyme transitions, indicating differentiation. However, if grown on a “soft” substrate (Hydrogel), intracellular vimentin levels were substantially reduced. Moreover, when hESCs were transferred back to feeder cells, expression of vimentin was again absent from the epithelial cell population. These results imply that on tissue culture substrates, vimentin expression is most likely a stress‐induced response, unrelated to differentiation.
Drivers of Germ Cell Maturation

Abstract: Spermatogenesis requires progression of germ line stem cells through a precisely ordered differentiation pathway to form spermatozoa. Diverse and dynamic signals from the transforming growth factor‐β (TGF‐β) superfamily influence many stages of germ cell development. For example, interactions between several TGF‐β superfamily ligands (bone morphogenetic proteins, activin, and glial‐derived neurotrophic growth factor [GDNF]) appear to govern the onset of spermatogenesis, and we are exploring how germ cells interpret these competing signals. We examined the in vivo impact of activin on testis development using two mouse models, the inhba−/− mouse (which lacks the gene encoding the activin A subunit and dies at birth) and BK mice, with inhbb (encoding the activin βB subunit) replacing inhba (which survive to adulthood and show delayed fertility onset in males). Distinct effects on Sertoli cell and germ cell populations during fetal and early postnatal development were measured. We recognize that specific proteins, including downstream targets of TGF‐β signals, such as Smads, must move into the nucleus to implement the gene transcription changes required for development. We hypothesized that changes at the level of cellular nuclear transport machinery may be required to mediate this. Examination of proteins involved in classical nuclear import, the importins, revealed that each importin has a developmentally regulated expression pattern in male germ cells. Because each importin binds a selected range of cargo proteins and mediates their nucleocytoplasmic passage, our findings suggest that each importin ferries cargo required for discrete stages of spermatogenesis.
Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-beta, and fibronectin with concomitant increase in nitric oxide bioavailability.

Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 +/- 8 vs. 150 +/- 2 mmHg in normal salt diet (0.5% NaCl), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F(2alpha)-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-beta (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg.kg(-1). day(-1)) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-beta1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 +/- 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-beta1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system.
Differential Toll-Like Receptor (TLR) mRNA Expression Patterns during Chicken Embryological Development

Toll-like receptors (TLRs), important components of innate immune response, play a pivotal role in early recognition of pathogen as well as in the initiation of robust and specific adaptive immune response. In the present study, the expression profile of chicken TLRs (TLR2A, TLR3, TLR4, TLR5, TLR7, TLR15, and TLR21) in various chicken embryonic tissues during embryo development was examined by real-time PCR assay. All the TLR mRNAs were expressed in whole embryonic tissue as early as 3rd embryonic day (ED). Four of the seven TLRs (TLR2, TLR3, TLR4, and TLR7) mRNA expressions were significantly (P < 0.01) higher at 12ED relative to expression at 3 ED, whereas TLR15 mRNA expression was significantly (P < 0.01) higher on 7ED and TLR5 and 21 were highly expressed on 18 ED. Among all the TLRs investigated TLR4 mRNA was the highest expressed and TLR15 mRNA expression was the lowest in all tissues during chicken embryo development. Tissue wise analysis of mRNA expression of TLRs showed that liver expressed significantly (P < 0.01) higher levels of most of the genes (TLR2, TLR4, and TLR21). However no significant difference was found in TLR15 mRNA expression among the tissues during development. Our results suggest the innate preparedness of chicken embryos and also a possible role for TLRs in the regulation of chicken embryo development that needs to be further evaluated.
Effects of ultraviolet‐B radiation on phycobilisomes of Synechococcus PCC 7942: Alterations in conformation and energy transfer characteristics

Phycobilisomes (PBS), the major light harvesting antenna of the cyanobacterium Synechococcus contain phycocyanin (PC) and allophycocyanin (APC) as major pigment‐protein complexes. PBS also absorb ultraviolet‐B (280‐320 nm) radiation. Exposure of Synechococcus PBS to low dose of UV‐B (∼0.28 mw.cm‐2) for 90 min induced change in absorption, emission and excitation characteristics of PBS and these changes got enhanced after 3 h of exposure. Room temperature excitation and emission spectra clearly indicated uncoupling of energy transfer from PC to APC on exposure to UV‐B. Also, the 77K emission spectra suggested that F682 emission originating from APC decreased by 42% after 3 h of exposure. Circular dichroism (CD) spectra of UV‐B exposed PBS indicated changes (14% decrease) in the α‐helical content after 90 min treatment. SDS‐PAGE analysis indicated degradation of a 75 kDa polypeptide (which appear to be a linker polypeptide) on UV‐B treatment. The degradation of this polypeptide seems to induce changes in pigment‐protein interaction and decoupling of energy transfer within the PBS. Our results for the first time clearly indicate that the PBS of Synechococcus are targets for UV‐B damage.
Regulation of ciliary adenylate cyclase by Ca2+ in Paramecium.

In the ciliated protozoan Paramecium, Ca2+ and cyclic nucleotides are believed to act as second messengers in the regulation of the ciliary beat. Ciliary adenylate cyclase was activated 20-30-fold (half-maximal at 0.8 microM) and inhibited by higher concentrations (10-20 microM) of free Ca2+ ion. Ca2+ activation was the result of an increase in Vmax. , not a change in Km for ATP. The activation by Ca2+ was seen only with Mg2+ATP as substrate; with Mn2+ATP the basal adenylate cyclase activity was 10-20-fold above that with Mg2+ATP, and there was no further activation by Ca2+. The stimulation by Ca2+ of the enzyme in cilia and ciliary membranes was blocked by the calmodulin antagonists calmidazolium (half-inhibition at 5 microM), trifluoperazine (70 microM) and W-7 (50-100 microM). When ciliary membranes (which contained most of the ciliary adenylate cyclase) were prepared in the presence of Ca2+, their adenylate cyclase was insensitive to Ca2+ in the assay. However, the inclusion of EGTA in buffers used for fractionation of cilia resulted in full retention of Ca2+-sensitivity by the ciliary membrane adenylate cyclase. The membrane-active agent saponin specifically suppressed the Ca2+-dependent adenylate cyclase without inhibiting basal activity with Mg2+ATP or Mn2+ATP. The ciliary adenylate cyclase was shown to be distinct from the Ca2+-dependent guanylate cyclase; the two activities had different kinetic parameters and different responses to added calmodulin and calmodulin antagonists. Our results suggest that Ca2+ influx through the voltage-sensitive Ca2+ channels in the ciliary membrane may influence intraciliary cyclic AMP concentrations by regulating adenylate cyclase.