Widespread Alu repeat-driven expansion of consensus DR2 retinoic acid response elements during primate evolution

BACKGROUND: Nuclear receptors are hormone-regulated transcription factors whose signaling controls numerous aspects of development and physiology. Many receptors recognize DNA hormone response elements formed by direct repeats of RGKTCA motifs separated by 1 to 5 bp (DR1-DR5). Although many known such response elements are conserved in the mouse and human genomes, it is unclear to which extent transcriptional regulation by nuclear receptors has evolved specifically in primates. RESULTS: We have mapped the positions of all consensus DR-type hormone response elements in the human genome, and found that DR2 motifs, recognized by retinoic acid receptors (RARs), are heavily overrepresented (108,582 elements). 90% of these are present in Alu repeats, which also contain lesser numbers of other consensus DRs, including 50% of consensus DR4 motifs. Few DR2s are in potentially mobile AluY elements and the vast majority are also present in chimp and macaque. 95.5% of Alu-DR2s are distributed throughout subclasses of AluS repeats, and arose largely through deamination of a methylated CpG dinucleotide in a non-consensus motif present in AluS sequences. We find that Alu-DR2 motifs are located adjacent to numerous known retinoic acid target genes, and show by chromatin immunoprecipitation assays in squamous carcinoma cells that several of these elements recruit RARs in vivo. These findings are supported by ChIP-on-chip data from retinoic acid-treated HL60 cells revealing RAR binding to several Alu-DR2 motifs. CONCLUSION: These data provide strong support for the notion that Alu-mediated expansion of DR elements contributed to the evolution of gene regulation by RARs and other nuclear receptors in primates and humans

Asymmetry and decoherence in a double-layer persistent-current qubit

Superconducting circuits fabricated using the widely used shadow evaporation technique can contain unintended junctions which change their quantum dynamics. We discuss a superconducting flux qubit design that exploits the symmetries of a circuit to protect the qubit from unwanted coupling to the noisy environment, in which the unintended junctions can spoil the quantum coherence. We present a theoretical model based on a recently developed circuit theory for superconducting qubits and calculate relaxation and decoherence times that can be compared with existing experiments. Furthermore, the coupling of the qubit to a circuit resonance (plasmon mode) is explained in terms of the asymmetry of the circuit. Finally, possibilities for prolonging the relaxation and decoherence times of the studied superconducting qubit are proposed on the basis of the obtained results.Comment: v.2: published version; 8 pages, 12 figures; added comparison with experiment, improved discussion of T_ph

Functional muscle hypertrophy by increased insulin-like growth factor 1 does not require dysferlin.

IntroductionDysferlin loss-of-function mutations cause muscular dystrophy, accompanied by impaired membrane repair and muscle weakness. Growth promoting strategies including insulin-like growth factor 1 (IGF-1) could provide benefit but may cause strength loss or be ineffective. The objective of this study was to determine whether locally increased IGF-1 promotes functional muscle hypertrophy in dysferlin-null (Dysf-/- ) mice.MethodsMuscle-specific transgenic expression and postnatal viral delivery of Igf1 were used in Dysf-/- and control mice. Increased IGF-1 levels were confirmed by enzyme-linked immunosorbent assay. Testing for skeletal muscle mass and function was performed in male and female mice.ResultsMuscle hypertrophy occurred in response to increased IGF-1 in mice with and without dysferlin. Male mice showed a more robust response compared with females. Increased IGF-1 did not cause loss of force per cross-sectional area in Dysf-/- muscles.DiscussionWe conclude that increased local IGF-1 promotes functional hypertrophy when dysferlin is absent and reestablishes IGF-1 as a potential therapeutic for dysferlinopathies

Surface Emissions Modulate Indoor SVOC Concentrations through Volatility-Dependent Partitioning.

Measurements by semivolatile thermal desorption aerosol gas chromatography (SV-TAG) were used to investigate how semivolatile organic compounds (SVOCs) partition among indoor reservoirs in (1) a manufactured test house under controlled conditions (HOMEChem campaign) and (2) a single-family residence when vacant (H2 campaign). Data for phthalate diesters and siloxanes suggest that volatility-dependent partitioning processes modulate airborne SVOC concentrations through interactions with surface-laden condensed-phase reservoirs. Airborne concentrations of SVOCs with vapor pressures in the range of C13 to C23 alkanes were observed to be correlated with indoor air temperature. Observed temperature dependencies were quantitatively similar to theoretical predictions that assumed a surface-air boundary layer with equilibrium partitioning maintained at the air-surface interface. Airborne concentrations of SVOCs with vapor pressures corresponding to C25 to C31 alkanes correlated with airborne particle mass concentration. For SVOCs with higher vapor pressures, which are expected to be predominantly gaseous, correlations with particle mass concentration were weak or nonexistent. During primary particle emission events, enhanced gas-phase emissions from condensed-phase reservoirs partitioned to airborne particles, contributing substantially to organic particulate matter. An emission event related to oven-usage was inferred to deposit siloxanes in condensed-phase reservoirs throughout the house, leading to the possibility of reemission during subsequent periods with high particle loading

Spin-dynamics of the low-dimensional magnet (CH3)2NH2CuCl3

Dimethylammonium copper (II) chloride (also known as DMACuCl3 or MCCL) is a low dimensional S=1/2 quantum spin system proposed to be an alternating ferro-antiferromagnetic chain with similar magnitude ferromagnetic (FM) and antiferromagnetic (AFM) exchange interactions. Subsequently, it was shown that the existing bulk measurements could be adequately modeled by considering DMACuCl3 as independent AFM and FM dimer spin pairs. We present here new inelastic neutron scattering measurements of the spin-excitations in single crystals of DMACuCl3. These results show significant quasi-one-dimensional coupling, however the magnetic excitations do not propagate along the expected direction. We observe a band of excitations with a gap of 0.95 meV and a bandwidth of 0.82 meV.Comment: 3 pages, 2 figures included in text, submitted to proceedings of International Conference on Neutron Scattering, December 200

Treatment of Fibromyalgia with Formula Acupuncture: Investigation of Needle Placement, Needle Stimulation, and Treatment Frequency

Objectives: The objective of this study was to investigate whether typical acupuncture methods such as needle placement, needle stimulation, and treatment frequency were important factors in fibromyalgia symptom improvement. Design/settings/subjects: A single-site, single-blind, randomized trial of 114 participants diagnosed with fibromyalgia for at least 1 year was performed. Intervention: Participants were randomized to one of four treatment groups: (1) T/S needles placed in traditional sites with manual needle stimulation (n = 29): (2) T/0 traditional needle location without stimulation (n = 30); (3) N/S needles inserted in nontraditional locations that were not thought to be acupuncture sites, with stimulation (n = 28); and (4) N/0 nontraditional needle location without stimulation (n = 2 7). All groups received treatment once weekly, followed by twice weekly, and finally three times weekly, for a total of 18 treatments. Each increase in frequency was separated by a 2-week washout period. Outcome measures: Pain was assessed by a numerical rating scale, fatigue by the Multi-dimensional Fatigue Inventory, and physical function by the Short Form–36. Results: Overall pain improvement was noted with 25%–35% of subjects having a clinically significant decrease in pain; however this was not dependent upon "correct" needle stimulation (t = 1.03; p = 0.307) or location (t = 0.76; p = 0.450). An overall dose effect of treatment was observed, with three sessions weekly providing more analgesia than sessions once weekly (t = 2.10; p = 0.039). Among treatment responders, improvements in pain, fatigue, and physical function were highly codependent (all p ≤ 0.002). Conclusions: Although needle insertion led to analgesia and improvement in other somatic symptoms, correct needle location and stimulation were not crucial.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63411/1/acm.2005.11.663.pd

Association of 6-Minute Walk Performance and Physical Activity With Incident Ischemic Heart Disease Events and Stroke in Peripheral Artery Disease.

BackgroundWe determined whether poorer 6-minute walk performance and lower physical activity levels are associated with higher rates of ischemic heart disease (IHD) events in people with lower extremity peripheral artery disease (PAD).Methods and resultsFive hundred ten PAD participants were identified from Chicago-area medical centers and followed prospectively for 19.0±9.5 months. At baseline, participants completed the 6-minute walk and reported number of blocks walked during the past week (physical activity). IHD events were systematically adjudicated and consisted of new myocardial infarction, unstable angina, and cardiac death. For 6-minute walk, IHD event rates were 25/170 (14.7%) for the third (poorest) tertile, 10/171 (5.8%%) for the second tertile, and 6/169 (3.5%) for the first (best) tertile (P=0.003). For physical activity, IHD event rates were 21/154 (13.6%) for the third (poorest) tertile, 15/174 (8.6%) for the second tertile, and 5/182 (2.7%) for the first (best) tertile (P=0.001). Adjusting for age, sex, race, smoking, body mass index, comorbidities, and physical activity, participants in the poorest 6-minute walk tertile had a 3.28-fold (95% CI 1.17 to 9.17, P=0.024) higher hazard for IHD events, compared with those in the best tertile. Adjusting for confounders including 6-minute walk, participants in the poorest physical activity tertile had a 3.72-fold (95% CI 1.24 to 11.19, P=0.019) higher hazard for IHD events, compared with the highest tertile.ConclusionsSix-minute walk and physical activity predict IHD event rates in PAD. Further study is needed to determine whether interventions that improve 6-minute walk, physical activity, or both can reduce IHD events in PAD

Connexin32 is a Myelin-Related Protein in the PNS and CNS

We have examined the expression of a gap junction protein, connexin32 (Cx32), in Schwann cells and oligodendrocytes. In peripheral nerve, Cx32 is found in the paranodal myelin loops and Schmidt-Lanterman incisures of myelinating Schwann cells, and the levels of Cx32 protein and mRNA change in parallel with those of other myelin-related genes during development, Wallerian degeneration, and axonal regeneration. In the central nervous system, Cx32 is found in oligodendrocytes and their processes, but not in compact myelin, and the levels of Cx32 protein and mRNA increase during development in parallel with those of the other myelin genes. Thus, Cx32 is expressed as part of the myelinating phenotype of both Schwann cells and oligodendrocytes, indicating that this gap junction protein plays in important role in the biology of myelin-forming cells

Can Determination of Circulating Endothelial Cells and Serum Caspase-Cleaved CK18 Predict for Response and Survival in Patients with Advanced Non–Small-Cell Lung Cancer Receiving Endostatin and Paclitaxel–Carboplatin Chemotherapy? A Retrospective Study

Introduction:Early prediction of the efficacy of a combination of an antiangiogenic drug with cytotoxic chemotherapy is a significant challenge. In that regard, circulating endothelial cells (CECs) and cytokeratins (CKs) seem to reflect their roles in both tumor angiogenesis and tumor cell death.Methods:Patients with advanced, previously untreated non–small-cell lung cancer were randomly assigned to an endostatin treatment group (paclitaxel + carboplatin + endostatin) and a control group (paclitaxel + carboplatin + placebo). A total of 122 patients were evaluated, of whom 107 had measurements of blood CECs, CK8, caspase-cleaved CK18 (ccCK18), and uncleaved CK18 (CK18) before and at weeks 3 and 6 of treatment, respectively.Results:Higher baseline CECs in patients with a tumor response (partial remission + stable disease, p = 0.002 for the entire group; p = 0.000 for the treatment group) were observed. The number of CECs decreased significantly after endostatin treatment (p = 0.000), whereas CK levels increased. Increased levels of ccCK18 and CK18, but not CK8, reached significance (p = 0.001 and p = 0.048, respectively) when compared with the baseline. Tumor response showed a strong correlation with reduction of CECs (p = 0.000) and increase of ccCK18 (p = 0.040) after endostatin therapy. Cutoff values of changes of CECs and ccCK18 for prediction of survival were 0.58/μl and 19.6 ng/ml, respectively. Reduction of CECs and increase of ccCK18 significantly correlated with longer median survival (p = 0.013 and p = 0.016 for progression-free survival; p = 0.009 and p = 0.012 for overall survival, respectively).Conclusions:CECs and CKs could be biomarkers for selecting patients with non–small-cell lung cancer who will benefit from treatment with endostatin in combination with paclitaxel plus carboplatin