Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study.

OBJECTIVE To evaluate dextromethorphan coadministered with quinidine as treatment of diabetic peripheral neuropathic pain. DESIGN In a 13-week, phase 3, randomized controlled trial, 379 adults with daily symmetric diabetic peripheral neuropathy (DPN) leg pain for ≥3 months received double-blind placebo, dextromethorphan/quinidine (DMQ) 45/30 mg, or DMQ 30/30 mg, administered once daily for 7 days and twice daily thereafter. Efficacy measures included four pain rating scales applied daily using patient diaries, and another two applied at five clinic visits. RESULTS On all six scales, DMQ 45/30 mg was significantly superior to placebo, including the primary efficacy analysis, which utilized mixed-effects modeling to test all scores on an 11-point numerical Pain Rating Scale (P < 0.0001). Sensitivity analyses gave consistent results. Efficacy vs placebo was also seen for diary ratings of present pain intensity, and pain interference with sleep and with activities (all P < 0.0001). Among clinic visit assessments, DMQ 45/30 mg demonstrated greater leg pain relief (P = 0.0002) and greater reduction of leg pain intensity (P = 0.0286) vs placebo. The efficacy of DMQ 30/30 mg was numerically less than for 45/30 mg but for most outcomes remained significantly greater vs placebo. Adverse events were mostly mild or moderate and of expected types. Discontinuation for adverse events in the DMQ groups was at least twice as common as placebo. CONCLUSIONS Throughout a 13-week trial, DMQ was effective, with an acceptable safety profile, for treatment of DPN pain. Other fixed-dose combinations of DMQ should be studied to improve overall tolerability while maintaining significant efficacy.
NMR and computational characterization of mitomycin cross-linked to adjacent deoxyguanosines in the minor groove of the d(T-A-C-G-T-A).d(T-A-C-G-T-A) duplex.

Two-dimensional homonuclear and heteronuclear NMR and minimized potential energy calculations have been combined to define the structure of the antitumor agent mitomycin C (MC) cross-linked to deoxyguanosines on adjacent base pairs in the d(T1-A2-C3-G4-T5-A6). d(T7-A8-C9-G10-T11-A12) duplex. The majority of the mitomycin and nucleic acid protons in the MC-X 6-mer complex have been assigned from through-bond and through-space two-dimensional proton NMR studies in aqueous solution at 5 and 20 degrees C. The C3.G10 and G4.C9 base pairs are intact at the cross-link site and stack on each other in the complex. The amino protons of G4 and G10 resonate at 9.36 and 8.87 ppm and exhibit slow exchange with solvent H2O. The NMR experimental data establish that the mitomycin is cross-linked to the DNA through the amino groups of G4 and G10 and is positioned in the minor groove. The conformation of the cross-link site is defined by a set of NOEs between the mitomycin H1" and H2" protons and the nucleic acid imino and amino protons of G4 and the H2 proton of A8 and another set of NOEs between the mitomycin geminal H10" protons and the nucleic acid imino and amino protons of G10 and the H2 proton of A2. Several phosphorus resonances of the d(T-A-C-G-T-A) duplex shift dramatically on mitomycin cross-link formation and have been assigned from proton-detected phosphorus-proton two-dimensional correlation experiments. The proton chemical shifts and NOEs establish fraying at the ends of the d(T-A-C-G-T-A) duplex, and this feature is retained on mitomycin cross-link formation. The base-base and base-sugar NOEs exhibit similar patterns for symmetry-related steps on the two nucleic acid strands in the MC-X 6-mer complex, while the proton and phosphorus chemical shifts are dramatically perturbed at the G10-T11 step on cross-link formation. The NMR distance constraints have been included in minimized potential energy computations on the MC-X 6-mer complex. These computations were undertaken with the nonplanar five-membered ring of mitomycin in each of two pucker orientations. The resulting low-energy structures MX1 and MX2 have the mitomycin cross-linked in a widened minor groove with the chromophore ring system in the vicinity of the G10-T11 step on one of the two strands in the duplex. (ABSTRACT TRUNCATED AT 400 WORDS)
Community Structure and Dynamics of the Industry Sector-Specific International-Trade-Network

We analyzed the industry sector-specific international trade data from 1995 to 2011 to clarify the structure and dynamics of communities that consist of industry sectors in various countries linked by international trade. We applied conventional community analysis to each time slice of the international trade network, and then identified the links between communities in adjoining years by using the World Input-Output Database. This database contains the industry sector specific international trade data on 41 countries and 35 industry sectors. The identified link structure shows that a triple backbone structure exists in the international trade network. We used the Hilbert transform to evaluate the phase time series of the growth rate of value added for 1435 nodes and then estimated the complex order parameters for communities. The respective amplitude for the order parameter of each community was observed to be greater than the amplitude for all sectors. This means active trade produces higher phase coherence within each community. Phase coherence decreased gradually in the late 1990's but increased sharply in 2001 and 2002.
Sand in the Chips? Evidence on Taxing Transactions in Modern Markets

We present evidence on the causal impact of nancial transaction taxes on market quality in a modern market structure by exploiting the introduction of such a levy in France on August 1st, 2012. Our evidence suggests that the substantial changes in market structure over the past decades play an important role in reassessing the long-standing idea of the FTT. While we document a surprisingly mild impact on exchange-based trading due to exemptions for liquidity provision, o-exchange trading declined by 40%, and the largest OTC trades virtually disappeared. This suggests that market segmentation poses a considerable challenge to current policy proposals.
Birc1e/Naip5 rapidly antagonizes modulation of phagosome maturation by Legionella pneumophila

Legionella survives intracellularly by preventing fusion with lysosomes, due to phagosome escape from the endocytic pathway at an early stage of phagosome maturation, and by creating a replicative organelle that acquires endoplasmic reticulum (ER) characteristics through sustained interactions and fusion with the ER. Intracellular replication of Legionella pneumophila in mouse macrophages is controlled by the Lgn1 locus. Functional complementation in vivo has identified the Birc1e/Naip5 gene as being responsible for the Lgn1 effect. To understand the function and temporal site of action of Birc1e/Naip5 in susceptibility to L. pneumophila, we examined the biogenesis of Legionella‐containing vacuoles (LCVs) formed in permissive A/J macrophages and in their Birc1e/Naip5 transgenic non‐permissive counterpart. Birc1e/Naip5 effects on acquisition of lysosomal and ER markers were evident within 1–2 h following infection. A significantly higher proportion of LCVs formed in Birc1e/Naip5 transgenic macrophages had acquired the lysosomal markers cathepsin D and Lamp1 by 2 h post infection, whereas a significantly higher proportion of LCVs formed in permissive macrophages were positively stained for the ER markers BAP31 and calnexin, 6 h post infection. Likewise, studies by electron microscopy showed acquisition of lysosomal contents (horseradish peroxidase), within the first hour following phagocytic uptake, by LCVs formed in Birc1e/Naip5 transgenic macrophages and delivery of the ER marker glucose 6‐phosphatase (G6Pase) only to the lumen of LCVs formed in A/J macrophages. Finally, a larger proportion of LCVs formed in A/J macrophages were studded with ribosomes 24 h post infection, compared with LCVs formed in Birc1e/Naip5 transgenic macrophages. These results suggest that sensing of L. pneumophila products by Birc1e/Naip5 in macrophages occurs rapidly following phagocytosis, a process that antagonizes the ability of L. pneumophila to remodel its phagosome into a specialized vacuole with ER characteristics.
Randomized control trial of live Lactobacillus acidophilus plus Bifidobacterium infantis in treatment of infantile acute watery diarrhea.

OBJECTIVE To evaluate the effectiveness of live Lactobacillus acidophilus plus Bifidobacterium infantis in the treatment of acute watery diarrhea. DESIGN Open, randomized control trial. SETTING King Chulalongkorn Memorial Hospital, Bangkok, Thailand. MATERIAL AND METHOD Seventy-one infants (aged 1-24 months) with acute watery diarrhea that presented at Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok were enrolled after parental signed informed consent. They were randomized into 2 groups. The Study group (n = 35) received live Lactobacillus plus Bifidobacterium (3 x 10(9) CFU) bid and ORS and the Control group (n = 36) received ORS only. All infants received lactose free milk. Case record forms were completed daily for 5 days by the parents. RESULTS All 71 infants completed the present study. There was no difference of the patients'characteristics and baseline clinical symptoms between the study group and the control group. Live Lactobacillus plus Bifidobacterium shortened the diarrhea duration (1.6 +/- 0.7 days vs 2.9 +/- 1.7 days, p < 0.01) compared to controls. However the stool frequency and duration of hospitalization were not significantly different (p > 0.05, study group vs control group). CONCLUSION Live Lactobacillus acidophilus plus Bifidobacterium infantis may be an effective treatment for acute watery diarrhea in infants. The 2-day course treatment can significantly shorten the duration of diarrhea.
Targeting cytokines in autoimmunity: new approaches, new promise

The increasing understanding of the pathophysiology of a number of human autoimmune diseases, and the realisation that cytokines play a major role, has provided the pharmaceutical industry with a wide array of new targets for therapeutic intervention. This has also resulted in a surge of interest for the development of ways of blocking cytokines and their actions in a specific and safe manner. This article reviews the current status of anticytokine therapy and the major efficacy that anti-TNF-α monoclonal antibodies (mAbs) and soluble TNF receptors have demonstrated in the clinic, which has led to their approval for the treatment of rheumatoid arthritis (RA), Crohn’s disease (CD), juvenile arthritis and psoriatic arthritis. In addition, the development of novel approaches of cytokine blockade that are based on the characterisation of intracellular signalling pathways regulating cytokine expression (e.g., nuclear factor kappa B [NF-κB] and p38 mitogen activated protein kinase [MAPK]) and the use of small molecule inhibitors are discussed. Whether these approaches will keep up with their early promise and become a major and widespread treatment for several devastating autoimmune diseases will depend on specificity, safety, durability of the benefit, and pharmacoeconomic issues.
Effects of transforming growth factor‐β subtypes on in vitro cartilage production and mineralization of human bone marrow stromal‐derived mesenchymal stem cells

Human bone marrow stromal‐derived mesenchymal stem cells (hBMSCs) will differentiate into chondrocytes in response to defined chondrogenic medium containing transforming growth factor‐β (TGFβ). Results in the literature suggest that the three mammalian subtypes of TGFβ (TGFβ1, TGFβ2 and TGFβ3) provoke certain subtype‐specific activities. Therefore, the aim of our study was to investigate whether the TGFβ subtypes affect chondrogenic differentiation of in vitro cultured hBMSCs differently. HBMSC pellets were cultured for 5 weeks in chondrogenic media containing either 2.5, 10 or 25 ng/ml of TGFβ1, TGFβ2 or TGFβ3. All TGFβ subtypes showed a comparable dose‐response curve, with significantly less cartilage when 2.5 ng/ml was used and no differences between 10 and 25 ng/ml. Four donors with variable chondrogenic capacity were used to evaluate the effect of 10 ng/ml of either TGFβ subtype on cartilage formation. No significant TGFβ subtype‐dependent differences were observed in the total amount of collagen or glycosaminoglycans. Cells from a donor with low chondrogenic capacity performed equally badly with all TGFβ subtypes, while a good donor overall performed well. After addition of β‐glycerophosphate during the last 2 weeks of culture, the expression of hypertrophy markers was analysed and mineralization was demonstrated by alkaline phosphatase activity and alizarin red staining. No significant TGFβ subtype‐dependent differences were observed in expression collagen type X or VEGF secretion. Nevertheless, pellets cultured with TGFβ1 had significantly less mineralization than pellets cultured with TGFβ3. In conclusion, this study suggests that TGFβ subtypes do affect terminal differentiation of in vitro cultured hBMSCs differently. Copyright © 2011 John Wiley & Sons, Ltd.
On the peripheral and central chemoreception and control of breathing: an emerging role of ATP

Peripheral and central respiratory chemoreceptors are ultimately responsible for maintenance of constant levels of arterial P O 2, P CO 2 and [H+], protecting the brain from hypoxia and ensuring that the breathing is always appropriate for metabolism. The aim of this discussion is to shed some light on the potential mechanisms of chemosensory transduction– the process which links chemosensory mechanisms to the central nervous mechanisms controlling breathing. Recent experimental data suggest that the purine nucleotide ATP acts as a common mediator of peripheral and central chemosensory transduction (within the carotid body and the medulla oblongata, respectively). In response to a decrease in P O 2 (hypoxia) oxygen‐sensitive glomus cells of the carotid body release ATP to activate chemoafferent fibres of the carotid sinus nerve which transmit this information to the brainstem respiratory centres. In response to an increase in P CO 2 /[H+] (hypercapnia) chemosensitive structures located on the ventral surface of the medulla oblongata rapidly release ATP, which acts locally within the medullary respiratory network. The functional role of ATP released at both sites is similar – to evoke adaptive enhancement in breathing. Understanding the mechanisms of ATP release in response to chemosensory stimulation may prove to be essential for further detailed analysis of cellular and molecular mechanisms underlying respiratory chemosensitivity.
Delayed Diagnosis and Elevated Mortality in an Urban Population With HIV and Lung Cancer: Implications for Patient Care

Objective: Lung cancer is more common in HIV-infected patients than in the general population. We examined how effectively lung cancer was being diagnosed in our HIV-infected patients. Methods: Retrospective study assessing clinical diagnosis of lung cancer in HIV-infected patients at Johns Hopkins Hospital between 1986 and 2004. Results: Ninety-two patients were identified. Compared to HIV-indeterminate patients (n = 4973), HIV-infected individuals were younger with more advanced cancer. CD4 counts and HIV-1 RNA levels indicated preserved immune function. Mortality was higher in HIV-infected patients, with 92% dying of lung cancer (hazard ratio, 1.57; 95% confidence interval, 1.25-1.96), compared to HIV-uninfected patients. Advanced stage and black race were associated with worse survival. After adjustment for these factors, HIV infection was not associated with increased mortality (hazard ratio, 1.04; 95% confidence interval, 0.83-1.32). Of 32 patients followed in our HIV clinic, 60% of chest radiographs had no evidence of neoplasm within 1 year of diagnosis compared to only 1 (4%) of 28 chest computed tomography scans. Nonspecific infiltrates were observed in 9 patients in the same area that cancer was subsequently diagnosed. Conclusions: HIV-infected lung cancer patients have shortened survival mainly due to advanced stage. Low clinical suspicion and overreliance on chest radiographs hindered earlier detection. Aggressive follow-up of nonspecific pulmonary infiltrates in these patients is warranted.
Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation

Extracellular stimuli that activate the transcription factor NF-kappaB cause rapid phosphorylation of the IkappaBalpha inhibitor, which retains NF-kappaB in the cytoplasm of nonstimulated cells. Phosphorylation of IkappaBalpha is followed by its rapid degradation, the inhibition of which prevents NF-kappaB activation. To determine the relationship between these events, we mapped the inducible phosphorylation sites of IkappaBalpha. We found that two residues, serines 32 and 36, were phosphorylated in response to either tumor necrosis factor, interleukin-1, or phorbol ester. Substitution of either serine blocks or slows down induction of IkappaBalpha degradation. Substitutions of the homologous sites in IkappaBbeta, serines 19 and 23, also prevent inducible IkappaBbeta degradation. We suggest that activation of a single IkappaB kinas e or closely related IkappaB kinases is the first cr itical step in NF-kappaB activation. Once phosphorylated, IkappaB is ubiquitinated. Unlike wild-type IkappaBalpha, the phosphorylation-defective mutants do not undergo inducible polyubiquitination. As substitution of a conserved lysine residue slows down the ubiquitination and degradation of IkappaBalpha without affecting its phosphorylation, polyubiquitination is required for inducible IkappaB degradation.
Sedimentation and the Reproductive Biology of the Hawaiian Reef-Building Coral Montipora capitata

Environmental conditions can influence the physiology of marine organisms and have important implications for their reproductive performance and capacity to supply new recruits. This study examined the seasonal reproductive patterns of the coral Montipora capitata in habitats exposed to different sedimentation regimes. Although M. capitata is a main reef-building coral in the Hawaiian Archipelago, little is known about the gametogenic cycle and reproductive ecology of this important species. Our results indicate that gamete production in M. capitata is a resilient process; no differences in gamete development or fecundity were observed among sites with very different sedimentation regimes. The gametogenic cycle of M. capitata lasts between 10 and 11 months, with spawning occurring over 3–5 months during warmer months (May–September). Oocytes were found throughout the year, but spermatocysts were only found April–August. The largest increases in oocyte size occurred during February to May, the months when solar radiation increased rapidly. The largest variation in oocyte sizes was found during July and August; during this period individual colonies contained mature oocytes for immediate spawning and new oocytes being formed for spawning the next year. The capacity of M. capitata to reproduce in areas with high sedimentation is an interesting finding highlighting the potential of the species for acclimatization, adaptation, or both. Despite this optimistic finding, the management of terrestrial runoff and the restoration of habitat quality for corals remains a top priority to ensure the renewal and maintenance of coral populations.
The effects of cold water immersion and active recovery on inflammation and cell stress responses in human skeletal muscle after resistance exercise

Cold water immersion and active recovery are common post‐exercise recovery treatments. A key assumption about the benefits of cold water immersion is that it reduces inflammation in skeletal muscle. However, no data are available from humans to support this notion. We compared the effects of cold water immersion and active recovery on inflammatory and cellular stress responses in skeletal muscle from exercise‐trained men 2, 24 and 48 h during recovery after acute resistance exercise. Exercise led to the infiltration of inflammatory cells, with increased mRNA expression of pro‐inflammatory cytokines and neurotrophins, and the subcellular translocation of heat shock proteins in muscle. These responses did not differ significantly between cold water immersion and active recovery. Our results suggest that cold water immersion is no more effective than active recovery for minimizing the inflammatory and stress responses in muscle after resistance exercise.
Dissection of GLUT4 recycling pathway into exocytosis and endocytosis in rat adipocytes. Evidence that GTP-binding proteins are involved in both processes

The effects of guanine nucleotides on either exocytosis or endocytosis of GLUT4 were examined in electrically permeabilized rat adipocytes by using Dk-(62-85), a major histocompatibility complex class I-derived peptide. Reversal of glucose transport activity that had been stimulated with insulin was completely blocked by Dk-(62-85). Likewise, endocytosis of the trypsin-cleaved 35-kDa fragment of GLUT4 was almost completely inhibited by the peptide. Insulin-stimulated glucose transport activity was enhanced about 50% by Dk-(62-85), whereas the basal transport activity was stimulated only slightly. Although guanosine 5′-O-(3-thiotriphosphate) (GTP gamma S) augmented glucose transport to the same extent as insulin in the absence of the peptide, glucose transport stimulated by GTP gamma S was only 60% of the insulin effect in the presence of the peptide; the effect of insulin was markedly enhanced by Dk-(62-85), whereas GTP gamma S-induced glucose transport was not affected, suggesting that GTP gamma S has an effect similar to that of the peptide. In fact, endocytosis of the 35-kDa fragment of GLUT4 was markedly inhibited by GTP gamma S. Additionally, GLUT4 endocytosis was accelerated by GTP but was inhibited by guanosine 5′-O-(2-thiodiphosphate). These results indicate that GTP gamma S induces translocation of GLUT4 by both stimulating exocytosis and inhibiting endocytosis. With respect to the dependence on GTP hydrolysis, distinct types of GTP-binding proteins are involved in exocytosis and endocytosis of GLUT4.
Implementation of Novel Pyrosequencing Assays to Screen for Common Mutations of BRAF and KRAS in a Cohort of Sporadic Colorectal Cancers

Activating mutations of the BRAF and KRAS genes cause constitutive stimulation of an important cell-signaling pathway promoting tumorigenesis, and are increasingly recognized as determinants of response to targeted cancer therapies. The V600E mutation accounts for most of the BRAF mutations in cancer, and KRAS mutations are predominantly encoded by nucleotide substitutions within codons 12 and 13. We designed novel pyrosequencing assays for the detection of the common “hotspot” mutations in these genes, which demonstrated analytical sensitivities of ≤10% in titrations of mutant cell lines. The KRAS pyrosequencing assay has the ability to simultaneously identify all potential nucleotide changes within the mutation cluster at codons 12 and 13, with a sequence output in the sense direction to facilitate results interpretation. These assays were used to determine the mutation status in a prospective series of 1198 sporadic colorectal cancers. The BRAF V600E mutation was detected in 13.2% of the colorectal cancers. The frequency of KRAS mutations in our cohort was 32.4%, with G>A transitions at position 2 of codons 12 and 13 being most prevalent. Both assays proved highly sensitive and specific when applied to clinical specimens, and were applicable to both fresh-frozen and formalin-fixed paraffin-embedded archival tissues. These assays would serve as a suitable platform for large-scale mutation detection in cancer specimens where the facility for pyrosequencing is available.