Miracle-dz/UniFAR-FTUs huggingface dataset:
Biological characterization of SN 32976 , a selective inhibitor of PI 3 K and mTOR with preferential activity to PI 3 K α , in comparison to established pan PI 3 K inhibitors

Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3K inhibitors, which target class Ia PI3K isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3K inhibitor, for its biochemical potency against PI3K isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3K inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474. SN32976 potently inhibited PI3K isoforms and mTOR, displaying preferential activity for PI3Kα and sparing of PI3Kδ relative to the other inhibitors, while showing less off-target activity than the clinical inhibitors in a panel of 442 kinases. The major metabolites of SN32976 were also potent PI3K inhibitors with similar selectivity for PI3Kα as the parent compound. SN32976 compared favorably with the clinically-evaluated PI3K inhibitors in cellular assays, inhibiting pAKT expression and cell proliferation at nM concentrations, and in animal models, inducing a greater extent and duration of pAKT inhibition in tumors than pictilisib, dactolisib and omipalisib at similarly tolerated dose levels and inhibiting tumor growth to a greater extent than dactolisib and ZSTK474 and with similar efficacy to pictilisib and omipalisib. These results suggest that SN32976 is a promising clinical candidate for cancer therapy with enhanced kinase selectivity and preferential inhibition of PI3Kα compared to first generation pan PI3K inhibitors, while retaining comparable anticancer activity. www.impactjournals. com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 29), pp: 47725-47740
Effectivity of arbuscular mycorrhizal fungi collected from reclaimed mine soil and tallgrass prairie

We examined suitability of arbuscular mycorrhizal fungi (AMF) associated with cool-season nonnative forages on reclaimed surface-mined land in southeast Ohio for establishment of native warm-season grasses. The goal of establishing these grasses is to diversify a post-reclamation landscape that is incapable of supporting native forest species. A 16-week glasshouse study compared AMF from a 30-year reclaimed mine soil (WL) with AMF from native Ohio tallgrass prairie soil (CL). Four native grasses were examined from seedling through 16 weeks of growth. Comparisons were made between CL and WL AMF on colonized (+AMF) and non-colonized plants (–AMF) at three levels of soil phosphorus (P). Leaves were counted at 4 week intervals. Shoot and root biomass and percent AMF root colonization were measured at termination. We found no difference between WL and CL AMF. Added soil P did not reduce AMF colonization, but did reduce AMF efficacy. Big bluestem (Andropogon gerardii Vitman), Indiangrass (Sorghastrum nutans (L.) Nash), and tall dropseed (Sporobolus asper (Michx.) Kunth) benefited from AMF only at low soil P while slender wheatgrass (Elymus trachycaulus (Link) Gould ex Shinners) exhibited no benefit. Establishment of tallgrass prairie dominants big blue-stem and Indiangrass would be supported by the mine soil AMF. It appears that the non-native forage species have supported AMF equally functional as AMF from a regionally native tallgrass prairie. Tall dropseed and slender wheatgrass were found to be less dependent on AMF than big bluestem or Indiangrass and thus would be useful in areas with little or no AMF inoculum.
Use of Boronic Acid Disk Tests To Detect Extended- Spectrum β-Lactamases in Clinical Isolates of KPC Carbapenemase-Possessing Enterobacteriaceae

ABSTRACT We evaluated boronic acid (BA)-based methods for their ability to detect extended-spectrum β-lactamases (ESBLs) among clinical isolates of KPC-producing members of the Enterobacteriaceae family. A total of 155 isolates of Klebsiella pneumoniae (n = 141), Escherichia coli (n = 6), Enterobacter aerogenes (n = 6), and Klebsiella oxytoca (n = 2) genotypically confirmed to be KPC producers were analyzed. As many as 118 isolates harbored ESBLs (103 harbored SHV-type ESBLs, 13 harbored CTX-M-type ESBLs, and 2 harbored both SHV- and CTX-M-type ESBLs); the remaining 37 isolates were genotypically negative for ESBL production. The CLSI ESBL confirmatory test was positive for 79 of the 118 ESBL producers (sensitivity, 66.9%), while all 37 non-ESBL producers were negative (specificity, 100%). When a ≥5-mm increase in the zone diameter of either the cefotaxime (CTX)-clavulanate (CA) or the ceftazidime (CAZ)-CA disks containing BA compared with the zone diameter of the CTX or CAZ disks containing BA was considered to be a positive result for ESBL production, the method detected all 118 ESBL producers (sensitivity, 100%) and showed no false-positive results for non-ESBL producers (specificity, 100%). Double-disk synergy tests, in which disks of CTX, CAZ, aztreonam, or cefepime in combination with BA were placed at distances of 20, 25, and 30 mm (center to center) from a disk containing amoxicillin (amoxicilline)-clavulanate-BA, were able to detect 116 (98.3%), 101 (85.6%), and 28 (23.7%) of the ESBL-positive isolates, respectively; no false-positive results for non-ESBL-producing isolates were detected. Our results demonstrate that the modified CLSI ESBL confirmatory test with antibiotic disks containing BA is the most accurate phenotypic method for the detection of ESBLs in Enterobacteriaceae producing KPC carbapenemases.
The Effect of Three Different Meditation Exercises on Hypertension: A Network Meta-Analysis

We aimed to use the pairwise and network meta-analysis to estimate the effects of different meditation exercises on the control of systolic blood pressure (SBP) and diastolic blood pressure (DBP). Randomized controlled trials (RCTs) were retrieved from PubMed and Embase up to June 2016, which are published in English and reported on meditation exercise for hypertensive patients. Risks of bias assessment of the included studies were assessed by Cochrane Collaboration Recommendations and network meta-analysis was performed by ADDIS. Mean difference (MD) and its 95% confidence interval (CI) were used as the effect size. A number of 19 RCTs were included in this study. Results of pairwise comparisons indicated that meditation exercise could significantly decrease the SBP and DBP, compared with other interventions (MD = −7.10, 95% CI: −10.82 to −3.39; MD = −4.02, 95% CI: −6.12 to −1.92). With good consistence and convergence, network meta-analysis showed that there were no significant differences between meditation and other interventions on SBP. For DBP, Qigong was significantly lower than “no intervention” (MD = −11.73, 95% CI: −19.85 to −3.69). Qigong may be the optimal exercise way in lowering SBP and DBP of hypertensive patients, but a detailed long-term clinical research should be needed in the future.
The impact of high dietary zinc oxide on the development of the intestinal microbiota in weaned piglets.

Weaned piglets were fed diets containing 57 (low) or 2425 (high) mg kg(-1) analytical grade ZnO for a period of 5 weeks. Intestinal contents were sampled in weekly intervals and analyzed for bacterial cell numbers and main bacterial metabolites. The most severe effects of high dietary zinc were observed 1 week after weaning in the stomach and small intestine. Pronounced reductions were observed for Enterobacteriaceae and the Escherichia group as well as for Lactobacillus spp. and for three of five studied Lactobacillus species. The impact of high dietary zinc diminished for enterobacteria with increasing age, but was permanent for Lactobacillus species. Bifidobacteria, enterococci, streptococci, Weissella spp. and Leuconostoc spp. as well as the Bacteroides-Prevotella-Porphyromonas group were not influenced by high dietary zinc throughout the trial. High dietary zinc reduced bacterial metabolite concentrations and increased molar acetate ratios at the expense of propionate in the proximal intestine, but differences diminished in older animals. Lower lactate concentrations were observed in the high dietary zinc group throughout the feeding trial. This study has shown that the application of dietary zinc at high concentrations leads to transient and lasting effects during the development of the intestinal microbiota, affecting composition as well as metabolic activity.
Erfolg von Crowdfunding-Kampagnen frühzeitig erkennen: Erfolgsprädiktoren auf Kickstarter und Indiegogo

Crowdfunding hat in den letzten Jahren sowohl in der Praxis als auch in der Forschung stark an Bedeutung gewonnen. Obwohl bereits viele wissenschaftliche Beitrage existieren, die potentielle Erfolgsfaktoren von Crowdfunding-Kampagnen untersuchen, ist noch wenig uber Erfolgspradiktoren bekannt, die bereits fruhzeitig Aussagen uber die Erfolgsaussichten einer Kampagne erlauben wurden. Zur Schliesung dieser Forschungslucke wird in dieser Studie der dynamische Verlauf von Crowdfunding-Kampagnen beleuchtet. Im Speziellen wird untersucht, ob der Erfolg einer Kampagne in der Fruh- beziehungsweise Endphase der Laufzeit und die Staffelung der Unterstutzungsbeitrage als Erfolgspradiktoren dienen konnen. Es zeigt sich, dass insbesondere das Erreichen einer kritischen Masse an Beitragen in den ersten 7 Tagen der Kampagnenlaufzeit und das Eintreten eines Deadline-Effekts vor Kampagnenende wesentlich die Erfolgsaussichten von Crowdfunding-Kampagnen bestimmen.
Intraductal breast carcinoma. Two decades of progress?

Los Angeles, 1991 A perfectly healthy woman has been told that she has breast cancer, albeit, a very favorable form called DCIS (duct carcinoma in situ). Confusing and contradictory data are presented. A range of expert opinions is heard. Then she is asked to make a decision. She has the final word, the decision is hers.
New advancements in charge-coupled device technology: subelectron noise and 4096 x 4096 pixel CCDs

This paper reports on two new advancements in CCD technology. The first area of development has produced a special purpose CCD designed for ultra low-signal level imaging and spectroscopy applications that require sub-electron read noise floors. A nondestructive output circuit operating near its 1/f noise regime is clocked in a special manner to read a single pixel multiple times. Off-chip electronics average the multiple values, reducing the random noise by the square-root of the number of samples taken. Noise floors below 0.5 electrons rms are reported. The second development involves the design and performance of a high resolution imager of 4096 x 4096 pixels, the largest CCD manufactured in terms of pixel count. The device utilizes a 7.5-micron pixel fabricated with three-level poly-silicon to achieve high yield.
Cost-effectiveness of routine and low-cost CD4 T-cell count compared with WHO clinical staging of HIV to guide initiation of antiretroviral therapy in resource-limited settings

Background:HIV is a major cause of disease and death in sub-Saharan Africa. Provision and scale-up of antiretroviral therapy (ART) in resource-limited settings is feasible and cost-effective. Initiation of ART is guided by WHO stage or CD4 cell count; the latter may not be available and up to 70% of eligible individuals are not identified. Low-cost CD4 cell count tests are comparable to conventional methods. We compared the direct healthcare costs and benefits using routine and low-cost CD4 cell count versus WHO staging to initiate ART. Methods:Using a Markov state transition model, we incorporated costs, survival and quality of life. We compared the direct healthcare costs and benefits in quality-adjusted life years gained using routine and low-cost CD4 cell count versus WHO staging to initiate ART. We estimated an incremental cost-effectiveness ratio in US$ per quality-adjusted life year gained and compared with threshold of gross domestic product per capita. Uncertainty was assessed by sensitivity analysis. Results:Routine and low-cost CD4 cell counts compared to WHO staging to guide initiation of ART improved quantity and quality of life and appears to be very cost-effective. The base case estimated an incremental cost-effectiveness ratio of US$939 and US$85 per quality-adjusted life years gained, respectively, and well below the cost effectiveness thresholds of gross domestic product per capita. Conclusion:Routine or low-cost CD4 cell count compared to WHO staging, to guide initiation of ART, is a very cost-effective intervention for sub-Saharan Africa and should be an integral part of the scale-up of ART programs.
Influence of Environmental Cadmium Exposure on Forearm Bone Density

Cadmium may have both direct and indirect effects on bone turnover. It is nephrotoxic and can interfere with vitamin D metabolism. Such perturbation may result in osteoporosis and osteomalacia. In this study, a total of 790 persons (302 males and 488 females) participated; they were all over 35 years old and resided in an area near a cadmium smelter in southeast China. All participants completed a questionnaire, and bone mineral density was measured by SPA‐4 single‐photon absorptiometry at the radius and ulna. Cadmium content of urine was determined by graphite‐furnace atomic absorption spectrophotometry as a measure of dose. The decline in bone mineral density with age in a heavily polluted area was greater than that in a control area for subjects over 60 years of age of both sexes (p < 0.05). In single regression, forearm bone densities were negatively correlated with urinary cadmium excretion in both males and females (p < 0.001), whereas stepwise regression showed that forearm bone density decreased linearly with age (p < 0.001) and urinary cadmium (p < 0.01) in both sexes, suggesting a dose‐effect relationship between cadmium dose and bone mineral density. Based on the World Health Organization criteria, (bone mineral density < −2.5 SDs below the normal young adult), the prevalence of osteoporosis in women increased from 34.0% in the control area to 51.9% in the heavily polluted area (p < 0.01) among subjects over 50 years old, and the odds ratio value was 2.09 (95% CI: 1.08–4.03) for the highly polluted area compared with the control area. A striking observation in the study was the marked increase of the prevalence of fracture in the cadmium‐polluted area in both sexes. It was concluded that environmental exposure to cadmium is associated with an increased loss of bone mineral density in both males and females, leading to osteoporosis and increased risk of fractures, especially in the elderly and in females.
Entrepreneurship for social impact: encouraging market access in rural Bangladesh

Purpose – In many developing countries those living in poverty are unable to participate in markets due to the weakness or complete absence of supportive institutions. This study aims to examine, in microcosm, such an institutional void and to illustrate the strategy and activities employed by an entrepreneurial actor in rural Bangladesh in addressing it.Design/methodology/approach – The paper is based on an in‐depth case study. Data were gathered over two years from field interviews, archives, and secondary sources.Findings – The data illustrate how market access for the poorest of the poor is facilitated through the creation of platforms for participation in the economy and broader society. The authors conceptualize this process as the crafting of new institutional arrangements and as resource and institutional bricolage occurring in parallel.Practical implications – The study offers insights for development agencies, policy makers and companies on how to combat poverty, fight corruption, and stimulate .
Exploratory experimental research on incentive-control mechanism of R&D personnel in technological enterprise

The paper examines the technology enterprise. After the literature review, key motivation choices are listed out, namely training and development, authorization of innovation, promotion, involvement in management, which are optional incentives relevant to personal capability, as well as improvement of R&D working environment. The R&D personnel incentive-control mechanism is proposed based on the principal-agent relationship. Six groups, including MBA students, R&D personnel were selected as experimental subjects and corresponding experimental studies were performed after careful designing. The paper presents explorative discussion on the effectiveness and efficiency of two incentive-control mechanisms — trust and incentive- and has proposed a series of useful conclusions. In regard to effects and benefits, the experiment suggests that the trust incentive control method can achieve the win-win result under the unremitting learning condition.
A bounded cost condition for the existence of average optimal stationary policies of linear stochastic systems

This note considers the long-run average cost control problem of a discrete-time stochastic system. The stochastic system is assumed to be linear with respect to the state but the controls possess a general structure, possibly nonlinear. The main contribution of this paper is to show the existence of an optimal stationary policy for the long-run average cost problem provided that (i) there exists an ε-optimal policy for the discounted problem and this policy generates uniform bounded costs by stage, and that (ii) a persistency of excitation condition is satisfied. A numerical example illustrates the derived result.
Similarity of dynamic range adjustment in auditory nerve and cochlear nuclei.

Rate versus level functions were recorded for responses to best-frequency (BF) tones of 116 cochlear nucleus units and 53 auditory-nerve fibers in the presence of interrupted tone backgrounds and continuous noise backgrounds of various intensities. The backgrounds shifted the dynamic ranges of rate-level functions to higher test intensities, so in the presence of backgrounds, rate saturation occurred at higher intensities than in quiet. The shift in saturation intensity evoked by each background was measured by comparing the rate-level function recorded with the background to one recorded without. The relation between change in saturation intensity and background intensity could be approximated by the formula (formula: see text) delta Isat is the shift in saturation intensity, I is the background intensity, theta is the threshold for evoking shift, and A is the ratio of shift to background intensity re theta. In the appendix, it is shown that A is a measure of a unit's ability to avoid saturation by the background stimulus. The optimal value of A is unity, at which point a unit's operating range is infinite. The value of A depended on BF for interrupted tone backgrounds, but not for continuous noise backgrounds. For BF less than 10 kHz, the mean value of A for tone backgrounds was 0.33 in the auditory nerve, 0.37 in the ventral cochlear nuclei (VCN), and 0.47 in the dorsal cochlear nucleus (DCN). The difference between auditory nerve and VCN was not statistically significant. For BF greater than 10 kHz, the mean A was 0.16 in auditory nerve and 0.30 in VCN. The mean value of A for noise backgrounds was 0.79 in auditory nerve, 0.86 in VCN, 0.86 in DCN units of response types II and III, and 1.04 in DCN type IV units. Only the differences between DCN type IV and the non-DCN unit groups were statistically significant. The qualitative changes produced in rate-level functions by tone and noise backgrounds were similar in auditory nerve and cochlear nuclei except for DCN type IV units. The shifts in rate functions produced by interrupted tone backgrounds did not prevent saturation of the rate response at background intensities above the dynamic range of the unit as recorded in quiet. However, the rate response to test tones was preserved in the presence of all noise background levels used (up to a 30-dB spectrum level). The shift in rate function produced by the noise was almost sufficient to allow the unit to encode test intensity relative to noise background intensity. (ABSTRACT TRUNCATED AT 400 WORDS)
Correction to Isoform-Selective Disruption of AKAP-Localized PKA Using Hydrocarbon Stapled Peptides

This correction is in regard to Figure ​Figure3a.3a. Compound 2K-3 contains a typo in its sequence at position 13 (S instead of K). The sequence should read KKLAKFLVS*ALK*ALK. Its scramble control, 2K-3-scramble, is listed correctly. Compound analysis and all experiments were performed using the compound with the correct sequence. This typo does not change any of the analysis or conclusions in this paper. We sincerely apologize for this typographical error. Figure 3
Patients' experiences of screening for type 2 diabetes: prospective qualitative study embedded in the ADDITION (Cambridge) randomised controlled trial

Objectives To provide insight into factors that contribute to the anxiety reported in a quantitative study of the psychological effect of screening for type 2 diabetes. To explore expectations of and reactions to the screening experience of patients with positive, negative, and intermediate results. Design Prospective qualitative interview study of patients attending a screening programme for type 2 diabetes. Setting Seven general practices in the ADDITION (Cambridge) trial in the east of England. Participants 23 participants (aged 50-69) attending different stages in the screening process. Results Participants' perceptions changed as they progressed through the screening programme; the stepwise process seemed to help them adjust psychologically. The first screening test was typically considered unimportant and was attended with no thought about its implications. By the final diagnostic test, type 2 diabetes was considered a strong possibility, albeit a “mild” form. After diagnosis, people with screen detected type 2 diabetes tended to downplay its importance and talked confidently about their plans to control it. Participants with intermediate results seemed uncertain about their diagnosis, and those who screened negative were largely unaware of their remaining high risk. Conclusions This study helps in understanding the limited psychological impact of screening for type 2 diabetes quantified previously, in particular by the quantitative substudy of ADDITION (Cambridge). The findings have implications for implementing such a screening programme in terms of timing and content.
Morbidity and disability in older persons in the years prior to death.

BACKGROUND A large proportion of the disease and disability which affects older persons occurs in the years just prior to death. Little prospective evidence is available which quantifies the burden of morbidity and disability during these years. METHODS In three community-based cohorts of persons age 65 and older, chronic conditions and disability were evaluated for the three years prior to death in 531 persons who had three annual assessments and then died within one year of the third assessment. Number of chronic conditions, prevalence of disability in activities of daily living (ADLs), and prevalence of disability on a modified Rosow-Breslau scale were determined for these decedents and compared to 8821 members of the cohorts known to have survived. RESULTS Prevalence rates of disease and disability increased during the follow-up for both decedents and survivors, with decedents generally having higher rates than survivors. Disability rates prior to death, but not the number of diseases, increased with increasing age at death. The odds ratio for disability in ADLs at any of the three assessments for decedents versus survivors ranged from 3.0 to 4.2 in the three communities. In each community the odds ratio for ADL disability was higher in women decedents versus survivors than in men decedents versus survivors. CONCLUSIONS These results have important implications for disability levels in future older populations in which death is projected to occur at increasingly higher ages.