Miracle-dz/UniFAR-FTUs huggingface dataset:
M 2698 is a potent dual-inhibitor of p 70 S 6 K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrier

Dysregulated PI3K/Akt/mTOR (PAM) pathway signaling occurs in ~30% of human cancers, making it a rational target for new therapies; however, the effectiveness of some PAM pathway inhibitors, such as mTORC rapalogs, may be compromised by a compensatory feedback loop leading to Akt activation. In this study, the p70S6K/ Akt dual inhibitor, M2698 (previously MSC2363318A), was characterized as a potential anti-cancer agent through examination of its pharmacokinetic, pharmacodynamic and metabolic properties, and anti-tumor activity. M2698 was highly potent in vitro (IC50 1 nM for p70S6K, Akt1 and Akt3 inhibition; IC50 17 nM for pGSK3β indirect inhibition) and in vivo (IC50 15 nM for pS6 indirect inhibition), and relatively selective (only 6/264 kinases had an IC50 within 10-fold of p70S6K). Orally administered M2698 crossed the blood-brain barrier in rats and mice, with brain tumor exposure 4-fold higher than non-disease brain. Dose-dependent inhibition of target substrate phosphorylation was observed in vitro and in vivo, indicating that M2698 blocked p70S6K to provide potent PAM pathway inhibition while simultaneously targeting Akt to overcome the compensatory feedback loop. M2698 demonstrated dose-dependent tumor growth inhibition in mouse xenograft models derived from PAM pathway-dysregulated human triple-negative (MDA-MB-468) and Her2-expressing breast cancer cell lines (MDA-MB-453 and JIMT-1), and reduced brain tumor burden and prolonged survival in mice with orthotopically implanted U251 glioblastoma. These findings highlight M2698 as a promising PAM pathway inhibitor whose unique mechanism of action and capacity to pass the bloodbrain barrier warrant clinical investigation in cancers with PAM pathway dysregulation, and those with central nervous system involvement.
The Removal of Indicator Microorganisms from Primary Treated Wastewater in Subsurface Reed Beds using Different Substrates

Subsurface, horizontal flow, experimental reed beds, were designed and built based on a combination of two design methodologies, that of the WRc and Severn Trent Water Plc and that of the USA, EPA. Four different growing media were used with a combination of top soil, gravel, river sand and mature sewage sludge compost, aiming to determine the best substrate for enteric pathogen removal. Eight units were constructed, two for each material. One bed for each pair was planted with Typha latifolia plants commonly known as cattails. Primary treated domestic wastewater, was continuously fed in to the bed for more than six months. All beds achieved a high reduction of Escherichia coli and faecal coliforms with the best results recorded in the gravel reed beds with an average removal above 3.3 log for E. coli and 3.0 for faecal coliforms. There was no significance difference in the performance of planted and unplanted reed beds.
Expression of p53, MDM2, and p21 proteins in high-grade cervical intraepithelial neoplasia and relationship to human papillomavirus infection.

The relationship between human papillomavirus (HPV) infection and cell cycle regulators p53, MDM2, and p21 in cervical intraepithelial neoplasia (CIN) has not been investigated. p53, MDM2, and p21 immunoreactivity were analyzed with respect to HPV DNA status in high-grade CIN (CIN II-III). Formalin-fixed, paraffin-embedded tissue sections from 169 biopsy specimens with high-grade CIN were examined for HPV DNA by polymerase chain reaction with the L1 and E1 consensus primers Gp5+/6+ and CpI/CpIIG. HPV-positive specimens were typed with the E6 type-specific primers for HPV 16 and 18. The biopsy specimens were stained with the monoclonal antibodies p53, MDM2, and p21. The interpretation of nuclear staining was regarded as focal (< 5%), regional (5% to 50%), or diffuse (> 50%). HPV DNA was found in 156 cases (92%); 122 (78%) were positive for HPV 16, 18, or both. Immunohistochemically, p53 was detected in 50 specimens (30%); nuclear staining was mainly focal. Focal nuclear staining for MDM2 was found in 6 specimens (4%), and regional and diffuse nuclear staining for p21 was present in 137 (81%). Significant correlation was found only between p53 and MDM2 immunoreactivity. These results indicate that there is no correlation between HPV status and expression of the cell cycle regulators p53, MDM2, and p21. Inactivation of p21 and p53 protein may be important, and MDM2 abnormalities seem to play a minor role in the development of high-grade CIN.
Personality Traits in Childhood and Adolescence

Like adults, children and adolescents can be described in terms of personality traits: characteristic patterns of thinking, feeling, and behaving. We review recent research examining how youths’ specific behavioral tendencies cohere into broader traits, how these traits develop across childhood and adolescence, and how they relate to important biological, social, and health outcomes. We conclude that there are both key similarities and key differences between youth and adult personality traits, that youths’ personality traits help shape the course of their lives, and that a full understanding of youth personality traits will require additional research at the intersection of personality, developmental, and clinical psychology.
EMPLOYEES ’ COPING STRATEGIES AND ADAPTABILITY IN A MULTIPLE DOWNSIZING CONTEXT

In a downsizing, employees have to cope with major changes. Their coping strategy influences their level of adaptability. Coping proceeds through sensemaking, and may be either reactive or proactive. This paper reports a study on employees’ sensemaking of critical incidents in a multiple downsizing context. The organization studied, experienced two downsizings in one year. Its culture was based on Life time employment, and the downsizing was expected to cause a shift in attitude. Using the Extended investment model and the Job crafting model as optional coping strategies, data of critical incidents discussed in focus groups were analyzed. Results showed that incidents have a cumulative effect. Although survivors of the first downsizing were willing to adapt to the changes, the second downsizing undermined this. Further, both downsizings showed the dominant culture in employees’ reactive attitude. The authors discuss the influence of the dominant organizational culture on the psychological and behavioral consequences for the coping strategy and employee adaptability. The process of sensemaking showed some aspects of job crafting, but primarily aspects of the extended investment model. Theoretical and practical implications are discussed.
Animating the archive: the trial and testimony of a Sufi saint

In 1895 the colonial administration of Senegal sentenced Sheikh Amadu Bamba to exile for stirring anti-colonial disobedience. At his trial, Bamba allegedly recited a prayer in defiance of the French authorities. Although there is no archival record to prove that the prayer was recited, since the 1970s Bamba's disciples have flocked to the former seat of colonial power to commemorate his act of resistance; their testimony has displaced the authority of the colonial archive and imagines a decolonial utopia in archival absence. This article examines how their prayer subverts the colonial archive, while it remains entangled in its substrate.
Quantitative estimates of propagation of chaos for stochastic systems with kernels

We derive quantitative estimates proving the propagation of chaos for large stochastic systems of interacting particles. We obtain explicit bounds on the relative entropy between the joint law of the particles and the tensorized law at the limit. We have to develop for this new laws of large numbers at the exponential scale. But our result only requires very weak regularity on the interaction kernel in the negative Sobolev space Ẇ−1,∞, thus including the Biot–Savart law and the point vortices dynamics for the 2d incompressible Navier–Stokes. Mathematics Subject Classification 35Q30 · 60F17 · 60H10 · 76R99 P. E. Jabin is partially supported by NSF Grant 1312142 and by NSF Grant RNMS (Ki-Net) 1107444. Z. Wang is partially supported by NSF Grant 1312142 and Ann G. Wylie Dissertation Fellowship. B Zhenfu Wang zwang423@math.umd. edu Pierre-Emmanuel Jabin pjabin@cscamm.umd. edu 1 CSCAMM and Department of Mathematics, University of Maryland, College Park, MD 20742, USA 2 PresentAddress:Department ofMathematics,University of Pennsylvania, Philadelphia, PA 19104, USA
Lysine supplementation of diets for yearling horses.

Forty-six Thoroughbred and Quarter Horse yearlings were used in two experiments designed to determine the amount of lysine in the concentrate necessary to promote maximum growth when fed the Coastal bermudagrass (Cynodon dactylon) hay provided at 1% body weight (BW)/day. In the first experiment, a 196-day trial, supplemental protein sources and analyses of the concentrates compared were: (1) soybean meal (SBM; 15.4% crude protein, .70% lysine); (2) SBM + . 2% lysine (15.7% crude protein, .81% lysine), and (3) brewers dried grains + . 2% lysine (15.9% crude protein, .59% lysine). Concentrate intake averaged 1.67% BW/day, and hay intake averaged . 94% BW, for a total of 2.61% BW/day. Protein and lysine intakes (grams/day) for horses fed the three diets were, respectively: (1) 1,106, 48; (2) 1,091, 52 and (3) 1,077 and 40. Growth and efficiency responses for animals on treatments 1, 2 and 3 were, respectively: weight gain - 125, 123 and 114 kg; height gain - 9.5, 9.3 and 8.1 cm; girth gain - 21.6, 19.0 and 17.0 cm (P greater than .05); length gain - 14.5, 13.7 and 14.9 cm. and feed/gain - 15.3, 15.0 and 16.0. In the second experiment, a 140-day trial, SBM-based concentrates provided (1) 16.1% crude protein and . 67% lysine, (2) 13.6% crude protein and.51% lysine and (3) 14.2% crude protein and . 64% lysine. Concentrate averaged 1.99% BW and hay intake averaged . 92% BW, for a total of 2.91% BW/day. Protein and lysine intakes (grams/day) for horses fed the three diets were (1) 1,432, 59; (2) 1,195, 46; and (3) 1,182, 53. Growth and efficiency responses for animals given the three treatments were: weight gain - 101, 87 and 101 kg (P greater than .05); height gain - 5.7, 6.0 and 6.4 cm; girth gain - 14.8, 12.2 and 16.3 (P greater than .05); length gain - 10.9, 10.9 and 11.9 cm, and feed/gain - 16.5, 17.9 and 15.0 kg (P greater than .05). No significant sex effects were detected. Results suggest that at least 1.9 g lysine/Mcal digestible energy is required to support maximum growth of yearling horses.
Ruler and Realm: The Division of Airlangga's Kingdom in the Fourteenth Century

Few topics in Classical Indonesian studies have attracted as much attention as has the division of Airlangga's realm by mpu Bharlda into the kingdoms of Janggala and Paijalu. The borders have been seen to run North-South (Krom), or East-West (Berg, Teeuw and Uhlenbeck, Pigeaud, Buchari), or both (Kern, Bosch, Stutterheim). The division has been seen as historical (Bosch, Buchari), apocryphal (Teeuw and Uhlenbeck), legendary (Pigeaud), and mythic (Berg). It has been taken as evidence of the prominence of duality symbolism and of the existence of kinship moieties. Evidence has been discerned of Indian meditational systems, of Polynesian demigods, and of quasi-universal lunar deities. In one view this act really did take place, or was regarded as having taken place, on Java; another view has removed the scene of action to Bali. In short, confusion reigns.
Association of the Tau haplotype with Parkinson's disease in the Greek population

We compared the distribution of the Tau H1 haplotype and related subhaplotypes in a group of clinically diagnosed Parkinson's disease patients (n = 133) and in control individuals (n = 113) from northern Greece. We were able to detect a statistically significant overrepresentation of the H1H1 genotype in our patient group (OR for H1H1 vs. H1H2 and H2H2: 1.73; 95% CI: 1.03–2.90; P = 0.037). The H1 subhaplotype significantly associated with the disease in our population was different from the one previously reported for a Norwegian population, suggesting that the nature of the association of Tau with Parkinson's disease is influenced by ethnic variation. © 2006 Movement Disorder Society
Clinical evaluation of patients with benign prostatic hyperplasia, treated with the natural product Calprost®: a randomized, controlled study

Context: Benign Prostatic Hyperplasia (BPH) is a common disease that course with Lower Urinary Tract Symptoms (LUTS), mainly in over 50 years-old men. Commonly indicated drugs such as alpha adrenergic-blockers are life-treatment with some adverse reactions. Center for Drug Research and Development produce a microencapsulated lipophilic extract of pumpkin seed oil (Calprost®) with anti-androgenic, anti-inflammatory, antioxidant, antiproliferative and diuretic properties. Aims: To evaluate the effect and safety of Calprost® in patients with BPH and LUTS. Methods: A multicenter, randomized, controlled, open exploratory clinical trial was conducted. Two experimental groups, study group (Calprost®, 140 mg daily) (n=81), and control group (terazosin, 2 mg daily) (n=50) were conformed. All the patients were treated during three months. Efficacy was evaluated through International Prostate Symptoms Score (IPSS), residual bladder volume and prostate volume. Results: Most of the included patients (74.0%) were white skin color and their mean age was 66 yrs. Fifteen patients, nine of them from terazosin group, withdraw the trial voluntarily. A significant reduction in the overall IPSS scale was obtained for both groups. Nevertheless, some obstructive (intermittency, straining) and irritative (frequency, urgency) urinary symptoms decreased more markedly in the Calprost® group being milder. Median residual and prostatic volumes decreased significantly (p=0.048 and p=0.002, respectively) only into the Calprost® group. Most of the adverse events were recorded in the terazosin group (79.4%), where postural hypotension prevailed. Conclusions: The natural product Calprost® was probed as a successful treatment of patients with BPH/LUTS, being also well-tolerated.
Basic transcription factor 3 is involved in gastric cancer development and progression.

AIM To further analyse cancer involvement of basic transcription factor 3 (BTF3) after detection of its upregulation in gastric tumor samples. METHODS BTF3 transcription rates in human gastric tumor tissue samples (n = 20) and adjacent normal tissue (n = 18) specimens as well as in the gastric cancer cell lines AGS, SGC-7901, MKN-28, MKN-45 and MGC803 were analyzed via quantitative real-time polymerase chain reaction. The effect of stable BTF3 silencing via infection with a small interfering RNA (siRNA)-BTF3 expressing lentivirus on SGC-7901 cells was measured via Western blotting analysis, proliferation assays, cell cycle and apoptosis profiling by flow cytometry as well as colony forming assays with a Cellomic Assay System. RESULTS A significant higher expression of BTF3 mRNA was detected in tumors compared to normal gastric tissues (P < 0.01), especially in section tissues from female patients compared to male patients, and all tested gastric cancer cell lines expressed high levels of BTF3. From days 1 to 5, the relative proliferation rates of stable BTF3-siRNA transfected SGC7901 cells were 82%, 70%, 57%, 49% and 44% compared to the control, while the percentage of cells arrested in the G1 phase was significantly decreased (P = 0.000) and the percentages of cells in the S (P = 0.031) and G2/M (P = 0.027) phases were significantly increased. In addition, the colony forming tendency was significantly decreased (P = 0.014) and the apoptosis rate increased from 5.73% to 8.59% (P = 0.014) after BTF3 was silenced in SGC7901 cells. CONCLUSION BTF3 expression is associated with enhanced cell proliferation, reduced cell cycle regulation and apoptosis and its silencing decreased colony forming and proliferation of gastric cancer cells.
The good and bad effects of statins on insulin sensitivity and secretion

Abstract Aims: Statins are the main lipid-lowering treatment in both primary and secondary prevention populations. Whether statins deteriorates glycemic control, predisposing to the onset of diabetes mellitus has been a matter of recent concern. Statins may accelerate progression to diabetes via molecular mechanisms that impact insulin sensitivity and secretion. In this review, we debate the relative effect of statins in driving insulin resistance and the impairment of insulin secretion. Methods: Narrative overview of the literature synthesizing the findings of literature was retrieved from searches of computerized databases, hand searches, and authoritative texts employing the key words “Statins”, “Randomized Clinical Trial”, “Insulin sensitivity”, “Insulin resistance”, “Insulin Secretion”, “Diabetes Mellitus” alone and/or in combination. Results: The weight of clinical evidence suggests a worsening effect of statins on insulin resistance and secretion, anyway basic science studies did not find a clear molecular explanation, providing conflicting evidence regarding both the beneficial and the adverse effects of statin therapy on insulin sensitivity. Conclusions: Although most of the clinical studies suggest a worsening of insulin resistance and secretion, the cardiovascular benefits of statin therapy outweigh the risk of developing insulin resistance, thus the data suggest the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control.
Modulation of Mycobacterium lepraemurium growth in murine macrophages: beneficial effect of tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor

Mycobacterium lepraemurium grew progressively in monolayers of Proteose Peptone-elicited macrophages from C57BL/6 mice. Treatment of macrophage monolayers with gamma interferon led to an enhancement of growth of M. lepraemurium in macrophages. Treatment with tumor necrosis factor alpha or granulocyte-macrophage colony-stimulating factor led to restriction of mycobacterial growth in macrophages.
Identification of Novel Selective Lysine‐Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore‐Based Virtual Screening Combined with Docking

Lysine‐specific demethylase 1 (LSD1) plays an important role in regulating the lysine methylation at residues K4 and K9 on histone H3. High levels of LSD1 expression have been observed in several malignant tumors. In this study, we presented a pharmacophore‐based virtual screening of a moderate database of 171 143 small molecules. A pharmacophore of LSD1 inhibitors was constructed for the first time and then used to screen the compound library combined with validated molecular docking tools followed by biochemical assays, led to the identification of 9 novel LSD1 inhibitors, showing their IC50 values in a range of 2.41–101 μm. Furthermore, compound XZ09 exhibited less inhibition against the homologous monoamine oxidase A (MAO‐A) and B (MAO‐B) displaying its moderate selectivity. Our study provides an effective virtual screening method to identify new LSD1 inhibitors and XZ09 represents a potent and selective lead compound to deserve further optimization for the treatment of LSD1 overexpressing cancers.
ASSOCIATION BETWEEN ADVANCE DIRECTIVES AND QUALITY OF END‐OF‐LIFE CARE: A NATIONAL STUDY

To the Editor: I read with interest the study by Teno et al., ‘‘Association Between Advance Directives and Quality of End-of-Life Care: A National Study,’’ published in the Journal of the American Geriatrics Society. This study is the first to examine the association between written advance directives (ADs) and the quality of end-of-life care in nontraumatic deaths regardless of care setting. An unfortunate finding by the authors was that ADs do not seem to improve the quality of end-of-life care, especially with regard to pain control. One in four family members reported that their loved one did not receive any or enough help with pain. In these unfortunate situations, palliative sedation (PS) can be initiated. PS is the administration of sedative drugs (typically benzodiazepines or barbiturates) to induce a continuous state of sleep. PS involves the decision to render the patient unconscious, but many physicians are not familiar with this medication regime and are not comfortable initiating it. According to a 2001 study, ‘‘The Effects of High Dose Opioids and Sedatives on Survival of Terminally Ill Cancer Patients,’’ physicians seem to exercise an atypical measure of caution with regard to pain when death is near, even though there is no empirically applied connection between analgesia and time of death. Palliative care experts indicate that physician training regarding end-of-life care is limited. End-of-life care should be presented to medical students in terms of what care options are available and not merely what treatment measures can be withheld. These experts believe that additional palliative care training in medical schools and clinics may improve the quality of end-of-life care. Healthcare professionals have an ethical obligation to address the question of pain control in end-of-life care. One in four patients with ADs should not be dying in pain. One of the reasons people complete ADs is to assure a peaceful death. By further educating care providers, medical students, and physicians about end-of-life care and palliative sedation, improvement can be made in this area.
Mitochondrial DNA phylogeography of lake cisco (Coregonus artedi): evidence supporting extensive secondary contacts between two glacial races

The comparative molecular phylogeography of regional fish fauna has revealed the wide distribution of young clades in freshwater fishes of formerly glaciated areas as well as interspecific incongruences in their refugial origins and recolonization routes. In this study, we employed single‐strand conformation polymorphism (SSCP) and sequence analyses to describe mitochondrial DNA (mtDNA) polymorphism among 27 populations of the lake cisco (Coregonus artedi) from its entire range of distribution in order to evaluate the hypothesis of dual glacial refuges proposed by Bernatchez & Dodson against the traditional view that this species is solely of Mississippian origin. Results indicate that this taxon is composed of two closely related groups that are widely distributed and intermixed over most of the sampled range. The estimated level of divergence (0.48%), the contrast in the geographical distribution of each group, as well as the general distribution of C. artedi in North America together support the hypothesis that one group dispersed from a Mississippian refuge via the proglacial lakes, while the other is of Atlantic origin and also took advantages of earlier dispersal routes towards eastern Hudson Bay drainages. However, the signal of past range fragmentation revealed by a nested clade analysis was weak, and did not allow to formally exclude the hypothesis of a single Mississippian origin for both lineages. Comparisons with the phylogeographic patterns of other Nearctic freshwater fishes suggest that the salinity tolerance and thermal sensitivity of lake cisco may have been determinant for its extensive postglacial dispersal. The presence or co‐occurrence of sympatric or allopatric eco/morphotypes were not found to be necessarily associated with the presence of both haplotype groups.