Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of FDA‐approved Drugs that Computationally Bind to MDM2

The integrity of the p53 tumor suppressor pathway is compromised in the majority of cancers. In 7% of cancers p53 is inactivated by abnormally high levels of MDM2 – an E3 ubiquitin ligase that polyubiquitinates p53, marking it for degradation. MDM2 engages p53 through its hydrophobic cleft, and blockage of that cleft by small molecules can re‐establish p53 activity. Small molecule MDM2 inhibitors have been developed, but there is likely to be a high cost and long time period before effective drugs reach the market. An alternative is to repurpose FDA‐approved drugs. This report describes a new approach, called Computational Conformer Selection, to screen for compounds that potentially inhibit MDM2. This screen was used to computationally generate up to 600 conformers of 3244 FDA‐approved drugs. Drug conformer similarities to 41 computationally‐generated conformers of MDM2 inhibitor nutlin 3a were ranked by shape and charge distribution. Quantification of similarities by Tanimoto combo scoring resulted in scores that ranged from 0.142 to 0.802. In silico docking of drugs to MDM2 was used to calculate binding energies and to visualize contacts between the top‐ranking drugs and the MDM2 hydrophobic cleft. We present 15 FDA‐approved drugs predicted to inhibit p53/MDM2 interaction.
An Updated Systematic Review with Meta-Analysis for the Clinical Evidence of Silymarin

Background: The potential benefit of silymarin (special extract from the fruits of Silybum marianum) in the treatment of liver diseases remains a controversial issue. Methods: For this systematic review electronic databases identified 65 papers for the search terms silymarin, silibinin, silicristin or milk thistle and clinical trial. Only 19 complied with the criteria ‘double-’ or ‘single-blind’. These publications were analysed from a clinical point of view and meta-analytic calculations were performed. Results: The clinical evidence of a therapeutic effect of silymarin in toxic liver diseases is scarce. There is no evidence of a favourable influence on the evolution of viral hepatitis, particularly hepatitis C. In alcoholic liver disease, comparing with placebo, aspartate aminotransferase was reduced in the silymarin-treated groups (p = 0.01) while alkaline phosphatase was not. In liver cirrhosis, mostly alcoholic, total mortality was 16.1% with silymarin vs. 20.5% with placebo (n.s.); liver-related mortality was 10.0% with silymarin vs. 17.3% with placebo (p = 0.01). Conclusions: Based on the available clinical evidence it can be concluded - concerning possible risks / probable benefits - that it is reasonable to employ silymarin as a supportive element in the therapy of Amanita phalloides poisoning but also (alcoholic and grade Child ‘A’) liver cirrhosis. A consistent research programme, consolidating existing evidence and exploring new potential uses, would be very welcome.
Metastasis Tumor Antigen 2 (MTA2) Is Involved in Proper Imprinted Expression of H19 and Peg3 During Mouse Preimplantation Development1

The epigenetic mechanisms involved in establishing and maintaining genomic imprinting are steadily being unmasked. The nucleosome remodeling and histone deacetylation (NuRD) complex is implicated in regulating DNA methylation and expression of the maternally expressed H19 gene in preimplantation mouse embryos. To dissect further the function of the NuRD complex in genomic imprinting, we employed an RNA interference (RNAi) strategy to deplete the NuRD complex component Metastasis Tumor Antigen 2 (MTA2). We found that Mta2 is the only zygotically expressed Mta gene prior to the blastocyst stage, and that RNAi-mediated knockdown of Mta2 transcript leads to biallelic H19 expression and loss of DNA methylation in the differentially methylated region in blastocysts. In addition, biallelic expression of the paternally expressed Peg3 gene, but not Snrpn, is also observed in blastocysts following Mta2 knockdown. Loss of MTA2 protein does not result in a decrease in abundance of other NuRD components, including methyl-binding-CpG-binding domain protein 3 (MBD3), histone deacetylases 1 and 2 (HDACs 1 and 2), and chromodomain helicase DNA-binding protein 4 (CHD4). Taken together, our results support a role for MTA2 within the NuRD complex in genomic imprinting.
Nonmosaic balanced homologous translocations of major clinical significance: Some may be mosaic

The main mechanism proposed for formation of homologous translocations/isochromosomes is mitotic and if this occurs in a chromosomally normal conceptus, mosaicism would be expected to be seen. The lack of mosaicism in published cases of rearrangement (REA) of mitotic origin might be explained by under‐detection due to the low level mosaicism for a normal line. Recently it was reported that sex‐specific centromere instability in early embryogenesis leads to a female prevalence among individuals with mosaicism for pericentromeric rearrangements. To determine whether carriers of apparent non‐mosaic homologous REA could be mosaics for a normal cell line, the sex ratio (male to female ratio) among carriers of balanced and unbalanced homologous translocations/isochromosomes was studied. This ratio was determined to establish if there is a female predominance similar to that seen in carriers of REA with mosaicism. In reviewing the literature, a female prevalence among fetuses with balanced homologous REA and among carriers of unbalanced homologous REA detected prenatally, postnatally and in miscarriages was found. Overall, there were 48 males and 72 females in the collected sample, and this ratio differed significantly from the expected sex ratio of 1.06 (P = 0.0075). There is not a male prevalence among miscarried fetuses, there is no evidence of selection against males in the collected material of this study. The analysis of sex ratios in different variants of trisomy 13 with respect to ascertainment (prenatal diagnosis, miscarriages, liveborn) also does not support an intrauterine selection against males as a cause of a female prevalence among carriers of homologous REA. Thus the data presented in this paper suggests that a proportion of the carriers of balanced homologous REA may have mosaicism for a normal line. Since low level mosaicism for a normal line in a translocation carrier would alter his/her reproductive options, it can be recommended that molecular polymorphic analysis be applied to these cases. This would allow those resulting from meiotic formation to be distinguished from those resulting from postzygotic formation. This latter mechanism may indicate the presence of a mosaicism for a normal line, making further intensive karyotypic analysis advisable. However, additional studies of healthy carriers of homologous REA of chromosome 14 or 15 should not be done. © 2007 Wiley‐Liss, Inc.
ISOLATION OF THE BRAIN‐RELATED FACTOR OF THE ERROR BETWEEN INTENDED AND ACHIEVED POSITION OF DEEP BRAIN STIMULATION ELECTRODES IMPLANTED INTO THE SUBTHALAMIC NUCLEUS FOR THE TREATMENT OF PARKINSON'S DISEASE

OBJECTIVE Although a few studies have quantified errors in the implantation of deep brain stimulation electrodes into the subthalamic nucleus (STN), a significant trend in error direction has not been reported. We have previously found that an error in axial plane, which is of most concern because it cannot be compensated for during deep brain stimulation programming, had a posteromedial trend. We hypothesized that this trend results from a predominance of a directionally oriented error factor of brain origin. Accordingly, elimination of nonbrain (technical) error factors could augment this trend. Thus, implantation accuracy could be improved by anterolateral compensation during target planning. METHODS Surgical technique was revised to minimize technical error factors. During 22 implantations, targets were selected on axial magnetic resonance imaging scans up to 1.5 mm anterolateral from the STN center. Using fusion of postoperative computed tomographic and preoperative magnetic resonance imaging scans, implantation errors in the axial plane were obtained and compared with distances from the lead to the STN to evaluate the benefit of anterolateral compensation. RESULTS Twenty errors and the mean error had a posteromedial direction. The average distances from the lead to the target and to the STN were 1.7 mm (range, 0.8–3.1 mm) and 1.1 mm (range, 0.1–1.9 mm), respectively. The difference between the 2 distances was significant (paired t test, P < 0.0001). The lower parts of the lead were consistently bent in the posteromedial direction on postoperative scout computed tomographic scans, suggesting that a brain-related factor is responsible for the reported error. CONCLUSION Elimination of the technical factors of error during STN deep brain stimulation implantation can result in a consistent posteromedial error. Implantation accuracy may be improved by compensation for this error in advance.
Assessment of Progesterone Receptors in Breast Carcinoma by PET with 21-18F-Fluoro-16α,17α-[(R)-(1′-α-furylmethylidene)Dioxy]-19-Norpregn-4-Ene-3,20-Dione

This first-in-human study was designed to evaluate the safety and dosimetry of the progesterone analog 21-18F-fluoro-16α,17α-[(R)-(1′-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione (18F-FFNP), as well the feasibility of imaging tumor progesterone receptors (PRs) by PET in breast cancer. Methods: Women with breast cancer underwent PET with 18F-FFNP. Tumor 18F-FFNP uptake was assessed semiquantitatively by determining maximum standardized uptake value and tumor-to-normal breast (T/N) activity ratio and by Logan graphical analysis. The PET results were correlated with estrogen receptor (ER) and PR status, assessed by in vitro assays of the tumor tissue. The biodistribution of 18F-FFNP was measured in patients by whole-body PET, and human dosimetry was estimated. Results: Twenty patients with 22 primary breast cancers (16 PR-positive [PR+] and 6 PR-negative [PR–]) were evaluated. Tumor maximum standardized uptake value was not significantly different in PR+ and PR− cancers (mean ± SD, 2.5 ± 0.9 vs. 2.0 ± 1.3, P = 0.386), but the T/N ratio was significantly greater in the PR+ cancers (2.6 ± 0.9 vs. 1.5 ± 0.3, P = 0.001). In addition, there was a significant correlation between distribution volume ratio and T/N ratio (r = 0.89; P = 0.001) but not between distribution volume ratio and either PR status or standardized uptake value, likely because of small sample size. On the basis of whole-body PET data in 12 patients, the gallbladder appeared to be the dose-limiting organ, with an average radiation dose of 0.113 mGy/MBq. The whole-body dose was 0.015 mGy/MBq, and the effective dose was 0.020 mSv/MBq. No adverse effects of 18F-FFNP were encountered. Conclusion: 18F-FFNP PET is a safe, noninvasive means for evaluating tumor PRs in vivo in patients with breast cancer. The relatively small absorbed doses to normal organs allow for the safe injection of up to 440 MBq of 18F-FFNP.
Diarrheal disease caused by enterotoxigenic Bacteroides fragilis in infant rabbits

Enterotoxigenic Bacteroides fragilis caused severe, nonhemorrhagic, watery diarrhea when 10(9) CFU of a porcine or human isolate was administered orogastrically to 3-day-old rabbits. The bacterium colonized the intestinal tract with a predilection for the large intestine (10(9) CFU/g of cecal contents). Diarrhea occurred at an average of 4.6 days postinoculation, and 84% of rabbits were dead or moribund at an average of 8.8 days postinoculation. The disease was characterized by watery diarrhea and dehydration. Severe histologic lesions including inflammation, exfoliation of epithelial cells, and crypt hyperplasia were observed throughout the colon. There was no indication of bacteremia or of bacterial adherence to or invasion of intestinal epithelial cells. Rabbits inoculated with nonenterotoxigenic B. fragilis were colonized with B. fragilis but did not develop clinical disease or intestinal lesions. While the pathogenesis of this disease is undefined, clinical signs of disease and histologic changes were consistent with a mechanism of net secretion of fluid into the small intestine and decreased absorption of fluid from the large intestine. Enteric disease caused by enterotoxigenic B. fragilis in infant rabbits was similar to naturally occurring enteric disease associated with the bacterium in humans and livestock. This study established that enterotoxigenic B. fragilis is enteropathogenic in intact infant rabbits.
Vibrotactile grasping force and hand aperture feedback for myoelectric forearm prosthesis users

Background: User feedback about grasping force and hand aperture is very important in object handling with myoelectric forearm prostheses but is lacking in current prostheses. Vibrotactile feedback increases the performance of healthy subjects in virtual grasping tasks, but no extensive validation on potential users has been performed. Objectives: Investigate the performance of upper-limb loss subjects in grasping tasks with vibrotactile stimulation, providing hand aperture, and grasping force feedback. Study design: Cross-over trial. Methods: A total of 10 subjects with upper-limb loss performed virtual grasping tasks while perceiving vibrotactile feedback. Hand aperture feedback was provided through an array of coin motors and grasping force feedback through a single miniature stimulator or an array of coin motors. Objects with varying sizes and weights had to be grasped by a virtual hand. Results: Percentages correctly applied hand apertures and correct grasping force levels were all higher for the vibrotactile feedback condition compared to the no-feedback condition. With visual feedback, the results were always better compared to the vibrotactile feedback condition. Task durations were comparable for all feedback conditions. Conclusion: Vibrotactile grasping force and hand aperture feedback improves grasping performance of subjects with upper-limb loss. However, it should be investigated whether this is of additional value in daily-life tasks. Clinical relevance This study is a first step toward the implementation of sensory vibrotactile feedback for users of myoelectric forearm prostheses. Grasping force feedback is crucial for optimal object handling, and hand aperture feedback is essential for reduction of required visual attention. Grasping performance with feedback is evaluated for the potential users.
Chronobiology by moonlight

Most studies in chronobiology focus on solar cycles (daily and annual). Moonlight and the lunar cycle received considerably less attention by chronobiologists. An exception are rhythms in intertidal species. Terrestrial ecologists long ago acknowledged the effects of moonlight on predation success, and consequently on predation risk, foraging behaviour and habitat use, while marine biologists have focused more on the behaviour and mainly on reproduction synchronization with relation to the Moon phase. Lately, several studies in different animal taxa addressed the role of moonlight in determining activity and studied the underlying mechanisms. In this paper, we review the ecological and behavioural evidence showing the effect of moonlight on activity, discuss the adaptive value of these changes, and describe possible mechanisms underlying this effect. We will also refer to other sources of night-time light (‘light pollution’) and highlight open questions that demand further studies.
Formation of male pronuclei in partitioned human oocytes.

Ninety-five metaphase II human oocytes, aged in vitro for either one day or for two days, and five fresh immature oocytes with no visible germinal vesicle nucleus were partitioned into small cytoplasts after removal of the zona pellucida and exposure to cytochalasin B. Seventy-one metaphase II and four immature oocytes were used as intact zona-free controls. The cytoplasts derived from each partitioned oocyte and all the zona-free whole oocytes were exposed to normal or subfertile donor sperm and later assessed for signs of male pronucleus development. A total of 711 fragments (an average of 8 fragments per partitioned egg) with a mean diameter of about 50 microns were produced from the 100 partitioned oocytes. When exposed to normal sperm, 76% of the 1-day-old metaphase II fragments, 67% of the 2-day-old metaphase II fragments, and 83% of the immature oocyte fragments were fertilized. The mean number of decondensing nuclei per partitioned oocyte was 11.9 for the 1-day-old metaphase II oocytes, 6.4 for the 2-day-old metaphase II oocytes, and 13 for the immature oocytes. The mean number of decondensing nuclei per a whole zona-free oocyte was 5.6 for the 1-day-old metaphase II oocytes (p < 0.05), 6.7 for the 2-day-old metaphase II oocytes (NS), and 13 for the immature oocytes. When exposed to subfertile sperm, 54% of the 1-day-old metaphase II fragments and 28% of the 2-day-old metaphase II fragments were fertilized. (ABSTRACT TRUNCATED AT 250 WORDS)
Data-Dependent Operation Speed-Up Through Automatically Inserted Signal Transition Detectors for Ultralow Voltage Logic Circuits

With the advent of mobile electronics requiring ever more computing power from a limited energy supply, there is a need for efficient systems capable of maximizing this ratio. Architectural enhancements must therefore be designed to enable high performance, all the while maintaining the power advantage. The technique proposed in this paper allows the acceleration of combinatorial circuits beyond the performance generally achievable by conventional synthesis and timing closure, by exploiting the data-dependent delay variations inherent in such circuits. Through the automatic insertion of transition detectors within the target circuit, the progress of operations underway can be monitored and prematurely completed, thereby increasing the operation speed from the worst toward the average case. In addition, a synthesis flow is proposed to increase the proportion of fast paths, thereby increasing the technique's impact. The proposed technique was applied automatically to a series of benchmark circuits, and the synthesis results show it to achieve good performance, with an average increase of 29% over conventional synthesis, for an average energy increase of ${<;}{21\%}$ overall.
Actin Disruption by Latrunculin B Causes Turgor-Related Changes in Tip Growth of Saprolegnia ferax Hyphae

Hyphae of Saprolegnia ferax growing under normal or low-turgor conditions were exposed to 0.1-10 &mgr;g/ml latrunculin B, an actin inhibitor. In the first 10 s of addition, hyphae with normal turgor levels accelerated while those with low turgor decelerated, consistent with the suggestion that actin restrains or protrudes tips under these respective turgor conditions. Both sets of hyphae then decelerated and eventually ceased extension within 60 s. These changes were reflected in rhodamine-phalloidin staining patterns, which showed that actin caps were disrupted progressively under both conditions in a time-dependent manner. After 60 s, normal-turgored hyphae started to swell rapidly while low-turgored hyphae showed little or no swelling. Swelling was characteristically subapical, which is best explained by tip growth models which incorporate actin-mediated exocytosis.
Untreated Head and Neck Surgical Disease in Sierra Leone

Objectives Demonstrate how the Surgeons OverSeas Assessment of Surgical Need (SOSAS) can be used to determine the burden of head and neck (H&N) surgical disease in developing countries and identify reasons for untreated disease. Study Design Cluster randomized, cross-sectional, countrywide survey. Setting Sierra Leone. Subjects and Methods The survey was administered to 75 of 9671 enumeration areas in Sierra Leone between January 9 and February 3, 2012, with 25 households in each cluster randomly selected for the survey. A household representative and 2 randomly selected household members were interviewed. Need for surgical care was based on participants’ responses to whether they had an H&N condition that they believed needed surgical care. Results Of 1875 households, data were analyzed for 1843 (98%), with 3645 total respondents. Seven hundred and one H&N surgical conditions were reported as occurring during the lifetime of the 3645 respondents (19.2%). The current prevalence of H&N conditions in need of a surgical consultation was 11.8%. No money (60.1%) was the most common reason respondents reported for not receiving medical care. A bivariate analysis demonstrated that age, village type, education, and type of condition may be predictors for seeking health care and/or receiving surgical care. Conclusions These results show limited access for patients to be evaluated for a potential H&N surgical condition in Sierra Leone. The true incidence of untreated surgical disease is unknown as most respondents were not evaluated by a surgeon. This survey could be used in other countries as health care professionals assess surgical needs throughout the world.
Global Economic History: a Personal View on the Agenda for future Research

This essay is an attempt to do different things at the same time – therefore it is almost as chaotic as life itself. One of the most important reasons for writing it was to bring some order into the research I am doing – it is an attempt to convince myself that behind the apparent chaos of projects and papers there is structure and meaning. It also an attempt to start thinking about ‘global economic history’ as the conceptual framework for the research I am doing (I could not find anything bigger). This (perhaps unhappy) combination is clear from its structure: it starts as a ‘real’ academic essay, and later on becomes more ‘personal’, outlining my personal research programme, and concluding with some personal hobbies.
Impact of Plug-in Hybrid Electric Vehicles in the Portuguese electric utility system

This research paper analyzes the potential impacts of the Plug-in Hybrid Electric Vehicles (PHEV) on the Portuguese electric consumption profile. The plug-in vehicles will affect utility operations by adding additional electricity demand. There has generally been the expectation that the grid will not be greatly affected by the use of these vehicles, because the recharging would only occur during off-peak hours. Several scenarios of PHEVs' penetration are studied considering the grid-for-vehicle (G4V) energy transferring as a primary approach. Depending on the power level, timing, and duration of the PHEV connection to the grid, there could be a wide variety of impacts on grid constraints, capacity needs and emissions generated. In a strong penetration scenario, if many households charge their PHEVs over the same time period, especially if it is when the owners first return home and the domestic consumption is increased, then the peak may be higher than the utility expects. Evaluating the potential impacts that different charging scenarios can have in the demand profile is important so that the distribution utility and regulator understand the problems involved and anticipate ideas that will better optimize the whole system in the future.
Stepped care in psychological therapies: access, effectiveness and efficiency

Background There is a significant gap between the demand for psychological therapy services and the available supply. One proposal to overcome this problem is to increase efficiency of provision through the adoption of briefer ‘minimal interventions' within stepped care models. Aims To examine the theoretical underpinnings of stepped care, together with the practicalities of the adoption of this system of care. Method Narrative literature review. Results The potential clinical and economic benefits of stepped care are dependent upon underlying assumptions of equivalence in terms of clinical outcomes, efficiency in terms of resource use and costs, and acceptability of ‘minimal interventions' to patients and therapists. Illustrative studies of these issues are considered. Conclusions Although psychological services might benefit from the adoption of the stepped care model, a substantial research agenda needs to be fulfilled before a judgement can be made as to whether stepped care might be an efficient method of delivering psychological services.