Miracle-dz/UniFAR-FTUs huggingface dataset:
Thalidomide-derived immunomodulatory drugs as therapeutic agents

Thalidomide, a drug originally used to treat morning sickness, was removed from the market place in the early 1960s after it was found to cause serious congenital birth defects. However, thalidomide has recently been investigated in a new light following its activity in a number of chronic diseases. Moreover, like thalidomide itself, its second-generation immunomodulatory drug (IMiD®) analogues have been shown to act as powerful anticancer agents and are clearly active in the treatment of patients with relapsed multiple myeloma. These new drugs, in particular the second-generation IMiDs, lenalidomide (CC-5013, REVLIMID™; Celgene Corp., NJ, USA) and CC-4047 (ACTIMID™; Celgene Corp.), offer improvements over thalidomide (a first-generation IMiD) in terms of efficacy and safety in human studies. The key to the therapeutic potential of IMiDs lies in the fact that the drugs have multiple mechanisms of action, which may produce both anti-inflammatory and antitumour effects. These effects are probably contextual, depending both on the cell type and the stimulus involved. Mechanisms associated with IMiD activity include TNF-α-inhibitory, T cell costimulatory and antiangiogenic activities. Studies of the mechanisms of action of these drugs are ongoing and will facilitate the continued development of this class of compound in a number of diseases.
Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.

OBJECTIVE Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants. METHOD The 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years. RESULTS Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills. CONCLUSIONS To the authors’ knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.
Sites of disruption within E1 and E2 genes of HPV16 and association with cervical dysplasia

Integration of HPV16 DNA into the host chromosome usually disrupts the E1 and/or E2 genes. The present study investigated the disruption of E1, E2 genes in a total of eighty four HPV16‐positive precancerous and cervical cancer specimens derived from Greek women (seventeen paraffin‐embedded cervical biopsies and sixty seven Thin Prep samples). Complete E2 and E1 genes were amplified using three and nine overlapping primer sets respectively, in order to define the sites of disruption. Extensive mapping analysis revealed that disruption/deletion events within E2 gene occurred in high grade and cervical cancer samples (x2 test, P < 0.01), while no evidence of E2 gene disruption was documented among low grade cervical intraepithelial neoplasias. In addition, disruptions within the E1 gene occur both in high and low grade cervical intraepithelial neoplasia. This leads to the assumption that in low grade cervical intraepithelial neoplasias only E1 gene disruption was involved (Fisher's exact test, P < 0.05), while in high grade malignancies and cervical cancer cases deletions in both E1 and E2 genes occurred. Furthermore, the most prevalent site of disruption of E1 gene was located between nucleotides 1059 and 1323, while the most prevalent deleted region of the E2 gene was located between nucleotides 3172 and 3649 (E2 hinge region). Therefore, it is proposed that each population has its own profile of frequencies and sites of disruptions and extensive mapping analysis of E1 and E2 genes is mandatory in order to determine suitable markers for HPV16 DNA integration analysis in distinct populations. J. Med. Virol. 87:1973–1980, 2015. © 2015 Wiley Periodicals, Inc.
Unravelling spatiotemporal tree-ring signals in Mediterranean oaks: a variance-covariance modelling approach of carbon and oxygen isotope ratios.

Identifying how physiological responses are structured across environmental gradients is critical to understanding in what manner ecological factors determine tree performance. Here, we investigated the spatiotemporal patterns of signal strength of carbon isotope discrimination (Δ(13)C) and oxygen isotope composition (δ(18)O) for three deciduous oaks (Quercus faginea (Lam.), Q. humilis Mill. and Q. petraea (Matt.) Liebl. ) and one evergreen oak (Q. ilex L.) co-occurring in Mediterranean forests along an aridity gradient. We hypothesized that contrasting strategies in response to drought would lead to differential climate sensitivities between functional groups. Such differential sensitivities could result in a contrasting imprint on stable isotopes, depending on whether the spatial or temporal organization of tree-ring signals was analysed. To test these hypotheses, we proposed a mixed modelling framework to group isotopic records into potentially homogeneous subsets according to taxonomic or geographical criteria. To this end, carbon and oxygen isotopes were modelled through different variance-covariance structures for the variability among years (at the temporal level) or sites (at the spatial level). Signal-strength parameters were estimated from the outcome of selected models. We found striking differences between deciduous and evergreen oaks in the organization of their temporal and spatial signals. Therefore, the relationships with climate were examined independently for each functional group. While Q. ilex exhibited a large spatial dependence of isotopic signals on the temperature regime, deciduous oaks showed a greater dependence on precipitation, confirming their higher susceptibility to drought. Such contrasting responses to drought among oak types were also observed at the temporal level (interannual variability), with stronger associations with growing-season water availability in deciduous oaks. Thus, our results indicate that Mediterranean deciduous and evergreen oaks constitute two clearly differentiated functional groups in terms of their carbon and water economies, despite co-existing in a wide range of environments. In contrast, deciduous oaks form a rather homogeneous group in terms of climate sensitivity.
Working memory training for children with cochlear implants: a pilot study.

PURPOSE This study investigated the feasibility and efficacy of a working memory training program for improving memory and language skills in a sample of 9 children who are deaf (age 7-15 years) with cochlear implants (CIs). METHOD All children completed the Cogmed Working Memory Training program on a home computer over a 5-week period. Feasibility and acceptability of the program were evaluated using parent report and measures of children's performance on the training exercises. Efficacy measures of working memory and sentence repetition were obtained prior to training, immediately after training, and 1 month and 6 months after training. RESULTS Children's performance improved on most training exercises, and parents reported no problems with children's hearing or understanding of the exercises. After completion of working memory training, children demonstrated significant improvement on measures of verbal and nonverbal working memory, parent-reported working memory behavior, and sentence-repetition skills. The magnitude of improvement in working memory decreased slightly at the 1-month follow-up and more substantially at 6-month follow-up. However, sentence repetition continued to show marked improvement at 6-month follow-up. CONCLUSIONS Working memory training may produce benefit for some memory and language skills for children with CIs, supporting the importance of conducting a large-scale, randomized clinical trial with this population.
Radioiodide Uptake in Brain, CSF, Thyroid, and Salivary Glands of Audiogenic Seizure Mice

Summary: DBA/2J (DBA) mice are susceptible to audiogenic seizures (ASs) in an age‐dependent manner. Anion transport as measured by radioiodide uptake was determined in thyroid gland, salivary gland, skeletal muscle, cerebral cortex, cerebellum, brainstem, and CSF from these mice at various ages. Anion transport was also determined in C57BL/6J(C57) mice, an AS‐resistant strain. In thyroid, DBA mice had an enhanced ability to concentrate iodide at 21 days of age when they have maximal AS susceptibility, as compared with the same‐aged C57 mice. This difference in thyroid function was less marked at 40 days of age, when DBA mice are less AS susceptible, and was absent at 110 days of age, when DBA mice are AS resistant. In brain, differences in iodide uptake were also noted between these two strains of mice at 21 days of age. DBA mice had an increased concentration of iodide in CSF, an indication that they have a defect in the transport of iodide out of the CSF across the choroid plexus. In addition, DBA mice had a lower ratio of cerebral cortex to CSF iodide, which suggests that DBA mice have a defect in the transport of this anion into cerebral cortical cells from brain interstitial fluid. These differences in iodide transport in brain decreased with age as the AS susceptibility of DBA mice decreased. These results suggest a relation between anion transport in thyroid gland, cerebral cortex, and choroid plexus and AS susceptibility in DBA mice at 21 days of age.
Throughput Analysis of Diversity and Multiplexing Schemes for MIMO-SIC OFDM systems

In wireless communications, different schemes for multiple antennas may be applied in order to achieve high data rates through spatial multiplexing (SM) or reliability through spatial diversity. In this paper, we analyze the throughput achieved by SM and quasi-orthogonal space-time block codes (QSTBC) using a successive interference cancellation (SIC) detector at the receiver. The structure of the feedback filter matrix R is analyzed and closed form expressions for the error probability for zero-forcing SIC detection are derived. We verify the theoretical results by numerical simulations. Furthermore, we show that SM provide a better balance between spectral efficiency and spatial diversity than QSTBC.
Multifunctional bioscaffolds for 3D culture of melanoma cells reveal increased MMP activity and migration with BRAF kinase inhibition

Significance Matrix metalloproteinases (MMPs) are a family of enzymes that enable cell-mediated remodeling of the local environment. Because of their ability to degrade the extracellular matrix, MMPs are an important component of the metastatic cascade. However, the effect of cancer drug treatment on MMP activity is not well-established. This study reveals that treatment with a clinically relevant BRAF protein kinase inhibitor (PLX4032) correlates with increases in melanoma MMP activity in 3D culture, which consequently leads to increased cell migration. Although PLX4032 initially causes significant tumor shrinkage, patients typically relapse due to metastatic lesions. This work may contribute to our understanding of how initially promising therapeutics ultimately lead to poor patient outcome through drug-induced effects on MMP activity and cell motility. Matrix metalloproteinases (MMPs) are important for many different types of cancer-related processes, including metastasis. Understanding the functional impact of changes in MMP activity during cancer treatment is an important facet not typically evaluated as part of preclinical research. With MMP activity being a critical component of the metastatic cascade, we designed a 3D hydrogel system to probe whether pharmacological inhibition affected human melanoma cell proteolytic activity; metastatic melanoma is a highly aggressive and drug-resistant form of skin cancer. The relationship between MMP activity and drug treatment is unknown, and therefore we used an in situ fluorogenic MMP sensor peptide to determine how drug treatment affects melanoma cell MMP activity in three dimensions. We encapsulated melanoma cells from varying stages of progression within PEG-based hydrogels to examine the relationship between drug treatment and MMP activity. From these results, a metastatic melanoma cell line (A375) and two inhibitors that inhibit RAF (PLX4032 and sorafenib) were studied further to determine whether changes in MMP activity led to a functional change in cell behavior. A375 cells exhibited increased MMP activity despite an overall decrease in metabolic activity with PLX4032 treatment. The changes in proteolytic activity correlated with increased cell elongation and increased single-cell migration. In contrast, sorafenib did not alter MMP activity or cell motility, showing that the changes induced by PLX4032 were not a universal response to small-molecule inhibition. Therefore, we argue the importance of studying MMP activity with drug treatment and its possible implications for unwanted side effects.
A Survey of Pharmacy Students' Experiences With Gambling

Objectives. To assess gambling among pharmacy students using the South Oaks Gambling Screen (SOGS). Methods. Six hundred fifty-eight pharmacy students enrolled at Creighton University were surveyed to determine the extent and characteristics of their gambling. Results. Four hundred eighty-eight students (74.2%) participated (mean age was 26.6 years and 63.4% were female). Almost two-thirds (63.1%) gambled at least once during the past 12 months. Slightly more than 16% (80) of students were identified as “at-risk” (SOGS scores of 1 to 2). Another 5% (24) were likely to be problem gamblers (SOGS scores of 3 to 4), while 1% of students were identified as probable pathological gamblers (SOGS scores ≥ 5). Students who gambled were significantly more likely than non-gamblers to be single males. Gamblers with a score ≥ 1were significantly more likely to report gambling had affected their relationships with others, compared to casual gamblers. Conclusions. Gambling is a common activity among pharmacy students. While the incidence of problem gambling is relatively small, the percentage of our students who may be at-risk for gambling-related problems is noteworthy.
Diffuse scattering prediction for 26GHz band in indoor office environments

This paper presents the accuracy of a diffuse scattering prediction method with an effective roughness model by using detailed structural data in the form of a point cloud for high frequency band in indoor office environments. It also presents the effect of diffuse scattering on propagation characteristics. We compared measurement and prediction results in the 26 GHz band. In so doing we clarified that almost the same accuracy prediction results were obtained as those for measured delay spread with the RMSE value 0.4 ns. We also confirmed that multiple bounce specular reflection waves obtained on the basis of rough surface are dominant because their total received power is larger by about 10 dB than those of diffuse scattering waves in the 26 GHz band in indoor office environments.
Evolutionary surface reconstruction

We propose a novel technique for surface reconstruction from a point cloud in 3D. The aim is to combine evolutionary algorithms with a recursive subdivision scheme. The algorithm starts from a base population where each individual represents an n-level surface approximation of an input object. Next, the population is evaluated and the offspring generation is created with a denser subdivision of a surface. In the process, the algorithm creates S different naturally-looking meshes approximating an input object. Additionally, we introduce the surface metrics to answer questions about the quality of output objects. The method is illustrated by a set of examples.
DNA polymerases from Chlamydomonas reinhardii. Purification and properties.

Three DNA polymerase activities, A, B and C, were identified in extracts of exponentially growing synchronous cultures of Chlamydomonas reinhardii, and DNA polymerases A and B were characterized in detail. Both enzymes have the same binding affinity for DEAE-cellulose at pH 7.8, but can be distinguished from each other by their behaviour on phosphocellulose and DNA-agarose. 'Activated' calf thymus DNA was used as template, and the pH, K+ and bivalent-cation optima were measured. DNA polymerase A sediments at 5.3 S in glycerol gradients, with an apparent mol.wt. of 90000-100000. Polymerase B sediments between 8S and 10S in 100mM-KCl, the predominant species having an apparent mol.wt. of 200000. In 200mM-KCl, polymerase B dissociates to a single species, which sediments at 5.8S. A 3S species was found in aged preparations of both enzymes. The activity of polymerase B from cells harvested during nuclear DNA synthesis is twice that found in Chlamydomonas at other times during the cell cycle.
Long-term responders without eradication of hepatitis C virus after interferon therapy: characterization of clinical profiles and incidence of hepatocellular carcinoma.

AIMS/BACKGROUND The aim of this study was to determine the characteristics of patients with chronic hepatitis C showing long-term normalization of alanine aminotransferase (ALT) without eradication of HCV RNA, as well as to investigate the incidence of hepatocellular carcinoma (HCC) in such patients. METHODS Four hundred and nineteen patients with histologically-proven chronic hepatitis C who had received interferon (IFN) therapy were studied. Complete response (CR) was defined as persistent normalization of ALT levels with eradication of serum HCV RNA (n= 126). Long-term biochemical response with positive HCV RNA (HCV-positive BR) was defined as a normal ALT level at 6 months after IFN therapy with further persistent normalization of ALT levels for 2 or more years without eradication of serum HCV RNA (n=49). All other patterns were classified as non-response (NR, n=244). RESULTS Mean follow-up periods of CR, HCV-positive BR and NR groups were 4.9, 5.2 and 4.9 years, respectively. The HCV-positive BR group had significantly higher serum HCV RNA levels and a higher rate of HCV serological group 1 classification than the CR group. The other characteristics of the HCV-positive BR group were lower histologic activity, lower ALT levels, and a higher rate of females when compared with both the CR and NR groups. Histologic staging in the HCV-positive BR group was significantly lower than that in the NR group. Cumulative incidences of HCC estimated by the Kaplan-Meier method in both the CR and HCV-positive BR groups were significantly lower than those in the NR group (log-rank test, CR vs NR p<0.001, HCV-positive BR vs NR p=0.026). CONCLUSION The patients with HCV-positive BR were virologically different from those with CR, and had lower ALT levels and histologic activity when compared to those with CR and NR.
A highly efficient ligand‐regulated Cre recombinase mouse line shows that LoxP recombination is position dependent

Conditional gene inactivation using the Cre/loxP system is widely used, but the difficulty in properly regulating Cre expression remains one of the bottlenecks. One approach to regulate Cre activity utilizes a mutant estrogen hormone‐binding domain (ERT) to keep Cre inactive unless the non‐steroidal estrogen analog 4‐hydroxytamoxifen (OHT) is present. Here we describe a mouse strain expressing Cre‐ERT from the ubiquitously expressed ROSA26 (R26) locus. We demonstrate efficient temporal and spatial regulation of Cre recombination in vivo and in primary cells derived from these mice. We show the existence of marked differences in recombination frequencies between different substrates within the same cell. This has important consequences when concurrent switching of multiple alleles within the same cell is needed, and highlights one of the difficulties that may be encountered when using reporter mice as indicator strains.
Signal Transduction in the Carnivorous Plant Sarracenia purpurea (Regulation of Secretory Hydrolase Expression during Development and in Response to Resources)

Carnivory in plants has developed as an evolutionary adaptation to nutrient-poor environments. A significant investment of the resources of a carnivorous plant is committed to producing the traps, attractants, and digestive enzymes needed for the carnivory. The cost:benefit ratio of carnivory can be improved by either maximizing the prey capture rate or by reducing the metabolic commitment toward carnivory. Using the pitcher plant Sarracenia purpurea, we have investigated whether the expression of the hydrolytic enzymes needed for digestion is regulated in response to the presence of prey. Expression of protease, RNase, nuclease, and phosphatase activities could be induced in the fluid of nonactive traps by the addition of nucleic acids, protein, or reduced nitrogen, suggesting that hydrolase expression is induced upon perception of the appropriate chemical signal. Hydrolase expression was also developmentally controlled since expression commenced upon opening of a trap, increased for several days, and in the absence of prey largely ceased within 2 weeks. Nevertheless, the traps remained competent to induce expression in response to the appropriate signals. These data suggest that in young traps hydrolase expression is developmentally regulated, which is later replaced by a signal transduction mechanism, and they demonstrate the ability of a carnivorous species to respond to the availability of resources.
Determining Ambiguity Classes for Part-of-Speech Tagging

We examine how words group together in the lexicon, in terms of ambiguity classes, and use this information in a redefined tagset to improve POS tagging. In light of errors in the training data and a limited amount of annotated data, we investigate ways to define ambiguity classes for words which consider the lexicon as a whole and predict unknown uses of words. Fitting words to typical ambiguity classes is shown to provide more accurate ambiguity classes for words and to significantly improve tagging performance.
A Brain-Machine-Brain Interface for Rewiring of Cortical Circuitry after Traumatic Brain Injury

Abstract : A small, lightweight microdevice has been developed for activity-dependent stimulation (ADS) and successfully tested for functionality in both anesthetized and ambulatory rats. Further, in semi-chronic experiments in rats with TBI using this microsystem, an unprecedented, potent effect of ADS on motor performance has been demonstrated, as compared to control rats (injured but no microdevice) and open-loop stimulation (OLS) rats. Specifically, open-loop stimulation does result in some recovery after injury, but ADS is significantly more efficacious, resulting in recovery to normal ranges of performance within 2 weeks after injury.