Miracle-dz/UniFAR-FTUs huggingface dataset:
RNA splicing and intron turnover are greatly diminished by a mutant yeast branch point.

Two mutant genes, both of which contain an A----C transversion at the absolutely conserved branch point of the yeast "TACTAAC box" (TACTAAC----TACTACC), were constructed and introduced into yeast cells. Splicing and gene expression are almost completely eliminated by this mutation, but a low level (approximately equal to 0.1%) of proper splicing is detectable. Branch point mapping indicates that the mutant branch is formed at the normal location--i.e., to cytidine rather than adenosine. The mutant branch is also a very poor substrate for the HeLa cell debranching enzyme. Although splicing of the mutant transcripts is very poor, the cells contain a high level of mutant intron because these excised introns are remarkably stable. The results imply that the normal branch point is important not only for branch formation and splicing but also for intron turnover.
Astrocyte IP3R2-dependent Ca2+ signaling is not a major modulator of neuronal pathways governing behavior

Calcium-dependent release of gliotransmitters by astrocytes is reported to play a critical role in synaptic transmission and be necessary for long-term potentiation (LTP), long-term depression (LTD) and other forms of synaptic modulation that are correlates of learning and memory. Further, physiological processes reported to be dependent on Ca2+ fluxes in astrocytes include functional hyperemia, sleep, and regulation of breathing. The preponderance of findings indicate that most, if not all, receptor dependent Ca2+ fluxes within astrocytes are due to release of Ca2+ through IP3 receptor/channels in the endoplasmic reticulum. Findings from several laboratories indicate that astrocytes only express IP3 receptor type 2 (IP3R2) and that a knockout of IP3R2 obliterates the GPCR-dependent astrocytic Ca2+ responses. Assuming that astrocytic Ca2+ fluxes play a critical role in synaptic physiology, it would be predicted that elimination of astrocytic Ca2+ fluxes would lead to marked changes in behavioral tests. Here, we tested this hypothesis by conducting a broad series of behavioral tests that recruited multiple brain regions, on an IP3R2 conditional knockout mouse model. We present the novel finding that behavioral processes are unaffected by lack of astrocyte IP3R-mediated Ca2+ signals. IP3R2 cKO animals display no change in anxiety or depressive behaviors, and no alteration to motor and sensory function. Morris water maze testing, a behavioral correlate of learning and memory, was unaffected by lack of astrocyte IP3R2-mediated Ca2+-signaling. Therefore, in contrast to the prevailing literature, we find that neither receptor-driven astrocyte Ca2+ fluxes nor, by extension, gliotransmission is likely to be a major modulating force on the physiological processes underlying behavior.
Distributed under Creative Commons Cc-by 4.0 Platelet-rich Concentrate in Serum Free Medium Enhances Osteogenic Differentiation of Bone Marrow-derived Human Mesenchymal Stromal Cells

Previous studies have shown that platelet concentrates used in conjunction with appropriate growth media enhance osteogenic differentiation of human mesenchymal stromal cells (hMSCs). However, their potential in inducing osteogenesis of hMSCs when cultured in serum free medium has not been explored. Furthermore, the resulting osteogenic molecular signatures of the hMSCs have not been compared to standard osteogenic medium. We studied the effect of infrequent supplementation (8-day interval) of 15% non-activated platelet-rich concentrate (PRC) in serum free medium on hMSCs proliferation and differentiation throughout a course of 24 days, and compared the effect with those cultured in a standard osteogenic medium (OM). Cell proliferation was analyzed by alamar blue assay. Gene expression of osteogenic markers (Runx2, Collagen1, Alkaline Phosphatase, Bone morphogenetic protein 2, Osteopontin, Osteocalcin, Osteonectin) were analyzed using Q-PCR. Immunocytochemical staining for osteocalcin, osteopontin and transcription factor Runx2 were done at 8, 16 and 24 days. Biochemical assays for the expression of ALP and osteocalcin were also performed at these time-points. Osteogenic differentiation was further confirmed qualitatively by Alizarin Red S staining that was quantified using cetylpyridinium chloride. Results showed that PRC supplemented in serum free medium enhanced hMSC proliferation, which peaked at day 16. The temporal pattern of gene expression of hMSCs under the influence of PRC was comparable to that of the osteogenic media, but at a greater extent at specific time points. Immunocytochemical staining revealed stronger staining for Runx2 in the PRC-treated group compared to OM, while the staining for Osteocalcin and Osteopontin were comparable in both groups. ALP activity and Osteocalcin/DNA level were higher in the PRC group. Cells in the PRC group had similar level of bone mineralization as those cultured in OM, as reflected by the intensity of Alizarin red stain. Collectively, these results demonstrate a great potential of PRC alone in inducing proliferation of hMSCs without any influence from other lineage-specific growth media. PRC alone has similar capacity to enhance hMSC osteogenic differentiation as a standard OM, without changing the temporal profile of the differentiation process. How to cite this article Samuel et al. (2016), Platelet-rich concentrate in serum free medium enhances osteogenic differentiation of bone marrow-derived human mesenchymal stromal cells. Thus, PRC could be used as a substitute medium to provide sufficient pool of pre-differentiated hMSCs for potential clinical application in bone regeneration.
Functional Magnetic Resonance Imaging Neurofeedback-guided Motor Imagery Training and Motor Training for Parkinson’s Disease: Randomized Trial

Objective: Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) uses feedback of the patient’s own brain activity to self-regulate brain networks which in turn could lead to a change in behavior and clinical symptoms. The objective was to determine the effect of NF and motor training (MOT) alone on motor and non-motor functions in Parkinson’s Disease (PD) in a 10-week small Phase I randomized controlled trial. Methods: Thirty patients with Parkinson’s disease (PD; Hoehn and Yahr I-III) and no significant comorbidity took part in the trial with random allocation to two groups. Group 1 (NF: 15 patients) received rt-fMRI-NF with MOT. Group 2 (MOT: 15 patients) received MOT alone. The primary outcome measure was the Movement Disorder Society—Unified PD Rating Scale-Motor scale (MDS-UPDRS-MS), administered pre- and post-intervention “off-medication”. The secondary outcome measures were the “on-medication” MDS-UPDRS, the PD Questionnaire-39, and quantitative motor assessments after 4 and 10 weeks. Results: Patients in the NF group were able to upregulate activity in the supplementary motor area (SMA) by using motor imagery. They improved by an average of 4.5 points on the MDS-UPDRS-MS in the “off-medication” state (95% confidence interval: −2.5 to −6.6), whereas the MOT group improved only by 1.9 points (95% confidence interval +3.2 to −6.8). The improvement in the intervention group meets the minimal clinically important difference which is also on par with other non-invasive therapies such as repetitive Transcranial Magnetic Stimulation (rTMS). However, the improvement did not differ significantly between the groups. No adverse events were reported in either group. Interpretation: This Phase I study suggests that NF combined with MOT is safe and improves motor symptoms immediately after treatment, but larger trials are needed to explore its superiority over active control conditions.
Efficacy of Mesenchymal Stem Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Background Mesenchymal stem cells (MSCs) have been broadly used experimentally in various clinical contexts. The addition of MSCs to initial steroid therapy for acute graft-versus-host disease (aGVHD) may improve patient outcomes. However, investigations regarding prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD remain controversial. We thus conducted a systematic review and meta-analysis of published clinical trials to determine possible prognostic factors affecting the efficacy of MSCs in treating steroid-refractory aGVHD. Methods and Findings Clinical trials using MSC therapy for steroid-refractory aGVHD were identified by searching PubMed and EMBASE databases. A total of 6,963 citations were reviewed, and 13 studies met the inclusion criteria. A total of 301 patients from thirteen studies were included. Of these, 136 patients showed a complete response (CR), and 69 patients displayed a partial (PR) or mixed response (MR). In total, 205 patients exhibited overall response (ORR). Patients with skin steroid-refractory aGVHD showed a better clinical response than gastrointestinal (CR: odds ratio [OR] = 1.93, 95% confidence interval [95%CI]: 1.05–3.57, p < 0.05) and liver (CR: OR = 2.30, 95%CI: 1.12–4.69, p < 0.05, and ORR: OR = 2.93, 95%CI: 1.06–8.08, p < 0.05) steroid-refractory aGVHD. Those with grade II steroid-refractory aGVHD exhibited a better clinical response following MSC therapy than recipients with grade III–IV (CR: OR = 3.22, 95%CI: 1.24–8.34, p < 0.05). Completion therapy may improve the CR but reduce ORR compared with induction therapy (CR: OR = 0.20, 95%CI: 0.09–0.44, p < 0.05; ORR: OR = 2.18, 95%CI: 1.17–4.05, p = 0.01). There was also a trend towards a better clinical response in children compared with adults (CR: OR = 2.41, 95%CI: 1.01–5.73, p = 0.05). Conclusions Age, skin involvement, lower aGVHD grade, and the number of infusions are the main prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD.
Autonomous Spectrum Balancing (ASB) for Frequency Selective Interference Channels

For frequency selective interference channels where interference is treated as noise, distributively attaining the boundary of the rate region is an open problem, and is particularly important for broadband DSL access. This paper develops, analyzes, and simulates a new algorithm for power allocation in frequency selective interference channels called autonomous spectrum balancing (ASB). It utilizes the concept of a "reference line", which mimics a typical victim line in the interference channel. Compared with the state-of-the-art iterative watefilling and optimum spectrum balancing methods, the ASB algorithm is completely autonomous, has linear complexity in both the number of users and tones, and gives close to near-optimal performance. Convergence of a version of ASB is proven for any number of users
Intermediate- and Low-Methylation Epigenotypes Do Not Correspond to CpG Island Methylator Phenotype (Low and -Zero) in Colorectal Cancer

Background: Most recent genome-wide studies on the CpG island methylation in colorectal cancer (CRC) have led to the discovery of at least 3 distinct methylation clusters. However, there remains an uncertainty whether the CRC clusters identified in these studies represent compatible phenotypes. Methods: We carried out comprehensive genome-scale DNA methylation profiling by Illumina Infinium HumanMethylation27 of 21 DNA pools that represent 84 CRC samples divided according to their high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME, respectively) and 70 normal-adjacent colonic tissues. We have also examined the relationship among 3 epigenotypes and chromosomal gains and deletions (assessed by Comparative Genomic Hybridization) in a group of 100 CRC samples. Results: The HME subgroup showed features associated with CpG island methylator phenotype – high (CIMP-high) including methylation of specific CpG sites (CpGs) as well as significantly lower mean number of chromosomal imbalances when compared with other epigenotypes. The IME subgroup displayed the lowest number of methylated CpGs (717 vs. 2,399 and 2,679 in HME and LME, respectively) and highest mean number of chromosomal imbalances when compared with HME (P, 0.001) and LME (P, 0.004). A comparison between the methylation profiles of 3 epigenotypes revealed more similarities between the HME and LME (1,669 methylated CpGs overlapped) than HME and IME (673 methylated CpGs overlapped). Conclusion: Our results provide evidence that IME and LME CRCs show opposite features to those that have been previously attributed to CIMP-low and CIMP-0 CRCs. Impact: These discrepancies should be considered when interpreting the data from a particular epigenotyping method. Cancer Epidemiol Biomarkers Prev; 22(2); 201–8. ©2012 AACR.
Bi-Directional Synthesis of 4-Bit Reversible Circuits

Reversible circuits play an important role in quantum computing, which is one of the most promising emerging technologies. In this paper, we investigate the problem of optimally synthesizing 4-bit reversible circuits. We present an enhanced bi-directional synthesis approach. Owing to the exponential nature of the memory and run-time complexity, all existing methods can only perform four steps for the Controlled-Not gate NOT gate, and Peres gate library. Our novel method can achieve 12 steps. As a result, we augment the number of circuits that can optimally be synthesized by over 5 × 106 times. We synthesized 1000 random 4-bit reversible circuits. The statistical analysis result supports our estimation. The quantum cost of our result is also better than the quantum cost of other approaches. The promising experimental results demonstrate the effectiveness of our approach.
Is depression associated with health risk-related behaviour clusters in adults?

BACKGROUND Depressive disorders have been linked to health risk-related behaviours (HRBs) considered separately. Our objective was to study whether depression is associated with the co-occurrence of HRBs in adults. METHODS A sample of 17 355 subjects aged > or =18 years, derived from the 2002-03 cross-sectional Decennial Health Survey; probable depression was assessed with the CES-D scale. A cluster analysis of various HRBs (tobacco use, alcohol use, binge drinking, physical inactivity, certain eating habits) was used to study their co-occurrence. Multiple regressions adjusted on demographic and socio-economic characteristics, Body Mass Index and chronic illnesses were performed to study associations between probable depression and the HRBs clusters obtained. RESULTS Five clusters were observed evidencing a gradient of cumulative exposure to HRBs: 'healthy lifestyles (Cluster 1), 'non-daily-consumers-fruit-and-green-vegetables' (Cluster 2), 'regular alcohol users' (Cluster 3), 'daily smokers' (Cluster 4) and 'cumulate risk takers' (Cluster 5). Compared with Cluster 1, positive associations were found between probable depression and Clusters 2, 4 and 5: OR 1.49 (95% CI 1.26-1.76) for Cluster 2; OR 1.81 (95% CI 1.54-2.12) for Cluster 4; OR 2.05 (95% CI 1.68-2.51) for Cluster 5. For Cluster 3, no association was found: OR 1.01 (95% CI 0.84-1.21). CONCLUSIONS HRBs tend to co-occur in the general population, more frequently in case of probable depression. Further research is necessary to disentangle the direction of the links between depression and HRB clusters. Nonetheless, these results question the classic design of education campaigns considering HRBs separately. Moreover, screening for depression should be systematic during prevention consultations and various HRBs should be monitored when treating depressive patients.
Early Education Essentials: Validation of Surveys Measuring Early Education Organizational Conditions

ABSTRACT Research Findings: The Early Education Essentials surveys use teacher and parent perceptions to measure 6 organizational conditions of early childhood education programs, extending and complementing existing measures of early childhood care and education (ECE) quality constructs. This study tests the reliability and concurrent validity of the Early Education Essentials in 81 school- and community-based ECE sites in a large Midwestern city selected using a stratified random sampling method. Using a Rasch item response theory model, scales were created; theory and exploratory factor analyses combined scales into higher level constructs called essentials. Multilevel models took into account individual measurement error to create site-level essential scores and assessed relationships between programs’ essential scores and site-level teacher–child interactions scores and student attendance. Findings suggest that the Early Education Essentials is reliable in multiple ECE settings; it is sensitive to site-level differences; and some, but not all, organizational conditions measured are associated in expected directions with site-level metrics indicative of center-based ECE quality. Practice or Policy: The Early Education Essentials has the potential to provide leaders and practitioners with actionable data about organizational supports that enable ECE practitioners to be more effective in their daily work with children and families.
Mental representation and the subjectivity of consciousness

Many have urged that the biggest obstacles to a physicalistic understanding of consciousness are the problems raised in connection with the subjectivity of consciousness. These problems are most acutely expressed in consideration of the knowledge argument against physicalism. I develop a novel account of the subjectivity of consciousness by explicating the ways in which mental representations may be perspectival. Crucial features of my account involve analogies between the representations involved in sensory experience and the ways in which pictorial representations exhibit perspectives or points of view. I argue that the resultant account of subjectivity provides a basis for the strongest response physicalists can give to the knowledge argument.
Mechanisms for Stable Bump Activity, Winner-Take-All and Group Selection in Neuronal Spiking Networks

A major function of central nervous systems is to discriminate different categories or types of sensory input. Neuronal networks accomplish such tasks by learning different sensory maps at several stages of neural hierarchy, such that different neurons fire selectively to reflect different internal or external patterns and states. The exact mechanisms of such map formation processes in the brain are not totally understood. Here we study the mechanism by which a simple recurrent/reentrant neuronal network accomplish group selection and discrimination to different inputs in order to generate sensory maps. We describe the conditions and mechanism of transition from a rhythmic epileptic state (in which all neurons fire synchronized and indiscriminately to any input) to a winner-take-all state in which only a subset of neurons fire for a specific input. We prove an analytic condition under which a stable bump solution and a soft winner-take-all state can emerge from the local recurrent excitation-inhibition interactions in a three-layer spiking network with distinct excitatory and inhibitory populations, and demonstrate the importance of surround inhibitory connection topology on the stability of dynamic patterns in spiking neural network.
Cognitive cost as dynamic allocation of energetic resources

While it is widely recognized that thinking is somehow costly, involving cognitive effort and producing mental fatigue, these costs have alternatively been assumed to exist, treated as the brain's assessment of lost opportunities, or suggested to be metabolic but with implausible biological bases. We present a model of cognitive cost based on the novel idea that the brain senses and plans for longer-term allocation of metabolic resources by purposively conserving brain activity. We identify several distinct ways the brain might control its metabolic output, and show how a control-theoretic model that models decision-making with an energy budget can explain cognitive effort avoidance in terms of an optimal allocation of limited energetic resources. The model accounts for both subject responsiveness to reward and the detrimental effects of hypoglycemia on cognitive function. A critical component of the model is using astrocytic glycogen as a plausible basis for limited energetic reserves. Glycogen acts as an energy buffer that can temporarily support high neural activity beyond the rate supported by blood glucose supply. The published dynamics of glycogen depletion and repletion are consonant with a broad array of phenomena associated with cognitive cost. Our model thus subsumes both the “cost/benefit” and “limited resource” models of cognitive cost while retaining valuable contributions of each. We discuss how the rational control of metabolic resources could underpin the control of attention, working memory, cognitive look ahead, and model-free vs. model-based policy learning.
Cortical Reorganization after Long-Term Adaptation to Retinal Lesions in Humans

Single-unit recordings demonstrated that the adult mammalian visual cortex is capable of reorganizing after induced retinal lesions. In humans, whether the adult cortex is capable of reorganizing has only been studied using functional magnetic resonance imaging, with equivocal results. Here, we exploited the phenomenon of visual crowding, a major limitation on object recognition, to show that, in humans with long-standing retinal (macular) lesions that afflict the fovea and thus use their peripheral vision exclusively, the signature properties of crowding are distinctly different from those of the normal periphery. Crowding refers to the inability to recognize objects when the object spacing is smaller than the critical spacing. Critical spacing depends only on the retinal location of the object, scales linearly with its distance from the fovea, and is approximately two times larger in the radial than the tangential direction with respect to the fovea, thus demonstrating the signature radial–tangential anisotropy of the crowding zone. Using retinal imaging combined with behavioral measurements, we mapped out the crowding zone at the precise peripheral retinal locations adopted by individuals with macular lesions as the new visual reference loci. At these loci, the critical spacings are substantially smaller along the radial direction than expected based on the normal periphery, resulting in a lower scaling of critical spacing with the eccentricity of the peripheral locus and a loss in the signature radial–tangential anisotropy of the crowding zone. These results imply a fundamental difference in the substrate of cortical processing in object recognition following long-term adaptation to macular lesions.
Neural Correlates of Visuospatial Working Memory in ADHD and Controls 7

152 7 ABSTRACT BACKGROUND Impaired visuospatial working memory (VSWM) is suggested to be a core neurocognitive deficit in Attention-Deficit/Hyperactivity Disorder (ADHD), yet the underlying neural activation patterns are poorly understood. Furthermore, it is unclear to what extent age and gender effects may play a role in VSWM-related brain abnormalities in ADHD.