Miracle-dz/UniFAR-FTUs huggingface dataset:
Total RNA Sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target

Mutations in the MeCP2 gene are responsible for the neurodevelopmental disorder Rett syndrome (RTT). MeCP2 is a DNA-binding protein whose abundance and ability to complex with histone deacetylase 3 is linked to the regulation of chromatin structure. Consequently, loss-of-function mutations in MeCP2 are predicted to have broad effects on gene expression. However, to date, studies in mouse models of RTT have identified a limited number of gene or pathway-level disruptions, and even fewer genes have been identified that could be considered amenable to classic drug discovery approaches. Here, we performed RNA sequencing (RNA-seq) on nine motor cortex and six cerebellar autopsy samples from RTT patients and controls. This approach identified 1887 significantly affected genes in the motor cortex and 2110 genes in the cerebellum, with a global trend toward increased expression. Pathway-level analysis identified enrichment in genes associated with mitogen-activated protein kinase signaling, long-term potentiation, and axon guidance. A survey of our RNA-seq results also identified a significant decrease in expression of the CHRM4 gene, which encodes a receptor [muscarinic acetylcholine receptor 4 (M4)] that is the subject of multiple large drug discovery efforts for schizophrenia and Alzheimer’s disease. We confirmed that CHRM4 expression was decreased in RTT patients, and, excitingly, we demonstrated that M4 potentiation normalizes social and cognitive phenotypes in Mecp2+/− mice. This work provides an experimental paradigm in which translationally relevant targets can be identified using transcriptomics in RTT autopsy samples, back-modeled in Mecp2+/− mice, and assessed for preclinical efficacy using existing pharmacological tool compounds.
Maximum Principle Based Algorithms for Deep Learning

The continuous dynamical system approach to deep learning is explored in order to devise alternative frameworks for training algorithms. Training is recast as a control problem and this allows us to formulate necessary optimality conditions in continuous time using the Pontryagin's maximum principle (PMP). A modification of the method of successive approximations is then used to solve the PMP, giving rise to an alternative training algorithm for deep learning. This approach has the advantage that rigorous error estimates and convergence results can be established. We also show that it may avoid some pitfalls of gradient-based methods, such as slow convergence on flat landscapes near saddle points. Furthermore, we demonstrate that it obtains favorable initial convergence rate per-iteration, provided Hamiltonian maximization can be efficiently carried out - a step which is still in need of improvement. Overall, the approach opens up new avenues to attack problems associated with deep learning, such as trapping in slow manifolds and inapplicability of gradient-based methods for discrete trainable variables.
The protective role of long-term meditation on the decline of the executive component of attention in aging: a preliminary cross-sectional study

ABSTRACT Life expectancy is constantly increasing. However, a longer life not always corresponds to a healthier life. Indeed, even normal aging is associated with a decline in different cognitive functions. It has been proposed that a central mechanism that could contribute to this widespread cognitive decline is an ineffective inhibitory attentional control. Meditation, to the other hand, has been associated, in young adults, to enhancement of several attentional processes. Nevertheless, attention is not a unitary construct. An influent model proposed the distinction of three subsystems: the alerting (the ability to reach and maintain a vigilance state), the orienting (the capacity of focusing attention on a subset of stimuli), and the conflict resolution or executive component (the ability to resolve conflict or allocate limited resources between competing stimuli). Here, we investigated, employing the Attentional Network Task (ANT), the specific impact of age on these three subcomponents, and the protective role of long-term meditation testing a group of older adults naïve to meditation, a group of age-matched adults with long-term practice of meditation, and a group of young adults with no previous meditation experience. We reported a specific decline of the efficiency of the executive component in elderly that was not observed in age-matched meditators. Our results are encouraging for the investigation of the potential beneficial impact of meditation on other cognitive processes that decline in aging such as memory. Moreover, they could inform geriatric healthcare prevention and intervention strategies, proposing a new approach for cognitive remediation in elderly populations.
Evolution of heterotrophy in chrysophytes as reflected by comparative transcriptomics

ABSTRACT Shifts in the nutritional mode between phototrophy, mixotrophy and heterotrophy are a widespread phenomenon in the evolution of eukaryotic diversity. The transition between nutritional modes is particularly pronounced in chrysophytes and occurred independently several times through parallel evolution. Thus, chrysophytes provide a unique opportunity for studying the molecular basis of nutritional diversification and of the accompanying pathway reduction and degradation of plastid structures. In order to analyze the succession in switching the nutritional mode from mixotrophy to heterotrophy, we compared the transcriptome of the mixotrophic Poterioochromonas malhamensis with the transcriptomes of three obligate heterotrophic species of Ochromonadales. We used the transcriptome of P. malhamensis as a reference for plastid reduction in the heterotrophic taxa. The analyzed heterotrophic taxa were in different stages of plastid reduction. We investigated the reduction of several photosynthesis related pathways e.g. the xanthophyll cycle, the mevalonate pathway, the shikimate pathway and the tryptophan biosynthesis as well as the reduction of plastid structures and postulate a presumable succession of pathway reduction and degradation of accompanying structures. Figure. No Caption available.
Recovery From Anorexia Nervosa and Bulimia Nervosa at 22-Year Follow-Up.

OBJECTIVE The course of eating disorders is often protracted, with fewer than half of adults achieving recovery from anorexia nervosa or bulimia nervosa. Some argue for palliative management when duration exceeds a decade, yet outcomes beyond 20 years are rarely described. This study investigates early and long-term recovery in the Massachusetts General Hospital Longitudinal Study of Anorexia and Bulimia Nervosa. METHODS Females with DSM-III-R/DSM-IV anorexia nervosa or bulimia nervosa were assessed at 9 and at 20 to 25 years of follow-up (mean [SD] = 22.10 [1.10] years; study initiated in 1987, last follow-up conducted in 2013) via structured clinical interview (Longitudinal Interval Follow-Up Evaluation of Eating Disorders [LIFE-EAT-II]). Seventy-seven percent of the original cohort was re-interviewed, and multiple imputation was used to include all surviving participants from the original cohort (N = 228). Kaplan-Meier curves estimated recovery by 9-year follow-up, and McNemar test examined concordance between recovery at 9-year and 22-year follow-up. RESULTS At 22-year follow-up, 62.8% of participants with anorexia nervosa and 68.2% of participants with bulimia nervosa recovered, compared to 31.4% of participants with anorexia nervosa and 68.2% of participants with bulimia nervosa by 9-year follow-up. Approximately half of those with anorexia nervosa who had not recovered by 9 years progressed to recovery at 22 years. Early recovery was associated with increased likelihood of long-term recovery in anorexia nervosa (odds ratio [OR] = 10.5; 95% CI, 3.77-29.28; McNemar χ²₁ = 31.39; P < .01) but not in bulimia nervosa (OR = 1.0; 95% CI, 0.49-2.05; McNemar χ²₁ = 0; P = 1.0). CONCLUSION At 22 years, approximately two-thirds of females with anorexia nervosa and bulimia nervosa were recovered. Recovery from bulimia nervosa happened earlier, but recovery from anorexia nervosa continued over the long term, arguing against the implementation of palliative care for most individuals with eating disorders.
Incomplete Contracts and Firm Boundaries: New Directions

The seminal work by Grossman and Hart (1986) made the study of firm boundaries susceptible to formal economic analysis, and illuminated an important role for markets in providing incentives. In this essay, I discuss some new directions that the literature has taken since. As a central challenge, I identify the need to provide a formal theory of the firm in which managerial direction and bureaucratic decision-making play a key role. Merging a number of existing incomplete contracting models, I propose two approaches with very different contracting assumptions. As in transaction cost economics, a central element in those theories is the presence of a central office who directs and coordinates the actions of subordinates. More novel, I highlight the superior ability of non-integrated firms to adapt to a changing environment.
Numerical approximation of nonhomogeneous boundary conditions on networks for a hyperbolic system of chemotaxis modeling the Physarum dynamics

Many studies have shown that Physarum polycephalum slime mold is able to find the shortest path in a maze. In this paper we study this behavior in a network, using a hyperbolic model of chemotaxis. Suitable transmission and boundary conditions at each node are considered to mimic the behavior of such an organism in the feeding process. Several numerical tests are presented for special network geometries to show the qualitative agreement between our model and the observed behavior of the mold.
Aligning science and policy to achieve evolutionarily enlightened conservation

There is increasing recognition among conservation scientists that long‐term conservation outcomes could be improved through better integration of evolutionary theory into management practices. Despite concerns that the importance of key concepts emerging from evolutionary theory (i.e., evolutionary principles and processes) are not being recognized by managers, there has been little effort to determine the level of integration of evolutionary theory into conservation policy and practice. We assessed conservation policy at 3 scales (international, national, and provincial) on 3 continents to quantify the degree to which key evolutionary concepts, such as genetic diversity and gene flow, are being incorporated into conservation practice. We also evaluated the availability of clear guidance within the applied evolutionary biology literature as to how managers can change their management practices to achieve better conservation outcomes. Despite widespread recognition of the importance of maintaining genetic diversity, conservation policies provide little guidance about how this can be achieved in practice and other relevant evolutionary concepts, such as inbreeding depression, are mentioned rarely. In some cases the poor integration of evolutionary concepts into management reflects a lack of decision‐support tools in the literature. Where these tools are available, such as risk‐assessment frameworks, they are not being adopted by conservation policy makers, suggesting that the availability of a strong evidence base is not the only barrier to evolutionarily enlightened management. We believe there is a clear need for more engagement by evolutionary biologists with policy makers to develop practical guidelines that will help managers make changes to conservation practice. There is also an urgent need for more research to better understand the barriers to and opportunities for incorporating evolutionary theory into conservation practice.
Are there urban signatures in the tropospheric ozone column products derived from satellite measurements

Abstract. In view of the proposed geostationary satellite missions to monitor air quality from space, it is important to first assess the capability of the current suite of satellite instruments to provide information on the urban scale pollution. We explore the possibility of detecting urban signatures in the tropospheric column ozone data derived from Total Ozone Mapping Spectrometer (TOMS)/Solar Backscattered Ultraviolet (SBUV) and Ozone Monitoring Instrument (OMI)/Microwave Limb Sounder (MLS) satellite data. We find that distinct isolated plumes of tropospheric ozone near several large and polluted cities around the world may be detected in these data sets. The ozone plumes generally correspond with the tropospheric column NO2 plumes around these cities as observed by the Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY) instrument. Similar plumes are also seen in tropospheric mean ozone mixing ratio distribution after accounting for the surface and tropopause pressure variations. The total column ozone retrievals indicate fairly significant sensitivity to the lower troposphere over the polluted land areas, which might help explain these detections. These results indicate that ultraviolet (UV) measurements may, in principle, be able to capture the urban signatures and may have implications for future missions using geostationary satellites.
Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10−53). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10−20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
A Fast In-Field Coarse Alignment and Bias Estimation Method for Stationary Intermediate-Grade IMUs

This paper presents an innovative in-field coarse bias estimation (CBE) method for stationary intermediate-grade inertial measurement units (IMUs), which is based on the existence of normality and orthogonality errors in the attitude matrix supplied by the traditional three-axis attitude determination stationary coarse alignment (CA) stage. Differently from the currently existing in-field bias estimation formulations, the proposed CBE method is conceived to be conducted in stationary conditions, jointly with the CA, and it allows the down accelerometer bias and the north and down angular rate sensor biases to be adequately estimated. As a main contribution of this paper, we demonstrate that the proposed CBE method is able to greatly accelerate the estimation process of the aforementioned biases, contributing, hence, to shorten the IMU setup time. A comprehensive error analysis is presented, and the conclusions are twofold: 1) the proposed CBE method is valid regardless of the IMU orientation and 2) its estimation accuracy is mainly constrained by the north accelerometer bias and the position location uncertainty, which are, in general, very reduced. Results from simulated and experimental test confirm the adequacy of the outlined verifications, also attesting the superiority of the proposed CBE method in situations where, due to time constraints, stationary fine alignment procedures are not allowed to be carried out.
Hybrid Duplex Wireless Peer Discovery With Imperfect Self-Interference Cancellation

This letter investigates the hybrid duplex wireless peer discovery (Hyb-WPD) that increases the average number of discovered peers (ADP), through arbitrating between half duplex and full duplex (FD) operations. FD allowing simultaneous tranceiving inherently introduces residual self-interference (RSI) due to non-ideal implementation; thus, this impairment yields a new design issue for transmission probability, which determines whether a peer receives or tranceives. This letter proposes the design principles for the Hyb-WPD depending on RSI through mathematically analyzing the ADP, and the numerical results demonstrate their performance.
Au th or ' s pe rs on al co py A new paradigm for assessing the role of agriculture in the climate system and in climate change

This paper discusses the diverse climate forcings that impact agricultural systems, and contrasts the current paradigm of using global models downscaled to agricultural areas (a top-down approach) with a new paradigm that first assesses the vulnerability of agricultural activities to the spectrum of environmental risk including climate (a bottom-up approach). To illustrate the wide spectrum of climate forcings, regional climate forcings are presented including land-use/land-cover change and the influence of aerosols on radiative and biogeochemical fluxes and cloud/precipitation processes, as well as how these effects can be teleconnected globally. Examples are presented of the vulnerability perspective, along with a small survey of the perceived drought impacts in a local area, in which a wide range of impacts for the same precipitation deficits are found. This example illustrates why agricultural assessments of risk to climate change and variability and of other environmental risks should start with a bottom-up perspective. # 2006 Elsevier B.V. All rights reserved.
A complete thermodynamic analysis of enzyme turnover links the free energy landscape to enzyme catalysis

Our understanding of how enzymes work is coloured by static structure depictions where the enzyme scaffold is presented as either immobile, or in equilibrium between well‐defined static conformations. Proteins, however, exhibit a large degree of motion over a broad range of timescales and magnitudes and this is defined thermodynamically by the enzyme free energy landscape (FEL). The role and importance of enzyme motion is extremely contentious. Much of the challenge is in the experimental detection of so called ‘conformational sampling’ involved in enzyme turnover. Herein we apply combined pressure and temperature kinetics studies to elucidate the full suite of thermodynamic parameters defining an enzyme FEL as it relates to enzyme turnover. We find that the key thermodynamic parameters governing vibrational modes related to enzyme turnover are the isobaric expansivity term and the change in heat capacity for enzyme catalysis. Variation in the enzyme FEL affects these terms. Our analysis is supported by a range of biophysical and computational approaches that specifically capture information on protein vibrational modes and the FEL (all atom flexibility calculations, red edge excitation shift spectroscopy and viscosity studies) that provide independent evidence for our findings. Our data suggest that restricting the enzyme FEL may be a powerful strategy when attempting to rationally engineer enzymes, particularly to alter thermal activity. Moreover, we demonstrate how rational predictions can be made with a rapid computational approach.
A systematic review of health promotion interventions to increase breast cancer screening uptake: from the last 12 years

Abstract Background The outcome of breast cancer treatment largely depends on the timing of detection. The health promotion interventions have an immense contribution to early detection and improved survival. Therefore, this review aimed to provide evidence on the efficacy of the health promotion interventions to increase the uptake of breast cancer screening and to develop effective interventions targeting women. Methods Online databases (PubMed/MEDLINE/PubMed Central, Ovid/MEDILINE, EMBASE, Web of Science and Google Scholar) were searched for studies published between January 2005 and January 2017. A quality coding system was assessed using Cochrane checklists for randomized controlled trial (RCT) and Downs and Black checklists for non-RCT. The score was rated for the included articles by each researcher independently and the average score is given accordingly. This study was registered in PROSPERO as [PROSPERO 2017: CRD42017060488]. Results The review dovetailed 22 studies. Thirteen studies (59.10%) were conducted in the Unite States, 4 in Iran (18.18%), 2 in India (9.09%) and 1 each in Turkey, Saudi Arabia and Israel. The interventions were classified as ‘individual-based’, ‘community-based’, ‘group-based teachings and training’ and ‘behavioral model based’. The majority of the studies showed favorable outcomes after health promotion interventions, including improvements in women’s view of breast screening, breast self-examination and knowledge of breast screening. Conclusion The review confirmed that most of the health promotion interventions targeting women boosted the breast screening in one or another way. However, the limited quality of the included studies showed that further research is needed to improve the trials in the next future.
Association Between Weekend Catch-up Sleep and Lower Body Mass: Population-Based Study

Study Objectives To determine if weekend catch-up sleep (CUS) impacts body mass index (BMI) in the general population. Methods A stratified random sample (2156 subjects; age 19-82 years old, 43.0 ± 14.5; 1183 male) from the general population was evaluated, in 2010, using face-to-face interviews about sociodemographic characteristics, height, weight, habitual sleep duration, and time-in-bed at night on weekdays and weekend, sleep-related profiles, mood and anxiety scales, and comorbid-medical conditions. Weekend CUS was identified when nocturnal sleep extension occurred over the weekend, and this was quantified. Average sleep duration, BMI, and chronotype were determined. The association of BMI with the presence and the amount of weekend CUS was analyzed, independent of average sleep duration, chronotype, and sociodemographic factors. Results BMI and average sleep duration was 23.0 ± 3.0 kg/m2 and 7.3 ± 1.2 hours, respectively. The weekend CUS group consisted of 932 subjects (43.2%) who slept longer on weekend than weekdays by 1.8 ± 1.1 hours. Weekend CUS subjects had a significantly lower BMI (22.8 ± 0.19 kg/m2) than the non-CUS (23.1 ± 0.19 kg/m2) group, after adjustment for age, sex, average sleep duration, chronotype, other sociodemographic factors, and anxiety/mood status (p = .01) The relationship between weekend CUS and BMI was dose-dependent (p = 0.02): Every additional hour of weekend CUS was associated with a decrease of 0.12 kg/m2 in BMI (95% confidence interval, -0.23 to -0.02). Conclusions Weekend sleep extension may have biological protective effects in preventing sleep-restriction induced or related obesity. The results suggest a simple population-level strategy to minimize effects of sleep loss.