Miracle-dz/UniFAR-FTUs huggingface dataset:
Conserved motifs on the cytoplasmic face of the protein translocation channel are critical for the transition between resting and active conformations

The Sec61 complex is the primary cotranslational protein translocation channel in yeast (Saccharomyces cerevisiae). The structural transition between the closed inactive conformation of the Sec61 complex and its open and active conformation is thought to be promoted by binding of the ribosome nascent-chain complex to the cytoplasmic surface of the Sec61 complex. Here, we have analyzed new yeast Sec61 mutants that selectively interfere with cotranslational translocation across the endoplasmic reticulum. We found that a single substitution at the junction between transmembrane segment TM7 and the L6/7 loop interferes with cotranslational translocation by uncoupling ribosome binding to the L6/7 loop from the separation of the lateral gate transmembrane spans. Substitutions replacing basic residues with acidic residues in the C-terminal tail of Sec61 had an unanticipated impact upon binding of ribosomes to the Sec61 complex. We found that similar charge-reversal mutations in the N-terminal tail and in cytoplasmic loop L2/3 did not alter ribosome binding but interfered with translocation channel gating. These findings indicated that these segments are important for the structural transition between the inactive and active conformations of the Sec61 complex. In summary our results have identified additional cytosolic segments of the Sec61 complex important for promoting the structural transition between the closed and open conformations of the complex. We conclude that positively charged residues in multiple cytosolic segments, as well as bulky hydrophobic residues in the L6/7–TM7 junction, are required for cotranslational translocation or integration of membrane proteins by the Sec61 complex.
Monitoring disease activity noninvasively in the mdx model of Duchenne muscular dystrophy

Significance Duchenne muscular dystrophy (DMD) is characterized by a catastrophic progression of muscle degeneration that leads to early death. Currently, there is neither a cure for DMD nor any treatments that effectively halt muscle degeneration. Novel methods that assess disease activity non-invasively would greatly accelerate the development of effective therapies. Here we present a novel preclinical animal model that uses bioluminescence imaging as a read-out of muscle degeneration, therefore constituting a non-invasive method to assess disease progression and response to experimental gene therapy in the mdx model of DMD. This model should be widely applicable for monitoring disease activity and responses to therapy in mouse models of muscular dystrophy. Duchenne muscular dystrophy (DMD) is a rare, muscle degenerative disease resulting from the absence of the dystrophin protein. DMD is characterized by progressive loss of muscle fibers, muscle weakness, and eventually loss of ambulation and premature death. Currently, there is no cure for DMD and improved methods of disease monitoring are crucial for the development of novel treatments. In this study, we describe a new method of assessing disease progression noninvasively in the mdx model of DMD. The reporter mice, which we term the dystrophic Degeneration Reporter strains, contain an inducible CRE-responsive luciferase reporter active in mature myofibers. In these mice, muscle degeneration is reflected in changes in the level of luciferase expression, which can be monitored using noninvasive, bioluminescence imaging. We monitored the natural history and disease progression in these dystrophic report mice and found that decreases in luciferase signals directly correlated with muscle degeneration. We further demonstrated that this reporter strain, as well as a previously reported Regeneration Reporter strain, successfully reveals the effectiveness of a gene therapy treatment following systemic administration of a recombinant adeno-associated virus-6 (rAAV-6) encoding a microdystrophin construct. Our data demonstrate the value of these noninvasive imaging modalities for monitoring disease progression and response to therapy in mouse models of muscular dystrophy.
On the Cost Complexity of Crowdsourcing

Existing efforts mainly use empirical analysis to evaluate the effectiveness of crowdsourcing methods, which is often unreliable across experimental settings. Consequently, it is of great importance to study theoretical methods. This work, for the first time, defines the cost complexity of crowdsourcing, and presents two theorems to compute the cost complexity. Our theorems provide a general theoretical method to model the trade-off between costs and quality, which can be used to evaluate and design crowdsourcing algorithms, and characterize the complexity of crowdsourcing problems. Moreover, following our theorems, we prove a set of corollaries that can obtain existing theoretical results for special cases. We have verified our work theoretically and empirically.
The MAPK Erk5 is necessary for proper skeletogenesis involving a Smurf-Smad-Sox9 molecular axis

ABSTRACT Erk5 belongs to the mitogen-activated protein kinase (MAPK) family. Following its phosphorylation by Mek5, Erk5 modulates several signaling pathways in a number of cell types. In this study, we demonstrated that Erk5 inactivation in mesenchymal cells causes abnormalities in skeletal development by inducing Sox9, an important transcription factor of skeletogenesis. We further demonstrate that Erk5 directly phosphorylates and activates Smurf2 (a ubiquitin E3 ligase) at Thr249, which promotes the proteasomal degradation of Smad proteins and phosphorylates Smad1 at Ser206 in the linker region known to trigger its proteasomal degradation by Smurf1. Smads transcriptionally activated the expression of Sox9 in mesenchymal cells. Accordingly, removal of one Sox9 allele in mesenchymal cells from Erk5-deficient mice rescued some abnormalities of skeletogenesis. These findings highlight the importance of the Mek5-Erk5-Smurf-Smad-Sox9 axis in mammalian skeletogenesis. Summary: The Erk5 pathway plays an important role in skeletogenesis in mesenchymal cells, by decreasing the stability of Smad proteins, thus reducing Sox9 expression.
Pure platelet-rich plasma and supernatant of calcium-activated P-PRP induce different phenotypes of human macrophages.

AIM This study aimed to evaluate the effect of two platelet preparations used in the clinic, pure platelet-rich plasma (P-PRP) and the supernatant of calcium-activated P-PRP (S-PRP), on the phenotype of human macrophages. MATERIALS & METHODS Surface markers and cytokine production of human monocyte-derived macrophages were analyzed after 24 h stimulation with P-PRP or S-PRP. RESULTS P-PRP and S-PRP present no difference in the expression of CD206, a M2 tissue-repair macrophage-related marker. However, these same macrophages presented different levels of CD163, CD86 as well as different IL-10 secretion capacities after 24 h incubation. CONCLUSION These platelet preparations do not have an equivalent biological effect over macrophages, which suggest that they may present different clinical regenerative potentials.
A review and critique of published real-world weight management program studies

ABSTRACT Background: Beyond the essential but somewhat artificial conditions that typify formal clinical studies, real-world evidence (RWE) of weight loss program effectiveness is paramount for an accurate assessment of such programs and refinement of best practices. Objectives: To evaluate the current state of RWE studies and publications on weight loss, identify the range of weight loss components being used in RWE programs, and to provide a general overview of the consistency or lack of consistency with regard to measuring and reporting outcomes. Methods: A structured search of PubMed was performed to identify relevant English-language publications from 2006 to December 2017 that reported real-world studies of weight loss among adults. Duplicates, non-relevant publications, articles on weight loss surgery, pediatric studies, randomized controlled trials, studies with self-reported weight loss, no objective weight measures, or that failed to include weight loss results were excluded. Results: This review included 62 RWE publications. Forty-nine studies included dietary intervention, 37 included exercise, 29 included motivational counseling, and 5 contained some patients who had pharmacologic treatment as part of their weight loss regimen. The numbers of participants per study ranged from 10 to more than 3 million. The interventions reported in the publications included diet, exercise, counseling to promote diet and/or exercise, motivational counseling, and pharmacotherapy, and various combinations of these. Conclusions: Despite general acceptance that weight loss programs are capable of facilitating successful outcomes, this review revealed substantial inconsistency in the design and reporting of such programs, making it very difficult to draw conclusions about the comparative merits of different real-world weight loss strategies/components. In addition, there was a marked lack of congruence with current weight loss management guidelines, and notably few studies incorporating anti-obesity medications. There clearly is a need for greater rigor and standardization among designing and reporting RWE weight-loss studies.
Formation and Evolution of aqSOA from Aqueous-Phase Reactions of Phenolic Carbonyls: Comparison between Ammonium Sulfate and Ammonium Nitrate Solutions.

We investigate the effects of sulfate and nitrate on the formation and evolution of secondary organic aerosol formed in the aqueous phase (aqSOA) from photooxidation of two phenolic carbonyls emitted from wood burning. AqSOA was formed efficiently from the photooxidation of both syringaldehyde (C9H10O4) and acetosyringone (C10H12O4) in ammonium sulfate and ammonium nitrate solutions, with mass yields ranging from 30% to 120%. Positive matrix factorization on the organic mass spectra acquired by an Aerosol Mass Spectrometer revealed a combination of functionalization, oligomerization, and fragmentation processes in the chemical evolution of aqSOA. Functionalization and oligomerization dominated in the first 4 h of reaction, with phenolic oligomers and their derivatives significantly contributing to aqSOA formation; and oxidation of the first-generation products led to an abundance of oxygenated ring-opening products. Degradation rates of syringaldehyde and acetosyringone in nitrate solutions were 1.5 and 3.5 times faster than rates in sulfate solutions, and aqSOA yields in nitrate experiments are twice as high as in sulfate experiments. Nitrate likely promoted the reactions because it is a photolytic source of OH radicals, while sulfate is not, highlighting the importance of aerosol-phase nitrate in the formation of aqSOA by facilitating the photooxidation of organic precursors.
Network Approximation using Tensor Sketching

Deep neural networks are powerful learning models that achieve state-of-the-art performance on many computer vision, speech, and language processing tasks. In this paper, we study a fundamental question that arises when designing deep network architectures: Given a target network architecture can we design a `smaller' network architecture that 'approximates' the operation of the target network? The question is, in part, motivated by the challenge of parameter reduction (compression) in modern deep neural networks, as the ever increasing storage and memory requirements of these networks pose a problem in resource constrained environments.In this work, we focus on deep convolutional neural network architectures, and propose a novel randomized tensor sketching technique that we utilize to develop a unified framework for approximating the operation of both the convolutional and fully connected layers. By applying the sketching technique along different tensor dimensions, we design changes to the convolutional and fully connected layers that substantially reduce the number of effective parameters in a network. We show that the resulting smaller network can be trained directly, and has a classification accuracy that is comparable to the original network.
Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response

Abstract A fundamental as yet incompletely understood feature of Notch signal transduction is a transcriptional shift from repression to activation that depends on chromatin regulation mediated by transcription factor RBP-J and associated cofactors. Incorporation of histone variants alter the functional properties of chromatin and are implicated in the regulation of gene expression. Here, we show that depletion of histone variant H2A.Z leads to upregulation of canonical Notch target genes and that the H2A.Z-chaperone TRRAP/p400/Tip60 complex physically associates with RBP-J at Notch-dependent enhancers. When targeted to RBP-J-bound enhancers, the acetyltransferase Tip60 acetylates H2A.Z and upregulates Notch target gene expression. Importantly, the Drosophila homologs of Tip60, p400 and H2A.Z modulate Notch signaling response and growth in vivo. Together, our data reveal that loading and acetylation of H2A.Z are required to assure tight control of canonical Notch activation.
Preconception Hb concentration and risk of preterm birth in over 2·7 million Chinese women aged 20–49 years: a population-based cohort study

Abstract Evidence on the association between maternal Hb concentration and preterm birth (PTB) risk is inconclusive. This paper aimed to explore whether women with anaemia or high Hb level before pregnancy would be at higher risk of PTB. We conducted a population-based cohort study with 2 722 274 women aged 20–49 years, who participated in National Free Pre-Pregnancy Checkups Project between 2013 and 2015 and delivered a singleton before 2016 in rural China. Logistic models were used to estimate OR and 95 % CI after adjusting for confounding variables. Restricted cubic spline models were applied to evaluate the dose–response relationships. A total of 192 819 (7·08 %) women had preterm deliveries. Compared with women with Hb of 110–149 g/l, the multivariable-adjusted OR for PTB was 1·19 (95 % CI 0·98, 1·44) for women with Hb<70 g/l, 1·01 (95 % CI 0·97, 1·03) for 70–99 g/l, 0·96 (95 % CI 0·95, 0·98) for 100–109 g/l, 1·04 (95 % CI 1·01, 1·06) for 150–159 g/l, 1·11 (95 % CI 1·05, 1·17) for 160–169 g/l and 1·19 (95 % CI 1·11, 1·27) for ≥170 g/l, respectively. The multivariable-adjusted OR for very PTB (VPTB) was 1·07 (95 % CI 1·03, 1·12) and 1·06 (95 % CI 1·01, 1·12) for women with Hb <110 and ≥150 g/l, compared with those with Hb of 110–149 g/l, respectively. Our study identified a U-shaped relationship between maternal preconception Hb concentration and PTB risk. Both preconception anaemia and high Hb level can significantly increase VPTB risk. Appropriate intervention for women with abnormal Hb levels before pregnancy is very necessary.
Application of Federal Kalman Filter with Neural Networks in the Velocity and Attitude Matching of Transfer Alignment

The centralized Kalman filter is always applied in the velocity and attitude matching of Transfer Alignment (TA). But the centralized Kalman has many disadvantages, such as large amount of calculation, poor real-time performance, and low reliability. In the paper, the federal Kalman filter (FKF) based on neural networks is used in the velocity and attitude matching of TA, the Kalman filter is adjusted by the neural networks in the two subfilters, the federal filter is used to fuse the information of the two subfilters, and the global suboptimal state estimation is obtained. The result of simulation shows that the federal Kalman filter based on neural networks is better in estimating the initial attitude misalignment angle of inertial navigation system (INS) when the system dynamic model and noise statistics characteristics of inertial navigation system are unclear, and the estimation error is smaller and the accuracy is higher.
Comparison of nine platelet function tests used to determine responses to different aspirin dosages in people with type 2 diabetes

Abstract The antiplatelet efficacy of aspirin (ASA) is reduced in type 2 diabetes (T2D). As the best ex vivo method of measuring ASA efficacy remains uncertain, we compared nine platelet function tests to assess responsiveness to three ASA dosing regimens in 24 T2D patients randomized in a three-treatment crossover design to ASA 100 mg/day, 200 mg/day, or 100 mg twice daily for 2-week treatment periods. Platelet function tests compared were as follows: light transmission aggregometry (LTA)–0.5 mg/mL of arachidonic acid (AA) and 10 µM adenosine diphosphate (ADP); multiplate whole blood aggregometry (WBA)–0.5 mM AA and 6.5 µM ADP; platelet function analyzer (PFA)-100™–collagen and ADP (CADP) and collagen and epinephrine (CEPI); VerifyNow™–ASA; and urinary 11-dehydro-thromboxane B2 (TxB2) and serum TxB2. All cyclo-oxygenase (COX-1)-dependent tests and some COX-1-independent tests (PFA-CEPI, LTA-ADP) demonstrated significant reductions in platelet reactivity with all ASA doses. Two COX-1-independent tests (WBA-ADP and PFA-CADP) showed no overall reduction in platelet reactivity. Overall classifications for detecting all ASA doses, compared to baseline, were as follows: very good–LTA-AA (k = 0.95) and VerifyNow™-ASA (k = 0.85); good–serum TxB2 (k = 0.79); moderate–LTA-ADP (k = 0.59), PFA-100™-CEPI (k = 0.56), urinary TxB2 (k = 0.55), WBA-AA (k = 0.47); and poor–PFA-100™-CADP (k = –0.02) and WBA-ADP (k = –0.07). No significant kappa statistic differences were seen for each test for each ASA dose. Correlations for each test with serum TxB2 measurements were as follows: very good–VerifyNow™-ASA (k = 0.81, R2 = 0.56) and LTA-AA (k = 0.85, R2 = 0.65); good–PFA-100TM-CEPI (k = 0.62, R2 = 0.30); moderate–urinary TxB2 (k = 0.57, R2 = 0.51) and LTA-ADP (k = 0.47, R2 = 0.56); fair–WBA-AA (k = 0.31, R2 = 0.31); and poor–PFA-100™-CADP (k = 0.04, R2 = 0.003) and WBA-ADP (k = –0.04, R2 = 0.0005). The platelet function tests we assessed were not equally effective in measuring the antiplatelet effect of ASA and correlated poorly amongst themselves, but COX-1-dependent tests performed better than non-COX-1-dependent tests.
Iodine Status and Consumption of Key Iodine Sources in the U.S. Population with Special Attention to Reproductive Age Women

We estimated iodine status (median urinary iodine concentration (mUIC (µg/L))) for the US population (6 years and over; n = 4613) and women of reproductive age (WRA) (15–44 years; n = 901). We estimated mean intake of key iodine sources by race and Hispanic origin. We present the first national estimates of mUIC for non-Hispanic Asian persons and examine the intake of soy products, a potential source of goitrogens. One-third of National Health and Nutrition Examination Survey (NHANES) participants in 2011–2014 provided casual urine samples; UIC was measured in these samples. We assessed dietary intake with one 24-h recall and created food groups using the USDA’s food/beverage coding scheme. For WRA, mUIC was 110 µg/L. For both non-Hispanic white (106 µg/L) and non-Hispanic Asian (81 µg/L) WRA mUIC was significantly lower than mUIC among Hispanic WRA (133 µg/L). Non-Hispanic black WRA had a mUIC of 124 µg/L. Dairy consumption was significantly higher among non-Hispanic white (162 g) compared to non-Hispanic black WRA (113 g). Soy consumption was also higher among non-Hispanic Asian WRA (18 g compared to non-Hispanic black WRA (1 g). Differences in the consumption pattern of key sources of iodine and goitrogens may put subgroups of individuals at risk of mild iodine deficiency. Continued monitoring of iodine status and variations in consumption patterns is needed.
Interleukin-33: Its Emerging Role in Allergic Diseases

Allergic diseases, which include asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS), atopic dermatitis (AD), food allergy (FA), allergic keratoconjunctivitis, seriously affect the quality of life of people all over the world. Recently, interleukin-33 (IL-33) has been found to play an important role in these refractory disorders, mainly by inducing T helper (Th) 2 immune responses. This article reviews the mobilization and biological function of IL-33 in allergic disorders, providing novel insights for addressing these hypersensitive conditions.
Gender and Handedness Prediction from Offline Handwriting Using Convolutional Neural Networks

Demographic handwriting-based classification problems, such as gender and handedness categorizations, present interesting applications in disciplines like Forensic Biometrics. This work describes an experimental study on the suitability of deep neural networks to three automatic demographic problems: gender, handedness, and combined gender-and-handedness classifications, respectively. Our research was carried out on two public handwriting databases: the IAM dataset containing English texts and the KHATT one with Arabic texts. The considered problems present a high intrinsic difficulty when extracting specific relevant features for discriminating the involved subclasses. Our solution is based on convolutional neural networks since these models had proven better capabilities to extract good features when compared to hand-crafted ones. Our work also describes the first approach to the combined gender-and-handedness prediction, which has not been addressed before by other researchers. Moreover, the proposed solutions have been designed using a unique network configuration for the three considered demographic problems, which has the advantage of simplifying the design complexity and debugging of these deep architectures when handling related handwriting problems. Finally, the comparison of achieved results to those presented in related works revealed the best average accuracy in the gender classification problem for the considered datasets.
Approval-Based Multi-Winner Rules and Strategic Voting

We investigate the possibility of strategic voting in approval-based multiwinner rules. In particular, we define three axiomatic properties that guarantee resilience to certain forms of strategic voting: independence of irrelevant alternatives (IIA), monotonicity, and SD-strategyproofness. In this paper, we systematically analyze multiwinner rules based on these axioms and provide a fine-grained picture of their resilience to strategic voting. Both our axiomatic and experimental analysis show that approval-based multiwinner rules are generally very susceptible to strategic voting---with one exception: multiwinner approval voting.
Distribution of Tetrodotoxin in the New Zealand Clam, Paphies australis, Established Using Immunohistochemistry and Liquid Chromatography-Tandem Quadrupole Mass Spectrometry

Tetrodotoxin (TTX) is one of the most potent neurotoxins known. It was originally thought to only occur in puffer fish but has now been identified in twelve different classes of freshwater and marine organisms, including bivalves. Despite being one of the world’s most studied biotoxins, its origin remains uncertain. There is contradictory evidence regarding the source of TTX and its pathway through food webs. To date, the distribution of TTX has not been examined in bivalves. In the present study, 48 Paphies australis, a TTX-containing clam species endemic to New Zealand, were collected. Thirty clams were dissected, and organs and tissues pooled into five categories (siphons, digestive gland, adductor muscles, and the ‘rest’) and analyzed for TTX using liquid chromatography-mass spectrometry (LC-MS). The micro-distribution of TTX was visualized in the remaining 18 individuals using an immunohistological technique incorporating a TTX-specific monoclonal antibody. The LC-MS analysis revealed that siphons contained the highest concentrations of TTX (mean 403.8 µg/kg). Immunohistochemistry analysis showed TTX in the outer cells of the siphons, but also in the digestive system, foot, and gill tissue. Observing TTX in organs involved in feeding provides initial evidence to support the hypothesis of an exogenous source in P. australis.