Miracle-dz/UniFAR-FTUs huggingface dataset:
Loss of β-adrenergic–stimulated phosphorylation of CaV1.2 channels on Ser1700 leads to heart failure

Significance Calcium entry initiates contraction in cardiac myocytes, and altered expression of voltage-gated calcium channel 1.2 (CaV1.2) causes heart failure in mice. Here we show that reducing β-adrenergic regulation of CaV1.2 by mutation of a PKA site in the C-terminal domain causes age-related heart failure. Dual mutation of a nearby casein-kinase II phosphorylation site accelerated heart failure. The PKA level was increased; PKA-mediated phosphorylation of ryanodine receptor type-2, phospholamban, and troponin-I was increased; the calcium pool in the sarcoplasmic reticulum was increased; and the activity of the calcium-dependent phosphoprotein phosphatase calcineurin was persistently elevated. These changes in mice with a mutation at the PKA site Ser1700 (SA mice) suggest that compensatory mechanisms may initially enhance contractility but eventually cause increased sensitivity to cardiovascular stress and heart failure. L-type Ca2+ currents conducted by voltage-gated calcium channel 1.2 (CaV1.2) initiate excitation–contraction coupling in the heart, and altered expression of CaV1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of CaV1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the CaV1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of CaV1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.
TwitterSensing: An Event-Based Approach for Wireless Sensor Networks Optimization Exploiting Social Media in Smart City Applications

Modern cities are subject to periodic or unexpected critical events, which may bring economic losses or even put people in danger. When some monitoring systems based on wireless sensor networks are deployed, sensing and transmission configurations of sensor nodes may be adjusted exploiting the relevance of the considered events, but efficient detection and classification of events of interest may be hard to achieve. In Smart City environments, several people spontaneously post information in social media about some event that is being observed and such information may be mined and processed for detection and classification of critical events. This article proposes an integrated approach to detect and classify events of interest posted in social media, notably in Twitter, and the assignment of sensing priorities to source nodes. By doing so, wireless sensor networks deployed in Smart City scenarios can be optimized for higher efficiency when monitoring areas under the influence of the detected events.
Fewer Flops at the Top: Accuracy, Diversity, and Regularization in Two-Class Collaborative Filtering

In most existing recommender systems, implicit or explicit interactions are treated as positive links and all unknown interactions are treated as negative links. The goal is to suggest new links that will be perceived as positive by users. However, as signed social networks and newer content services become common, it is important to distinguish between positive and negative preferences. Even in existing applications, the cost of a negative recommendation could be high when people are looking for new jobs, friends, or places to live. In this work, we develop novel probabilistic latent factor models to recommend positive links and compare them with existing methods on five different openly available datasets. Our models are able to produce better ranking lists and are effective in the task of ranking positive links at the top, with fewer negative links (flops). Moreover, we find that modeling signed social networks and user preferences this way has the advantage of increasing the diversity of recommendations. We also investigate the effect of regularization on the quality of recommendations, a matter that has not received enough attention in the literature. We find that regularization parameter heavily affects the quality of recommendations in terms of both accuracy and diversity.
All-optical graphene modulator based on optical Kerr phase shift

Graphene-based optical modulators have recently attracted much attention because of their characteristic ultrafast and broadband response. Their modulation depth (MD) and overall transmittance (OT), however, are often limited by optical loss arising from interband transitions. We report here an all-optical, all-fiber optical modulator with a Mach–Zehnder interferometer structure that has significantly higher MD and OT than graphene-based loss modulators. It is based on the idea of converting optically induced phase modulation in the graphene-cladded arm of the interferometer to intensity modulation at the output of the interferometer. The device has the potential to be integrable into a photonic system in real applications.
Calcium-Sensing Receptor and Transient Receptor Ankyrin-1 Mediate Emesis Induction by Deoxynivalenol (Vomitoxin)

The common foodborne mycotoxin deoxynivalenol (DON, vomitoxin) can negatively impact animal and human health by causing food refusal and vomiting. Gut enteroendocrine cells (EECs) secrete hormones that mediate DON’s anorectic and emetic effects. In prior work utilizing a cloned EEC model, our laboratory discovered that DON-induced activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor (GPCR), and transient receptor ankyrin-1 (TRPA1), a transient receptor potential (TRP) channel, drives Ca2+-mediated hormone secretion. Consistent with these in vitro findings, CaSR and TRPA1 mediate DON-induced satiety hormone release and food refusal in the mouse, an animal model incapable of vomiting. However, the roles of this GPCR and TRP in DON’s emetic effects remain to be determined. To address this, we tested the hypothesis that DON triggers emesis in mink by activating CaSR and TRPA1. Oral gavage with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate; AITC) rapidly elicited emesis in the mink in dose-dependent fashion. Oral pretreatment of the animals with the CaSR antagonist NPS-2143 or the TRP antagonist ruthenium red (RR), respectively, inhibited these responses. Importantly, DON-induced emesis in mink was similarly inhibited by oral pretreatment with NPS-2143 or RR. In addition, these antagonists suppressed concurrent DON-induced elevations in plasma peptide YY3-36 and 5-hydroxytryptamine—hormones previously demonstrated to mediate the toxin’s emetic effects in mink. Furthermore, antagonist co-treatment additively suppressed DON-induced emesis and peptide YY 3-36 release. To summarize, the observations here strongly suggest that activation of CaSR and TRPA1 might have critical roles in DON-induced emesis.
Northridge earthquake rupture models based on the global positioning system measurements

We use global positioning system (GPS) data to study the rupture mechanism of the 1994 Northridge earthquake in southern California. We include data from 62 observation sites, of which two (Palos Verdes and Jet Propulsion Lab) are permanent GPS geodetic array (PGGA) sites. We use a grid-search scheme to study the range of single- and dual-plane, uniform and varied slip models consistent with the data. We find that in order to fit the geodetic data with a fault model whose primary fault patch is confined to a plane through the aftershocks, a secondary fault plane is required above the primary fault plane. The moment release of the secondary fault can be as large as 1.9 × 1018 N-m, 14% of the moment release of the primary fault. This result implies significant deformation in the shallow crust associated with the mainshock. Our preferred model has a 14 × 14 array of dislocation patches on a plane through the main aftershock cluster and a 5 × 6 array of patches in the hanging wall west of the epicenter. We estimate the displacements on the patches by linear inversion with a first-order smoothness constraint. The estimated displacements on the main fault for this model are confined to a simple region between depths of 5 and 18 km, in the interior of the modeled fault surface. The mainshock lies at the bottom of the aftershock zone, near which about 1-m slip is shown on our modeled fault surface. The maximum slip on the fault surface is about 2.2 m, located at 34.28° N, 118.55° W, and 12.4 km at depth. The seismic moment release estimate of 1.34 ± 0.15 × 1019 N-m on the main fault at the 95% confidence is consistent with the estimate from strong-motion studies.
Denoised Maximum Likelihood Estimation of Chest Wall Displacement from the IR-UWB Spectrum

We present a novel method of estimating the chest wall displacement in the frequency domain from a narrow portion of the IR-UWB radar received spectrum. A Maximum Likelihood (ML) estimator of the displacement is designed, and the associated bias and Cramér-Rao lower bound of the ML estimator are analyzed. To improve estimation accuracy, empirical mode decomposition is applied to denoise the ML-estimated displacement. Simulation studies are conducted to evaluate the performance of the proposed method under realistic system parameter values. The computational complexity of the proposed method is low and equal to that of the Discrete Fourier Transform.
Family Assessment Device: Real-World Validity in Urban Families of Children With Asthma

Ecological momentary assessment (EMA) was used to further validate the real-world predictability of the Family Assessment Device (FAD) among low income, racial and ethnic minority, urban families of children (7–12 years) with asthma. Caregivers completed self-report measures at baseline, as well as daily assessments of family functioning for 2 weeks through EMA delivered via smartphone. Concurrent validity was established with measures of caregiver perceived stress and positive and negative affect at baseline. Better family functioning at baseline was associated with EMA reports of families getting along better and of being better able to balance multiple family needs, including child asthma management. Consistent with previous literature, findings suggest the FAD is an ecologically valid measure for use with urban families of children with asthma. Researchers and clinicians may be confident that assessments of family functioning in research and clinical settings are predictive of what may be happening in the family’s everyday life.
"Recovery Speaks": A Photovoice Intervention to Reduce Stigma Among Primary Care Providers.

OBJECTIVE Preliminary findings are reported from a photovoice intervention, "Recovery Speaks," to reduce primary care provider stigma in regard to people with mental illness and addiction. METHODS Twenty-seven primary care providers were recruited through a practice-based research network. Participants were randomly assigned to the intervention-attending a one-hour performance followed by discussion-or to no intervention. Provider stigma was evaluated by using established measures of stigma and recovery and qualitative responses. Linear mixed models controlling for baseline differences compared changes in provider stigma across time and groups. RESULTS Providers who attended Recovery Speaks demonstrated significantly decreased negative stereotypes, attribution of dangerousness, fear, desire to coerce people into treatment, desire to segregate people from the community, and desire for avoidance. More desire to help and more hope for recovery were also found. CONCLUSIONS Witnessing people's unique recovery stories and how they contribute to their communities may reduce provider stigma.
Gene copy number alteration profile and its clinical correlation in B-cell acute lymphoblastic leukemia

Abstract The genes related to B-cell development are frequently altered in B-cell acute lymphoblastic leukemia (B-ALL). One hundred sixty-two newly diagnosed B-ALL cases, median age 8.5 years (2 months–67 years), were prospectively analyzed for copy number alterations (CNAs) in CDKN2A/B, IKZF1, PAX5, RB1, ETV6, BTG1, EBF1, and pseudoautosomal region genes (CRLF2, CSF2RA, IL3RA) using multiplex ligation-dependent probe amplification. The CNAs were detected in 114 (70.4%) cases; most commonly affected genes being CDKN2A/B-55 (34%), PAX5-51 (31.5%), and IKZF1-43 (26.5%). IKZF1 and RB1 deletions correlated with higher induction failure. Patients classified as good-risk, according to the integrated CNA profile and cytogenetic criteria, had lower induction failure [5 (8.6%) vs. 20 (25.3%); p = 0.012]. Those classified as good-risk, based on CNA profile irrespective of cytogenetics, also showed lower induction failure [6 (9.4%) vs. 19 (26%); p = 0.012]. The CNA profile identified patients with better induction outcome and has a potential role in better risk stratification of B-ALL.
Brain Structure Linking Delay Discounting and Academic Performance

As a component of self‐discipline, delay discounting refers to the ability to wait longer for preferred rewards and plays a pivotal role in shaping students’ academic performance. However, the neural basis of the association between delay discounting and academic performance remains largely unknown. Here, we examined the neuroanatomical substrates underlying delay discounting and academic performance in 214 adolescents via voxel‐based morphometry (VBM) by performing structural magnetic resonance imaging (S‐MRI). Behaviorally, we confirmed the significant correlation between delay discounting and academic performance. Neurally, whole‐brain regression analyses indicated that regional gray matter volume (rGMV) of the left dorsolateral prefrontal cortex (DLPFC) was associated with both delay discounting and academic performance. Furthermore, delay discounting partly accounted for the association between academic performance and brain structure. Differences in the rGMV of the left DLPFC related to academic performance explained over one‐third of the impact of delay discounting on academic performance. Overall, these results provide the first evidence for the common neural basis linking delay discounting and academic performance. Hum Brain Mapp 38:3917–3926, 2017. © 2017 Wiley Periodicals, Inc.
Evolutionary mechanisms that generate morphology and neural‐circuit diversity of the cerebellum

The cerebellum is derived from the dorsal part of the anterior‐most hindbrain. The vertebrate cerebellum contains glutamatergic granule cells (GCs) and gamma‐aminobutyric acid (GABA)ergic Purkinje cells (PCs). These cerebellar neurons are generated from neuronal progenitors or neural stem cells by mechanisms that are conserved among vertebrates. However, vertebrate cerebella are widely diverse with respect to their gross morphology and neural circuits. The cerebellum of cyclostomes, the basal vertebrates, has a negligible structure. Cartilaginous fishes have a cerebellum containing GCs, PCs, and deep cerebellar nuclei (DCNs), which include projection neurons. Ray‐finned fish lack DCNs but have projection neurons termed eurydendroid cells (ECs) in the vicinity of the PCs. Among ray‐finned fishes, the cerebellum of teleost zebrafish has a simple lobular structure, whereas that of weakly electric mormyrid fish is large and foliated. Amniotes, which include mammals, independently evolved a large, foliated cerebellum, which contains massive numbers of GCs and has functional connections with the dorsal telencephalon (neocortex). Recent studies of cyclostomes and cartilaginous fish suggest that the genetic program for cerebellum development was already encoded in the genome of ancestral vertebrates. In this review, we discuss how alterations of the genetic and cellular programs generated diversity of the cerebellum during evolution.
Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy

Abstract Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofatumumab pharmacokinetics. Trial registration: www.clinicaltrials. gov (NCT00410163).
Force matters in hospital-acquired infections

Extremely strong forces help staphylococci to colonize biomaterials and infect humans Bacterial pathogens show a remarkable capacity to stick to host tissues and implanted biomaterials, grow, and form biofilms on these surfaces (1). These multicellular communities protect the bacteria from the host immune system and from drugs, thereby causing infections that are difficult to eradicate. Today, biofilms are estimated to be involved in half of all infections acquired in hospitals. On page 1527 of this issue, Milles et al. (2) combine single-molecule experiments and molecular dynamics simulations to study the forces involved in the adhesion of bacterial pathogens to host proteins, the first step of biofilm formation.
Reactive glia promote development of CD103+CD69+ CD8+ T‐cells through programmed cell death‐ligand 1 (PD‐L1)

Previous work from our laboratory has demonstrated in vivo persistence of CD103+CD69+ brain resident memory CD8+ T‐cells (bTRM) following viral infection, and that the PD‐1: PD‐L1 pathway promotes development of these TRM cells within the brain. Although glial cells express low basal levels of PD‐L1, its expression is upregulated upon IFN‐γ‐treatment, and they have been shown to modulate antiviral T‐cell effector responses through the PD‐1: PD‐L1 pathway.
Chain of Trust: Can Trusted Hardware Help Scaling Blockchains?

As blockchain systems proliferate, there remains an unresolved scalability problem of their underlying distributed consensus protocols. Byzantine Fault Tolerance (BFT) consensus protocols offer high transaction throughput, but can only support small networks. Proof-of-Work (PoW) consensus protocol, on the other hand, can support thousands of nodes, but at the expense of poor transaction throughput. Two potential approaches to address these scalability barriers are by relaxing the threat model, or employing sharding technique to deal with large networks. Nonetheless, their effectiveness against data-intensive blockchain workloads remains to be seen. In this work, we study the use and effectiveness of trusted hardware on scaling distributed consensus protocols, and by their extension, blockchain systems. We first analyze existing approaches that harness trusted hardware to enhances scalability, and identify their limitations. Drawing insights from these results, we propose two design principles, namely scale up by scaling down and prioritize consensus messages, that enable the consensus protocols to scale. We illustrate the two principles by presenting optimizations that improve upon state-of-the-art solutions, and demonstrate via our extensive evaluations that they indeed offer better scalability. In particular, integrating our optimizations into Hyperledger Fabric achieves up to 7x higher throughput, while enabling the system to remain operational as the network size increases. Another optimization that we introduce to Hyperledger Sawtooth allows the system to sustain high throughput as the network grows. Finally, our new design for sharding protocols reduces the cost of shard creation phase by upto 35x.
Wireless powering of mm-scale fully-on-chip neural interfaces

This paper presents guidelines for the design and optimization of on-chip coils used for wirelessly-powered mm-scale neural implants. Since available real estate is limited, on-chip coil design involves managing difficult trade-offs between the number of turns, trace width and spacing, proximity to other active circuits and metalization, quality factor, matching network performance/size, and load impedance conditions, all towards achieving high power transfer efficiency. To illustrate the design optimization procedure, a 3 × 3 mm2 on-chip coil is designed, and measurement results reveal a 3.82 % power transfer efficiency for a 1.6 kΩ load that mimics a 100 μW neural interface.
High-Performance GPU Transactional Memory via Eager Conflict Detection

GPUs transactional memory (TM) proposals to date have relied on lazy, value-based conflict detection, assuming that GPUs can amortize the latency by executing other warps. In practice, however, concurrency must be throttled to a few warps per core to avoid high abort rates, and TM performance has remained far below that of fine-grained locks. We trace this to the latency cost of validating transactions: two round trips across the crossbar required for most commits and aborts. With limited concurrency, the warp scheduler cannot amortize this, and leaves the core idle most of the time. In this paper, we show that value-based validation does not scale to high thread counts, and eager conflict detection becomes more efficient as the number of threads grows. We leverage this insight to propose GETM, a GPU TM with eager conflict detection. GETM relies on a novel distributed logical clock scheme to implement eager conflict detection without the need for cache coherence or signature broadcasts. GETM is up to 2.1 times faster than the state-of-the art prior work WarpTM (gmean 1.2 times), with 3.6 times lower silicon area overheads and 2.2 times lower power overheads.