bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Safety of a Fixed-Dose Combination Therapy of Tamsulosin and Tadalafil for Patients with Lower Urinary Tract Symptoms and Erectile Dysfunction: Results of a Randomized, Double-Blinded, Active-Controlled Trial
Authors: Kim Sae Woong , Park Nam Cheol , Lee Seung Wook , Yang Dae Yul , Park Jong Kwan , Moon Du Geon , Yang Sang-Kuk , Lee Sung Won , Moon Ki Hak , Ahn Tai Young , Kim Soo Woong , Park Kwangsung , Min Kweon Sik , Ryu Ji-Kan , Son Hankil , Jung Jina , Hyun Jae Seog
Published: July 2017

Background

Phosphodiesterase type 5 inhibitors and α-adrenergic blocking agents (α-blockers) are widely used for the treatment of erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

Aims

To assess the efficacy and safety of fixed-dose combinations (FDCs) of tamsulosin and tadalafil compared with tadalafil monotherapy in patients with comorbid BPH-associated LUTS and ED.

Methods

A randomized, double-blinded, active-controlled trial was conducted of 510 men with BPH-associated LUTS and ED. Patients were treated with FDCs of tamsulosin 0.4 mg plus tadalafil 5 mg (FDC 0.4/5 mg), tamsulosin 0.2 mg plus tadalafil 5 mg (FDC 0.2/5 mg), or tadalafil 5 mg for a 12-week treatment period. For a subsequent 12-week extension period, the patients were administered FDC 0.4/5 mg.

Outcomes

The primary outcomes were changes from baseline in total International Prostate Symptom Score (IPSS) and International Index of Erectile Function erectile function domain (IIEF-EF) score at week 12 to prove superiority and non-inferiority of FDCs compared with tadalafil 5 mg. The safety assessments were adverse reactions, laboratory test results, and vital signs at week 24.

Results

The mean changes in total IPSS and IIEF-EF scores were −9.46 and 9.17 for FDC 0.4/5 mg and −8.14 and 9.49 for tadalafil 5 mg, respectively, which indicated superiority in LUTS improvement (P = .0320) and non-inferiority in ED treatment with FDC 0.4/5 mg compared with tadalafil 5 mg. However, the results from FDC 0.2/5 mg failed to demonstrate superiority in LUTS improvement. No clinically significant adverse events regarding the investigational products were observed during the 24-week period.

Clinical Implications

The FDC 0.4/5 mg is the first combined formulation of an α-blocker and a phosphodiesterase type 5 inhibitor that offers benefits in patient compliance and as add-on therapy in patients with comorbid BPH-associated LUTS and ED.

Strengths and Limitations

The study clearly demonstrated the advantage of FDC 0.4/5 mg. The main advantage of FDC 0.4/5 mg was the enhanced efficacy on BPH-associated LUTS comorbidity with ED, the lower incidence of side effects, and the simplification and convenience of therapy, which led to better overall patient compliance. However, the lack of a tamsulosin monotherapy control group was a limitation of this study.

Conclusion

The FDC 0.4/5 mg therapy was safe, well tolerated, and efficacious, indicating that combination therapy could provide clinical benefits for patients with BPH-associated LUTS complaints and ameliorate the comorbidity of ED.
Deciphering the regulation of metabolism with dynamic optimization: an overview of recent advances
Authors: Ewald Jan , Bartl Martin , Kaleta Christoph
Published: July 2017

Understanding optimality principles shaping the evolution of regulatory networks controlling metabolism is crucial for deriving a holistic picture of how metabolism is integrated into key cellular processes such as growth, adaptation and pathogenicity. While in the past the focus of research in pathway regulation was mainly based on stationary states, more recently dynamic optimization has proved to be an ideal tool to decipher regulatory strategies for metabolic pathways in response to environmental cues. In this short review, we summarize recent advances in the elucidation of optimal regulatory strategies and identification of optimal control points in metabolic pathways. We discuss biological implications of the discovered optimality principles on genome organization and provide examples how the derived knowledge can be used to identify new treatment strategies against pathogens. Furthermore, we briefly discuss the variety of approaches for solving dynamic optimization problems and emphasize whole-cell resource allocation models as an important emerging area of research that will allow us to study the regulation of metabolism on the whole-cell level.
Cardiovascular susceptibility to in vivo ischemic myocardial injury in male and female rat offspring exposed to prenatal hypoxia
Authors: Shah Amin , Matsumura Nobutoshi , Quon Anita , Morton Jude S. , Dyck Jason R.B. , Davidge Sandra T.
Published: July 2017

Intrauterine growth restriction (IUGR) following prenatal hypoxia exposure leads to a higher risk of developing cardiovascular disease (CVD) in later life. Our aim was to evaluate cardiac susceptibility and its pathophysiological mechanisms following acute myocardial infarction (MI) in adult rat offspring exposed to prenatal hypoxia. Male and female rat offspring, which experienced normoxia (21% O2) or hypoxia (11% O2) in utero underwent sham or MI surgery at 12 weeks of age. Echocardiographic data revealed that both sexes had systolic dysfunction following MI surgery, independent of prenatal hypoxia. Male offspring exposed to prenatal hypoxia, however, had left ventricular dilatation, global dysfunction, and signs of diastolic dysfunction following MI surgery as evident by increased left ventricular internal diameter (LVID) during diastole (MI effect, P<0.01), Tei index (MI effect, P<0.001), and E/E′ ratio (prenatal hypoxia or MI effect, P<0.01). In contrast, diastolic dysfunction in female offspring was not as evident. Cardiac superoxide levels increased only in prenatal hypoxia exposed male offspring. Cardiac sarcoendoplasmic reticulum Ca2+-ATPase2a (SERCA2a) levels, a marker of cardiac injury and dysfunction, decreased in both male and female MI groups independent of prenatal hypoxia. Prenatal hypoxia increased cardiac ryanodine receptor 2 (RYR2) protein levels, while MI reduced RYR2 in only male offspring. In conclusion, male offspring exposed to prenatal hypoxia had an increased susceptibility to ischemic myocardial injury involving cardiac phenotypes similar to heart failure involving diastolic dysfunction in adult life compared with both offspring from healthy pregnancies and their female counterparts.
PD FPR CP high‐gain MIMO antenna
Authors: Karamzadeh S. , Rafiei V. , Saygin H.
Published: July 2017

A novel configuration of a Fabry–Perot resonator (FPR) antenna for C band application, which produces a high gain, wider impedance and 3‐dB axial ratio bandwidth is presented. Radiation element of the antenna is a square patch coupled with four points of crossed aperture. A feed network can change the rotation of the phase in aperture points and, by this technique, change the polarisation diversity (PD). This antenna is capable of variation circularly PD by changing the input port, also partially of the reflective surface which plays as the role of FPR resonator due to the structure and arrangement of cells capable of changing the PD. Experimental results clarify that the FPR antenna covers the impedance bandwidth of 4–6 for S11 ≤ −10 dB. Furthermore, the proposed antenna approximately has a constant gain from 4.4–7.5 GHz with a peak value of 18.1 dBic for each of the input ports. The antenna covers 3 dB axial‐ratio bandwidth, between 4.35–7.85 GHz.
Towards X‐ray free endovascular interventions – using HoloLens for on‐line holographic visualisation
Authors: Kuhlemann Ivo , Kleemann Markus , Jauer Philipp , Schweikard Achim , Ernst Floris
Published: July 2017

A major challenge during endovascular interventions is visualising the position and orientation of the catheter being inserted. This is typically achieved by intermittent X‐ray imaging. Since the radiation exposure to the surgeon is considerable, it is desirable to reduce X‐ray exposure to the bare minimum needed. Additionally, transferring two‐dimensional (2D) X‐ray images to 3D locations is challenging. The authors present the development of a real‐time navigation framework, which allows a 3D holographic view of the vascular system without any need of radiation. They extract the patient's surface and vascular tree from pre‐operative computed tomography data and register it to the patient using a magnetic tracking system. The system was evaluated on an anthropomorphic full‐body phantom by experienced clinicians using a four‐point questionnaire. The average score of the system (maximum of 20) was found to be 17.5. The authors’ approach shows great potential to improve the workflow for endovascular procedures, by simultaneously reducing X‐ray exposure. It will also improve the learning curve and help novices to more quickly master the required skills.
Exact throughput analysis of random cooperative medium access control networks in the presence of shadowing
Authors: Nikbakht Homa , Rabiei Amir Masoud , Shah‐Mansouri Vahid
Published: July 2017

The throughput performance of a random cooperative medium access control (CoopMAC) network in the presence of shadowing and path loss is considered. The nodes are assumed to be distributed as a homogeneous two‐dimensional Poisson point process with constant intensity. The helpers are divided into several tiers each having a distinct operating region and a distinct cooperative throughput. Then, the conditions under which a helper in a particular tier can improve the transmission rate between a given pair of nodes are examined. Based on these conditions, an exact analytical expression is derived for the average cooperative throughput of a Poisson CoopMAC network that is subject to path loss and shadowing. The expression is then used to investigate the effects of shadowing, intensity of helpers and distance between source and destination nodes on the average cooperative throughput of the network.
Multi‐channel fingerprint localisation algorithm for wireless sensor network in multipath environment
Authors: Fang Xuming , Nan Lei , Jiang Zonghua , Chen Lijun
Published: July 2017

Fingerprint localisation technology based on received signal strength indication (RSSI) is an active area of study in wireless sensor network (WSN) research, mainly because it is cheap and easy to implement. However, due to measurement noise and the multipath effect in RSSI, the accuracy of state‐of‐the‐art fingerprint positioning algorithms is diminished. To solve this problem, the authors propose a multi‐channel fingerprint localisation algorithm for WSNs in multipath environments. This algorithm also addresses the issue of existing techniques based on multi‐channel signal strength requiring an accurate initial estimate of target–beacon distance or prior knowledge of the target–reference distance. Their proposed algorithm first uses an adaptive Kalman filter to reduce the noise in RSSI measured in different channels, and then calculates the matched fingerprint according to the weight of different channels. Finally, a memetic algorithm is utilised to generate the optimised estimate of fingerprint and location. Extensive experimental results on an actual WSN testbed show that the proposed algorithm improves the accuracy of the existing fingerprint localisation algorithm by at least 50%, regardless of the placement of target node, the number of beacon nodes, and the number of calibration points.
Sweep frequency response analysis based diagnosis of shorts within transformer windings
Authors: Rajamani Rajesh , Rajappa Muthaiah , Madanmohan Balasubramanian
Published: July 2017

Sweep frequency response analysis (SFRA) is a diagnostic technique which can identify faults within transformers. Though SFRA approaches are used to identify faults, their effectiveness in discriminating two same level faults at two different locations within transformer is not much analysed and reported. Experiments were carried out on a 1 kVA, single phase, 240 V/240 V laboratory transformers and on a 315 kVA, three phase, 11 kV/433 V, Dyn11, ONAN, distribution transformer, to analyse the usefulness of SFRA in inter turn short identification and discriminations. Faulty conditions were created artificially in transformers, by shorting the tappings provided in one of their windings, at different levels and locations. Open circuit self‐impedance and transfer voltage transfer function approaches were experimented and transfer function plots representing winding impedance and voltage transfer ratios at various frequencies were developed for transformers, under normal and faulty conditions. Significant differences were identified at some frequencies while comparing normal case plots with faulty case plots. It was observed that the SFRA is effective in identifying shorts within transformer winding as well as, discriminating two same level shorts (i.e.) locating shorts. Statistical analysis using absolute difference and min–max ratio also confirmed the efficacy of these approaches.
Hardware‐based hybrid scheme to improve the fault ride through capability of doubly fed induction generator under symmetrical and asymmetrical fault
Authors: Uddin Waqar , Zeb Kamran , Tanoli Ayesha , Haider Aun
Published: July 2017

A hybrid scheme for enhancing fault ride through (FRT) capability of doubly fed induction generator under symmetrical and asymmetrical grid faults is presented. The hybrid strategy is composed of switch type fault current limiter (STFCL), braking chopper and energy storage system (ESS). The hybrid scheme guarantees the safety and controllability of rotor side converter and DC‐link capacitor. The proposed FRT scheme has ability to overcome the transients and oscillation produced during the voltage dip. The hybrid strategy is capable of keeping the fault current, DC‐link voltage, rotor current and voltage and electromagnetic torque within the limits and damps the oscillations during the voltage dip. The results of hybrid scheme are compared with STFCL only and are found better for the former case. MATLAB/Simulink is used for simulation of 9 MW wind turbine interfaced with grid.
Improved finite‐range gain formula for open‐ended rectangular waveguides and pyramidal horns
Authors: Bird Trevor S. , Lingasamy V. , Selvan Krishnasamy T. , Sun Haihan
Published: July 2017

A finite‐range gain expression given in the literature for open‐ended rectangular waveguide is improved by employing the gain correction factor approach of Polk by returning to the original aperture field integrals. In these, the phase factor is approximated to third order and the amplitude factor to second order with distance from the antenna from which series approximations have been obtained to simplify computation of gain. Comparison with measured and/or simulated results shows that the closed‐form solution is as accurate as a previous expression beyond the far‐field boundary, and is more accurate at shorter distances. The formulation is extended to pyramidal horns where results obtained compare well with experiment.
The spatially resolved star formation history of mergers
Authors: Cortijo-Ferrero C. , González Delgado R. M. , Pérez E. , Cid Fernandes R. , García-Benito R. , Di Matteo P. , Sánchez S. F. , de Amorim A. L. , Lacerda E. A. D. , López Fernández R. , Tadhunter C.
Published: July 2017

This paper presents the spatially resolved star formation history (2D-SFH) of a small sample of four local mergers: the early-stage mergers IC 1623, NGC 6090, and the Mice, and the more advanced merger NGC 2623, by analyzing IFS data from the CALIFA survey and PMAS in LArr mode. Full spectral fitting techniques are applied to the datacubes to obtain the spatially resolved mass growth histories, the time evolution of the star formation rate intensity (ΣSFR), and the local specific star formation rate (sSFR), over three different time scales (30 Myr, 300 Myr, and 1 Gyr). The results are compared with non-interacting Sbc–Sc galaxies, to quantify if there is an enhancement of the star formation and to trace its time scale and spatial extent. Our results for the three LIRGs (IC 1623 W, NGC 6090, and NGC 2623) show that a major phase of star formation is occurring in time scales of 107 yr to few 108 yr, with global SFR enhancements of between approximately two and six with respect to main-sequence star forming (MSSF) galaxies. In the two early-stage mergers IC 1623 W and NGC 6090, which are between first pericentre passage and coalescence, the most remarkable increase of the SFR with respect to non-interacting spirals occurred in the last 30 Myr, and it is spatially extended, with enhancements of factors between two and seven both in the centres (r < 0.5 half light radius, HLR), and in the disks (r > 1 HLR). In the more advanced merger NGC 2623 an extended phase of star formation occurred on a longer time scale of ~1 Gyr, with a SFR enhancement of a factor of approximately two-to-three larger than the one in Sbc–Sc MSSF galaxies over the same period, probably relic of the first pericentre passage epoch. A SFR enhancement in the last 30 Myr is also present, but only in NGC 2623 centre, by a factor of three. In general, the spatially resolved SFHs of the LIRG-mergers are consistent with the predictions from high spatial resolution simulations. In contrast, the star formation in the Mice, specially in Mice B, is not enhanced but inhibited with respect to Sbc–Sc MSSF galaxies. The fact that the gas fraction of Mice B is smaller than in most non-interacting spirals, and that the Mice are close to a prograde orbit, represents a new challenge for the models, which must cover a larger space of parameters in terms of the availability of gas and the orbital characteristics.
Dynamic expression of long noncoding RNAs reveals their potential roles in spermatogenesis and fertility†
Authors: Wichman Lauren , Somasundaram Saigopal , Breindel Christine , Valerio Dana M. , McCarrey John R. , Hodges Craig A. , Khalil Ahmad M.
Published: July 2017

Mammalian reproduction requires that males and females produce functional haploid germ cells through complex cellular differentiation processes known as spermatogenesis and oogenesis, respectively. While numerous studies have functionally characterized protein-coding genes and small noncoding RNAs (microRNAs and piRNAs) that are essential for gametogenesis, the roles of regulatory long noncoding RNAs (lncRNAs) are yet to be fully characterized. Previously, we and others have demonstrated that intergenic regions of the mammalian genome encode thousands of long noncoding RNAs, and many studies have now demonstrated their critical roles in key biological processes. Thus, we postulated that some lncRNAs may also impact mammalian spermatogenesis and fertility. In this study, we identified a dynamic expression pattern of lncRNAs during murine spermatogenesis. Importantly, we identified a subset of lncRNAs and very few mRNAs that appear to escape meiotic sex chromosome inactivation, an epigenetic process that leads to the silencing of the X- and Y-chromosomes at the pachytene stage of meiosis. Further, some of these lncRNAs and mRNAs show a strong testis expression pattern suggesting that they may play key roles in spermatogenesis. Lastly, we generated a mouse knockout of one X-linked lncRNA, Tslrn1 (testis-specific long noncoding RNA 1), and found that males carrying a Tslrn1 deletion displayed normal fertility but a significant reduction in spermatozoa. Our findings demonstrate that dysregulation of specific mammalian lncRNAs is a novel mechanism of low sperm count or infertility, thus potentially providing new biomarkers and therapeutic strategies.
Metagenomic Sequencing of an Echovirus 30 Genome From Cerebrospinal Fluid of a Patient With Aseptic Meningitis and Orchitis
Authors: Piantadosi Anne , Mukerji Shibani S , Chitneni Pooja , Cho Tracey A , Cosimi Lisa A , Hung Deborah T , Goldberg Marcia B , Sabeti Pardis C , Kuritzkes Daniel R , Grad Yonatan H
Published: July 2017

Enteroviruses cause a wide spectrum of clinical disease. In this study, we describe the case of a young man with orchitis and aseptic meningitis who was diagnosed with enterovirus infection. Using unbiased “metagenomic” massively parallel sequencing, we assembled a near-complete viral genome, the first use of this method for full-genome viral sequencing from cerebrospinal fluid. We found that the genome belonged to the subgroup echovirus 30, which is a common cause of aseptic meningitis but has not been previously reported to cause orchitis.
Techniques of Neutralization and Identity Work Among Accused Genocide Perpetrators
Authors: Bryant Emily , Schimke Emily Brooke , Nyseth Brehm Hollie , Uggen Christopher
Published: July 2017

Following the 1994 Rwandan genocide, many defendants on trial at the International Criminal Tribunal for Rwanda (ICTR) testified on their own behalf. This article analyzes transcripts of their testimonies to learn (1) how defendants discuss the grave crimes of which they are accused, and (2) how their explanatory styles allow them to rationalize their actions and negotiate their tarnished identities. We find that defendants employ Gresham Sykes and David Matza’s (1957) classic techniques of neutralization as a means of rationalization, impression management, and identity negotiation. Nevertheless, these techniques, along with those developed in the decades since, do not capture all aspects of defendants’ accounts. We thus identify additional techniques of neutralization to provide a more comprehensive understanding of how defendants account for their actions. By extending this classic literature, we call attention to the situational context of international trials, the nature of the crime of genocide, the relatively high social status many defendants once occupied, and existing narratives surrounding the legitimacy of the ICTR. In doing so, our analysis contributes to understandings of narratives of violence and accused genocide perpetrators.
116 independent genetic variants influence the neuroticism personality trait in over 329,000 UK Biobank individuals
Authors: Luciano Michelle , Hagenaars Saskia P , Davies Gail , Hill W David , Clarke Toni-Kim , Shirali Masoud , Marioni Riccardo E , Harris Sarah E , Liewald David C , Fawns-Ritchie Chloe , Adams Mark J , Howard David M , Lewis Cathryn M , Gale Catharine R. , McIntosh Andrew M , Deary Ian J
Published: July 2017

Neuroticism is a stable personality trait1; twin studies report heritability between 30% and 50%2, and SNP-based heritability is about 15%3. Higher levels of neuroticism are associated with poorer mental and physical health4,5, and the economic burden of neuroticism for societies is high6. To date, genome-wide association (GWA) studies of neuroticism have identified up to 11 genetic loci3,7. Here we report 116 significant independent genetic loci from a GWA of neuroticism in 329,821 UK Biobank participants, with replication available in a GWA meta-analysis of neuroticism in 122,867 individuals. Genetic signals for neuroticism were enriched in neuronal genesis and differentiation pathways, and substantial genetic correlations were found between neuroticism and depressive symptoms (rg= .82, SE=.03), major depressive disorder (rg= .69, SE=.07) and subjective wellbeing (rg = -.68, SE=.03) alongside other mental health traits. These discoveries significantly advance our understanding of neuroticism and its association with major depressive disorder.
Rule Activation and Ventromedial Prefrontal Engagement Support Accurate Stopping in Self-Paced Learning
Authors: O’Bryan Sean R. , Walden Eric , Serra Michael J. , Davis Tyler
Published: July 2017

When weighing evidence for a decision, individuals are continually faced with the choice of whether to gather more information or act on what has already been learned. The present experiment employed a self-paced category learning task and fMRI to examine the neural mechanisms underlying stopping of information search and how they contribute to choice accuracy. Participants learned to classify triads of face, object, and scene cues into one of two categories using a rule based on one of the stimulus dimensions. After each trial, participants were given the option to explicitly solve the rule or continue learning. Representational similarity analysis (RSA) was used to examine activation of rule-relevant information on trials leading up to a decision to solve the rule. We found that activation of rule-relevant information increased leading up to participants’ stopping decisions. Stopping was associated with widespread activation that included medial prefrontal cortex and visual association areas. Engagement of ventromedial prefrontal cortex (vmPFC) was associated with accurate stopping, and activation in this region was functionally coupled with signal in dorsolateral prefrontal cortex (dlPFC). Results suggest that activating rule information when deciding whether to stop an information search increases choice accuracy, and that the response profile of vmPFC during such decisions may provide an index of effective learning.
Decline of auditory-motor speech processing in older adults with hearing loss
Authors: Panouillères Muriel TN , Möttönen Riikka
Published: July 2017

Older adults often experience difficulties in understanding speech, partly because of age-related hearing loss. In young adults, activity of the left articulatory motor cortex is enhanced and it interacts with the auditory cortex via the left-hemispheric dorsal stream during speech processing. Little is known about the effect of ageing and age-related hearing loss on this auditory-motor interaction and speech processing in the articulatory motor cortex. It has been proposed that up-regulation of the motor system during speech processing could compensate for hearing loss and auditory processing deficits in older adults. Alternatively, age-related auditory deficits could reduce and distort the input from the auditory cortex to the articulatory motor cortex, suppressing recruitment of the motor system during listening to speech. The aim of the present study was to investigate the effects of ageing and age-related hearing loss on the excitability of the tongue motor cortex during listening to spoken sentences using transcranial magnetic stimulation and electromyography. Our results show that the excitability of the tongue motor cortex was facilitated during listening to speech in young and older adults with normal hearing. This facilitation was significantly reduced in older adults with hearing loss. These findings suggest a decline of auditory-motor processing of speech in adults with age-related hearing loss.
Discrete confidence levels revealed by sequential decisions
Authors: Lisi Matteo , Mongillo Gianluigi , Gorea Andrei
Published: July 2017

Whether humans are optimal decision makers is still a debated issue in the realm of perceptual decisions. Taking advantage of the direct link between an optimal decision-making and the confidence in that decision, we offer a new dual-decisions method of inferring such confidence without asking for its explicit valuation. Our method circumvents the well-known miscalibration issue with explicit confidence reports as well as the specification of the cost-function required by ‘opt-out’ or post-decision wagering methods. We show that observers’ inferred confidence in their first decision and its use in a subsequent decision (conditioned upon the correctness of the first) fall short of both the ideal Bayesian strategy, as well as of an under-sampling approximation or a modified Bayesian strategy augmented with an additional bias term to accommodate global miscalibration of confidence. The observed data are instead significantly better fitted by a model positing that observers use only few confidence levels or states, at odds with the continuous confidence function of stimulus level prescribed by a normative behavior. These findings question the validity of normative-Bayesian accounts of subjective confidence and metaperceptual judgments.
Convis: A Toolbox To Fit and Simulate Filter-based Models of Early Visual Processing
Authors: Huth Jacob , Masquelier Timothée , Arleo Angelo
Published: July 2017

1

We developed Convis, a Python simulation toolbox for large scale neural populations which offers arbitrary receptive fields by 3D convolutions executed on a graphics card. The resulting software proves to be flexible and easily extensible in Python, while building on the PyTorch library [32], which was previously used successfully in deep learning applications, for just-in-time optimization and compilation of the model onto CPU or GPU architectures. An alternative implementation based on Theano [33] is also available, although not fully supported.

Through automatic differentiation, any parameter of a specified model can be optimized to approach a desired output which is a significant improvement over e.g. Monte Carlo or particle optimizations without gradients. We show that a number of models including even complex non-linearities such as contrast gain control and spiking mechanisms can be implemented easily.

We show in this paper that we can in particular recreate the simulation results of a popular retina simulation software VirtualRetina [35], with the added benefit of providing (1) arbitrary linear filters instead of the product of Gaussian and exponential filters and (2) optimization routines utilizing the gradients of the model. We demonstrate the utility of 3d convolution filters with a simple direction selective filter. Also we show that it is possible to optimize the input for a certain goal, rather than the parameters, which can aid the design of experiments as well as closed-loop online stimulus generation. Yet, Convis is more than a retina simulator. For instance it can also predict the response of V1 orientation selective cells.

Convis is open source under the GPL-3.0 license and available from https://github.com/jahuth/convis/ with documentation at https://jahuth.github.io/convis/.
Translational regulation by bacterial small RNAs via an unusual Hfq-dependent mechanism
Authors: Azam Muhammad S. , Vanderpool Carin K.
Published: July 2017

In bacteria, the canonical mechanism of translational repression by small RNAs (sRNAs) involves sRNA-mRNA base pairing that occludes the ribosome binding site (RBS), directly preventing translation. In this mechanism, the sRNA is the direct regulator, while the RNA chaperone Hfq plays a supporting role by stabilizing the sRNA. There are a few examples where the sRNA does not directly interfere with ribosome binding, yet translation of the target mRNA is still inhibited. Mechanistically, this non-canonical regulation by sRNAs is poorly understood. Our previous work demonstrated repression of the mannose transportermanXmRNA by the sRNA SgrS, but the regulatory mechanism was unknown. Here, we report thatmanXtranslation is controlled by a molecular role-reversal mechanism where Hfq, not the sRNA, is the direct repressor. Hfq binding adjacent to themanXRBS is required for sRNA-mediated translational repression. Translation ofmanXis also regulated by another sRNA, DicF, via the same non-canonical Hfq-dependent mechanism. Our results suggest that the sRNAs recruit Hfq to its binding site or stabilize the mRNA-Hfq complex. This work adds to the growing number of examples of diverse mechanisms of translational regulation by sRNAs in bacteria.
Divergent gene expression levels between diploid and autotetraploidTolmiea(Saxifragaceae) relative to the total transcriptome, the cell, and biomass
Authors: Visger Clayton J. , Wong Gane K-S. , Zhang Yong , Soltis Pamela S. , Soltis Douglas E.
Published: July 2017

Studies of gene expression and polyploidy are typically restricted to characterizing differences in transcript concentration. Integrating multiple methods of transcript analysis, we document a difference in transcriptome size, and make multiple comparisons of transcript abundance in diploid and autotetraploidTolmiea.

We use RNA spike-in standards to identify and correct for differences in transcriptome size, and compare levels of gene expression across multiple scales: per transcriptome, per cell, and per biomass.

In total, ~17% of all loci were identified as differentially expressed (DEGs) between the diploid and autopolyploid species. A shift in total transcriptome size resulted in only ~58% of the total DEGs being identified as differentially expressed following a per transcriptome normalization. When transcript abundance was normalized per cell, ~82% of the total DEGs were recovered. The discrepancy between per-transcriptome and per-cell recovery of DEGs occurs because per-transcriptome normalizations are concentration-based and therefore blind to differences in transcriptome size.

While each normalization enables valid comparisons at biologically relevant scales, a holistic comparison of multiple normalizations provides additional explanatory power not available from any single approach. Notably, autotetraploid loci tend to conserve diploid-like transcript abundance per biomass through increased gene expression per cell, and these loci are enriched for photosynthesis-related functions.
Evolving Bacterial Fitness with an Expanded Genetic Code
Authors: Tack Drew S. , Cole Austin C. , Shroff R. , Morrow B.R. , Ellington Andrew D.
Published: July 2017

Evolution has for the most part used the canonical 20 amino acids of the natural genetic code to construct proteins. While several theories regarding the evolution of the genetic code have been proposed, experimental exploration of these theories has largely been restricted to phylogenetic and computational modeling. The development of orthogonal translation systems has allowed noncanonical amino acids to be inserted at will into proteins. We have taken advantage of these advances to evolve bacteria to accommodate a 21 amino acid genetic code in which the amber codon ambiguously encodes either 3-nitro-L-tyrosine or stop. Such an ambiguous encoding strategy recapitulates numerous models for genetic code expansion, and we find that evolved lineages first accommodate the unnatural amino acid, and then begin to evolve on a neutral landscape where stop codons begin to appear within genes. The resultant lines represent transitional intermediates on the way to the fixation of a functional 21 amino acid code.
Endogenous synthesis of pyrethrins by cannabis
Authors: Devitt-Lee Adrian , Smith Douglas R. , Chen David , McKernan Kevin , Groves Simone , McCarthy Ciaran
Published: July 2017

Pyrethrins are a class of natural terpenoid pesticides produced byTanacetum cinerariifolium, commonly known as chrysanthemum. Here we present evidence that cannabis may be able to produce pyrethrins endogenously. Flower from a cannabis plant grown in a closed hydroponic environment contained 2.48 parts per million pyrethrin I by weight. A comparison of the genetics ofT. cinerariifoliumandCannabisdemonstrates Cannabis homologues of the genes that contribute to pyrethrins production inT. cinerariifolium. This provides a plausible pathway for the biosynthesis of pyrethrins in cannabis. Although preliminary, these data indicate a potentially significant confounding variable in both cannabis research and regulations on allowable pyrethrins residues in cannabis products.
Experience-dependent translational state defined by cell type-specific ribosome profiling
Authors: Eacker Stephen M. , Crawford Khadijah , Brichta Lars , Riessland Markus , Ingolia Nicholas T. , Greengard Paul , Dawson Ted M. , Dawson Valina L.
Published: July 2017

Experience-dependent neuronal activity regulates the translation of mRNA, supporting memory formation. We have developed a new method termedtranslating ribosome affinity purification andribosomeprofiling (TRiP) which allows us to determine cell type-specific ribosome occupancy of mRNA with nucleotide resolution. Using TRiP we show that a memory-inducing experience creates a distinct translational state in mouse CA1 pyramidal cells. The experience-dependent translation state is characterized by enhanced translation of protein-coding open reading frames (ORFs) including numerous components of the actin cytoskeleton and calcium/calmodulin binding proteins, and by decreased translation of a defined subset of genes containing upstream ORFs (uORFs). Using animals heterozygous for an unphosphorylatable allele of the eukaryotic translation initiation factor 2α (eIF2α), we show that dephosphorylation of eIF2α contributes significantly to the experience-dependent translation state. These observations demonstrate that TRiP is a valuable methodology for studying physiologically relevant changes in translational state in genetically defined cell types.
Mammalian Orthoreovirus Factories Modulate Stress Granule Protein Localization by Interaction with G3BP1
Authors: Choudhury Promisree , Bussiere Luke , Miller Cathy L.
Published: July 2017

Mammalian orthoreovirus (MRV) infection induces phosphorylation of translation initiation factor eIF2α which promotes formation of discrete cytoplasmic inclusions, termed stress granules (SGs). SGs are emerging as a component of the innate immune response to virus infection, and modulation of SG assembly is a common mechanism employed by viruses to counter this antiviral response. We previously showed that MRV infection induces SGs early, then interferes with SG formation as infection proceeds. In this work, we found that SG associated proteins localized to the periphery of virus-encoded cytoplasmic structures, termed virus factories (VFs), where viral transcription, translation, and replication occur. The localization of SG proteins to VFs was dependent on polysome dissociation and occurred via association of SG effector protein, G3BP1, with MRV non-structural protein σNS, which localizes to VFs via association with VF nucleating protein, μNS. Deletion analysis of the σNS RNA binding domain and G3BP1 RNA (RRM) and ribosomal (RGG) binding domains showed that the association and VF localization of G3BP1 is not occurring solely through RNA or ribosomal binding, but requires both RNA and ribosomal binding domains of G3BP1 for maximal VFL localization and σNS association. Co-expression of σNS and μNS resulted in disruption of normal SG puncta, and in cells lacking G3BP1, MRV replication was enhanced in a manner correlating with strain-dependent induction of host translation shutoff. These results suggest that σNS association with and relocalization of G3BP1 to the VF periphery plays a role in SG disruption to facilitate MRV replication in the host translational shutoff environment.

IMPORTANCE

SGs and SG effector proteins have emerged as important, yet poorly understood, players in the host’s innate immune response to virus infection. MRV infection induces SGs early during infection that are dispersed and/or prevented from forming during late stages of infection despite continued activation of the eIF2α signaling pathway. Cellular and viral components involved in disruption of SGs during late stages of MRV infection remain to be elucidated. This work provides evidence that MRV disruption of SGs may be facilitated by association of MRV non-structural protein σNS with major SG effector protein G3BP1 and subsequent localization of G3BP1 and other SG associated proteins around the periphery of virus encoded factories, interrupting the normal formation of SGs. Our findings also reveal the importance of G3BP1 as an inhibitor of MRV replication during infection for the first time.
Rapid and scalable characterization of CRISPR technologies using an E. coli cell-free transcription-translation system
Authors: Marshall Ryan , Maxwell Colin S. , Collins Scott P. , Luo Michelle L. , Jacobsen Thomas , Beisel Chase L. , Noireaux Vincent
Published: July 2017

CRISPR-Cas systems have offered versatile technologies for genome engineering, yet their implementation has been outpaced by the ongoing discovery of new Cas nucleases and anti-CRISPR proteins. Here, we present the use of E. coli cell-free transcription-translation systems (TXTL) to vastly improve the speed and scalability of CRISPR characterization and validation. Unlike prior approaches that require protein purification or live cells, TXTL can express active CRISPR machinery from added plasmids and linear DNA, and TXTL can output quantitative dynamics of DNA cleavage and gene repression. To demonstrate the applicability of TXTL, we rapidly measure guide RNA-dependent DNA cleavage and gene repression for single- and multi-effector CRISPR-Cas systems, accurately predict the strength of gene repression in E. coli, quantify the inhibitory activity of anti-CRISPR proteins, and develop a fast and scalable high-throughput screen for protospacer-adjacent motifs. These examples underscore the potential of TXTL to facilitate the characterization and application of CRISPR technologies across their many uses.
Budding yeast Wpl1p regulates cohesin functions in cohesion, condensation and DNA repair by a common mechanism
Authors: Bloom Michelle S. , Guacci Vincent , Koshland Douglas
Published: July 2017

Cohesin tethers DNA to mediate sister chromatid cohesion, chromosome condensation, and DNA repair. How the cell regulates cohesin to perform these distinct functions remains to be elucidated. One cohesin regulator, Wpl1p, was characterized in the budding yeast,Saccharomyces cerevisiae, as a promoter of cohesion and as an inhibitor of condensation. Here we provide evidence that Wpl1p has an additional function in promoting the timely repair of DNA damage induced during S-phase. In addition to these biological functions, Wpl1p has been implicated as an inhibitor of cohesin’s ability to stably bind DNA by modulating the interface between two subunits (Mcd1p and Smc3p) of the core cohesin complex. We show that Wpl1p likely modulates this interface to regulate all cohesin’s biological functions. Furthermore, we show that Wpl1p regulates cohesion and condensation through the formation of a functional complex with another cohesin-associated factor, Pds5p. In contrast, Wpl1p regulates DNA repair independently of its interaction with Pds5p. Together these results suggest that Wpl1p regulates distinct biological functions of cohesin by Pds5p-dependent and – independent modulation of the Smc3p-Mcd1p interface.
ciRS-7 exonic sequence is embedded in a long non-coding RNA locus
Authors: Barrett Steven P. , Parker Kevin R. , Horn Caroline , Mata Miguel , Salzman Julia
Published: July 2017

ciRS-7 is an intensely studied, highly expressed and conserved circRNA. Essentially nothing is known about its biogenesis, including the location of its promoter. A prevailing assumption has been that ciRS-7 is an exceptional circRNA because it is transcribed from a locus lacking any mature linear RNA transcripts of the same sense. Our interest in the biogenesis of ciRS-7 led us to develop an algorithm to define its promoter. This approach predicted that the human ciRS-7 promoter coincides with that of the long non-coding RNA, LINC00632. We validated this prediction using multiple orthogonal experimental assays. We also used computational approaches and experimental validation to establish that ciRS-7 exonic sequence is embedded in linear transcripts that are flanked by cryptic exons in both human and mouse. Together, this experimental and computational evidence generate a new view of regulation in this locus: (a) ciRS-7 is like other circRNAs, as it is spliced into linear transcripts; (b) expression of ciRS-7 is primarily determined by the chromatin state of LINC00632 promoters; (c) transcription and splicing factors sufficient for ciRS-7 biogenesis are expressed in cells that lack detectable ciRS-7 expression. These findings have significant implications for the study of the regulation and function of ciRS-7, and the analytic framework we developed to jointly analyze RNA-seq and ChlP-seq data reveal the potential for genome-wide discovery of important biological regulation missed in current reference annotations.

Author Summary

circRNAs were recently discovered to be a significant product of ‘host’ gene expression programs but little is known about their transcriptional regulation. Here, we have studied the expression of a well-known circRNA named ciRS-7. ciRS-7 has an unusual function for a circRNA; it is believed to be a miRNA sponge. Previously, ciRS-7 was thought to be transcribed from a locus lacking any mature linear isoforms, unlike all other circular RNAs known to be expressed in human cells. However, we have found this to be false; using a combination of bioinformatic and experimental genetic approaches, in both human and mouse, we discovered that linear transcripts containing the ciRS-7 exonic sequence, linking it to upstream genes. This suggests the potential for additional functional roles of this important locus and provides critical information to begin study on the biogenesis of ciRS-7.
Chemical Gating of the Mechanosensitive Piezo1 Channel by Asymmetric Binding of its Agonist Yoda1
Authors: Lacroix Jerome J. , Botello-Smith Wesley M. , Luo Yun
Published: July 2017

Piezo proteins are homotrimeric ion channels that play major roles in normal and pathological mechanotransduction signaling in mammalian organisms. Their pharmacological control hence represents a potential therapeutic avenue. Yoda1, a Piezo1-selective small molecule agonist, is the only known selective Piezo modulator. How Yoda1 selectively interacts with Piezo1 and opens its pore is unknown. Here, by engineering and characterizing chimeras, we identified a minimal region responsible for Yoda1 binding. This region is located at the interface between the pore and the putative mechanosensory domains in each subunit. By characterizing hybrid channels containing Yoda1-insensitive and Yoda1-sensitive monomers, we demonstrate that the presence of only one Yoda1-sensitive Piezo1 subunit is sufficient for chemical activation, implicating that the asymmetric binding of Yoda1 to a single subunit enables channel opening. These findings shed light onto the gating mechanisms of Piezo channels and will pave the way for the rationale design of new Piezo channels modulators.
Suppression of Transposable Elements in Leukemic Stem Cells
Authors: Colombo Anthony R. , Zubair Asif , Thiagarajan Devi , Nuzhdin Sergey , Triche Timothy J. , Ramsingh Giridharan
Published: July 2017

Genomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing ‘viral mimicry’, causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.