bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of NAMS members’ prescription patterns of hormone therapy before and after the 2016 NAMS Annual Meeting
Authors: Bonnett Lindsay P. , Jiang Xuezhi , Pinkerton JoAnn V. , Schnatz Peter F.
Published: November 2018

Objective:

Hormone therapy (HT) prescription patterns have varied enormously over time and across specialties. The present study attempts to look at practice variation in specific controversial scenarios and to determine if attendance at The North American Menopause Society (NAMS) 2016 Annual Meeting, where the draft of the 2017 NAMS HT Position Statement was presented, had any impact on members’ HT prescribing patterns.

Methods:

An anonymous survey with 11 case scenarios was sent to all NAMS members before and after the 2016 NAMS Annual Meeting. Pre- and postmeeting responses were pooled into a single cohort. For those who responded to both surveys, only the postmeeting survey responses were included in the cohort. The impact of attendance at the 2016 NAMS Annual Meeting was investigated by comparing paired responses with “controversial questions” between pre- and postmeeting surveys in the matched population who either attended the 2016 NAMS Annual Meeting (intervention arm) or did not (control arm). “Controversial questions” were defined as those where 25% to 75% of responders answered “YES” to a question. McNemar's test was applied to analyze paired responses using SAS statistical software, with P ≤ 0.05 being considered statistically significant.

Results:

A total of 1,786 NAMS members were surveyed before and after the 2016 NAMS meeting, 234 (13%) completed the premeeting survey, 166 (9%) completed the postmeeting survey, and 52 completed both surveys. Of the 52, 27 attended the 2016 NAMS Annual Meeting and 25 did not. The pooled cohort contains 348 responses which represents a 20% response rate. Six complex case scenarios with “controversial questions” were identified from the pooled cohort and reexamined in the intervention and control arm, respectively. In the intervention arm, significant changes toward being more likely to prescribe HT in guideline-consistent cases were noted in four out of six cases, whereas significant changes in HT use were not seen in any of six complex cases in the control arm.

Conclusions:

NAMS members’ prescribing patterns of HT vary in complex clinical scenarios. After the 2016 NAMS Annual Meeting where a draft of the 2017 NAMS HT Position Statement was presented and discussed, in four challenging and complex clinical situations a significant number of practitioners changed their prescription patterns toward prescribing HT which was consistent with the new guideline.
The migraine eye: distinct rod-driven retinal pathways' response to dim light challenges the visual cortex hyperexcitability theory
Authors: Bernstein Carolyn A. , Nir Rony-Reuven , Noseda Rodrigo , Fulton Anne B. , Huntington Shaelah , Lee Alice J. , Bertisch Suzanne M. , Hovaguimian Alexandra , Buettner Catherine , Borsook David , Burstein Rami
Published: November 2018

Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is the most bothersome symptom accompanying an attack. Using subjective psychophysical assessments, we showed that migraine patients are more sensitive to all colors of light during ictal than during interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in both phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual-evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b wave, which was consistently larger (by 14%-19% in the light-adapted and 18%-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a wave or the visual-evoked potentials that differs most strikingly between the 2 groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that nonmigraineurs feel as if they are in a cave.
The association between obesity and outcomes in acute pancreatitis: an individual patient data meta-analysis
Authors: Smeets Xavier J.N.M. , Knoester Iris , Grooteman Karina V. , Singh Vikesh K. , Banks Peter A. , Papachristou Georgios I. , Duarte-Rojo Andres , Robles-Diaz Guillermo , Kievit Wietske , Besselink Marc G.H. , Verdonk Robert C. , Van Santvoort Hjalmar C. , Drenth Joost P.H. , Belias Michael , Van Geenen Erwin J.M.
Published: November 2018

Objectives

There are data to suggest that obesity is associated with local and systemic complications as well as mortality in acute pancreatitis (AP). Cohort studies to date, however, have shown conflicting results from mostly unadjusted analyses. Therefore, we performed an individual patient data meta-analysis with the primary aim to investigate the association between obesity and mortality in AP. Our secondary aim was to investigate the association between obesity and necrosis, organ failure, multiple organ failure, and invasive intervention.

Patients and methods

We systematically searched four electronic databases for prospective studies on obesity and outcomes in AP. Researchers of eligible studies were invited to share individual patient data using a standardized data collection form. All end points were investigated with a one-stage mixed effects Poisson model with random intercepts and forced entry of relevant confounders.

Results

We included five databases with 1302 patients, of whom 418 (32%) were obese. In total, 466 (36%) patients had necrosis, 328 (25%) had organ failure, 188 (14%) had multiple organ failure, 210 (16%) had an intervention, and 84 (7%) patients died. We found no significant association between obesity and mortality [relative risk (RR) 1.40, 95% confidence interval (CI): 0.89–2.20], necrosis (RR: 1.08, 95% CI: 0.90–1.31) or invasive intervention (RR: 1.10, 95% CI: 0.83–1.47) after adjustment for confounders. However, obesity was independently associated with the development of organ failure (RR: 1.38, 95% CI: 1.11–1.73) and multiple organ failure (RR: 1.81, 95% CI: 1.35–2.42).

Conclusion

Obesity is independently associated with the development of organ failure and multiple organ failure in AP. However, there is no association between obesity and mortality, necrosis, and an intervention.
Classical-contextual interactions in V1 may rely on dendritic computations
Authors: Jin Lei , Behabadi Bardia F. , Jadi Monica P. , Ramachandra Chaithanya A. , Mel Bartlett W.
Published: November 2018

A signature feature of the neocortex is the dense network of horizontal connections (HCs) through which pyramidal neurons (PNs) exchange “contextual” information. In primary visual cortex (V1), HCs are thought to facilitate boundary detection, a crucial operation for object recognition, but how HCs modulate PN responses to boundary cues within their classical receptive fields (CRF) remains unknown. We began by “asking” natural images, through a structured data collection and ground truth labeling process, what function a V1 cell should use to compute boundary probability from aligned edge cues within and outside its CRF. The “answer” was an asymmetric 2-D sigmoidal function, whose nonlinear form provides the first normative account for the “multiplicative” center-flanker interactions previously reported in V1 neurons (Kapadia et al. 1995, 2000; Polat et al. 1998). Using a detailed compartmental model, we then show that this boundary-detecting classical-contextual interaction function can be computed with near perfect accuracy by NMDAR-dependent spatial synaptic interactions within PN dendrites – the site where classical and contextual inputs first converge in the cortex. In additional simulations, we show that local interneuron circuitry activated by HCs can powerfully leverage the nonlinear spatial computing capabilities of PN dendrites, providing the cortex with a highly flexible substrate for integration of classical and contextual information.

Significance Statement

In addition to the driver inputs that establish their classical receptive fields, cortical pyramidal neurons (PN) receive a much larger number of “contextual” inputs from other PNs through a dense plexus of horizontal connections (HCs). However by what mechanisms, and for what behavioral purposes, HC’s modulate PN responses remains unclear. We pursued these questions in the context of object boundary detection in visual cortex, by combining an analysis of natural boundary statistics with detailed modeling PNs and local circuits. We found that nonlinear synaptic interactions in PN dendrites are ideally suited to solve the boundary detection problem. We propose that PN dendrites provide the core computing substrate through which cortical neurons modulate each other’s responses depending on context.
Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease
Authors: Özen Ayşegül , Lin Kuan-Hung , Romano Keith P , Tavella Davide , Newton Alicia , Petropoulos Christos J. , Huang Wei , Aydin Cihan , Schiffer Celia A.
Published: November 2018

Hepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechanism for resistance of non-active site mutations is unclear. R155K and V36M often co-evolve and while R155K alters the electrostatic network at the binding site, V36M is more than 13 Å away. In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three protease inhibitors: telaprevir, boceprevir and danoprevir. The R155K and R155K/V36M crystal structures differ in the α-2 helix and E2 strand near the active site, with alternative conformations at M36 and side chains of active site residues D168 and R123, revealing an allosteric coupling, which persists dynamically in MD simulations, between the distal mutation and the active site. This allosteric modulation validates the network hypothesis and elucidates how distal mutations confer resistance through propagation of conformational changes to the active site.
A High-Resolution Luminescent Assay for Rapid and Continuous Monitoring of Protein Translocation Across Biological Membranes
Authors: Pereira Gonçalo C. , Allen William J. , Watkins Daniel W. , Buddrus Lisa , Noone Dylan , Liu Xia , Richardson Andrew , Chacinska Agnieszka , Collinson Ian
Published: November 2018

Protein translocation is a fundamental process in biology. Major gaps in our understanding of this process arises due the poor sensitivity, low time-resolution and irreproducibility of translocation assays. To address this, we applied NanoLuc split-luciferase to produce a new strategy for measuring protein transport. The system reduces the timescale of data collection from days to minutes, and allows continuous acquisition with a time-resolution in the order of seconds – yielding kinetics parameters suitable for mechanistic elucidation and mathematical fitting. To demonstrate its versatility, we implemented and validated the assayin vitroandin vivofor the bacterial Sec system, and the mitochondrial protein import apparatus. Overall, this technology represents a major step forward, providing a powerful new tool for fundamental mechanistic enquiry of protein translocation and for inhibitor (drug) screening, with an intensity and rigour unattainable through classical methods.
AMPK-Fyn signaling promotes Notch1 stability to potentiate hypoxia-induced breast cancer stemness and drug resistance
Authors: Lahiry Mohini , Kumar Saurav , Hari Kishore , Chedere Adithya , Jolly Mohit Kumar , Rangarajan Annapoorni
Published: November 2018

Hypoxia is a hall mark of solid tumor microenvironment and contributes to tumor progression and therapy failure. The developmentally important Notch pathway is implicated in cellular response of cancer cells to hypoxia. Yet, the mechanisms that potentiate Notch signaling under hypoxia are not fully understood. Hypoxia is also a stimulus for AMP-activated protein kinase (AMPK), a major cellular energy sensor. In this study, we investigated if AMPK interacts with the Notch pathway and influences the hypoxia-response of breast cancer cells. Activating AMPK with pharmacological agent or genetic approaches led to an increase in the levels of cleaved Notch1 and elevated Notch signaling in invasive breast cancer cell lines. In contrast, inhibition or depletion of AMPK reduced the amount of cleaved Notch1. Significantly, we show that the hypoxia-induced increase in cleaved Notch1 levels requires AMPK activation. Probing into the mechanism, we demonstrate that AMPK activation impairs the interaction between cleaved Notch1 and its ubiquitin ligase, Itch/AIP4 through the tyrosine kinase Fyn. Under hypoxia, the AMPK-Fyn axis promotes inhibitory phosphorylation of Itch which abrogates its interaction with substrates, thus stabilizing cleaved Notch1 by reducing its ubiquitination and degradation. We further show that inhibition of AMPK alleviates the hypoxia-triggered, Notch-mediated stemness and drug resistance phenotype. Breast cancer patient samples also showed co-expression of hypoxia/AMPK/Notch gene signature. Our work thus establishes AMPK as a key component in the adaptation of breast cancer cells to hypoxia, and proposes therapeutic inhibition of AMPK to mitigate the hypoxia-triggered aggressiveness.
Dedicated acetic acid preference coded by broad spectrum ionotropic receptors in a moth species
Authors: Tang Rui , Jiang Nan-Ji , Ning Chao , Huang Ling-Qiao , Wang Chen-Zhu
Published: November 2018

Acetic acid as one of the food related odorant cues attracts many insect species. In the moth Mythimna separata, the olfaction of acid was coded via multiple pathways including 3 sensilla types on the antennae and 3 glomeruli in the antennal lobes. Among, suitable dosages of acetic acid exclusively activated DC3 glomerulus that receives integrated projections across sensilla types, which drives attractiveness and feeding attempts of the moth. This circuit encodes broad spectrum ionotropic receptors 8a, 75q1 and 75q2 which were sufficient to confer acid responsiveness in Xenopus oocytes. Ir75q2 was expressed in vivo with Ir75q1 and it enhanced sensitivity of the receptor functional group toward acids. Furthermore, Ir75q1 and Ir75q2 are both necessary for the moth to conduct acetic acid induced reactions of sensilla, DC3 glomerulus as well as attractiveness. Together, it reveals that an indispensable tetramer IR-based unit is employed to fulfill acetic acid specialized preference under suitable dosages through balancing of transcription and peripheral coding. Understanding of the Ir75q1/2 olfactory pathway provides insights into investigations on acid sensory process in insects.

Author Summary

The preference to acids are common in various organisms, and it may involve both olfactory and gustatory reception. In particular, airborne acidity volatiles can be sensed through antennae of insects and later assessed to help locating foraging, mating, and egg laying sites. However, these stimulatory processes can only be delivered by suitable dosages of acids, as we all know that, high acidity could be fatal in most circumstances. To date, avoidance to acids has been well explained in insects, but attractiveness and its basis remain uncharted. In the brain of oriental armyworm Mythimna separata, we have located 3 olfactory pathways which may play roles in acetic acid reception. Fortunately, when acetic acid was applied at attractive dosages, it only activated 1 dedicated pathway among the three. Later we found that this attractiveness pathway employed two ionotropic receptor genes namely Ir75q1 and Ir75q2, to successfully deliver this trait. Both genes were necessary for the moth to conduct acetic acid preference, but their roles are different. Ir75q1 recognized the acetic acid ligand and Ir75q2 later amplify the sensitivity. By comparing with evidences from electrophysiology and brain imaging tests, we found that the expression bias of either of the two genes has caused the separation of the pathways. It has been revealed in this moth that a smart decision system for olfactory reception exists, and this system may extrapolate to other insect species, as Ir75q1 and Ir75q2 are commonly expressed in many insect families.
Intracellular anti-leishmanial effect of Spergulin-A, a triterpenoid saponin of Glinus oppositifolius
Authors: Banerjee Saswati , Mukherjee Niladri , Gajbhiye Rahul L. , Jaisankar Parasuraman , Datta Sriparna , Das Saha Krishna
Published: November 2018

Many of present chemotherapeutics are inadequate and also resistant against visceral leishmaniasis (VL) an immunosuppressive ailment caused by Leishmania donovani. Despite the interest in plant-based drug development, very few number of antileishmanial drugs from plant source is available. Glinus oppositifolius had been reported in favor of being immunomodulators along with other traditional uses. Novel anti-VL therapies can rely on host immune-modulation with associated leishmanicidal action. With this rationale, an n-BuOH fraction of the methanolic extract of the plant and obtained triterpenoid saponin Spergulin-A were evaluated against acellular and intracellular L. donovani. Immunostimulatory activity of them was confirmed by elevated TNF-α and extracellular NO production from treated MФs and was found nontoxic to the host cells. Identification and structure confirmation for isolated Spergulin-A was performed by ESI-MS, 13C, and 1H NMR. Spergulin-A was found ineffective against the acellular forms while, against the intracellular parasites at 30μg/ml, the reduction was 92.6% after 72h. Spergulin-A enhanced ROS and nitric oxide (NO) release and changes in Gp91-phox, i-NOS, and pro and anti-inflammatory cytokines elaborated its intracellular anti-leishmanial activity. The results supported that G. oppositifolius and Spergulin-A can potentiate new lead molecules for the development of alternative drugs against VL.
RNA-DNA hybrids support recombination-based telomere maintenance in fission yeast
Authors: Hu Yan , Bennett Henrietta W. , Liu Na , Moravec Martin , Williams Jessica F. , Azzalin Claus M. , King Megan C.
Published: November 2018

A subset of cancers rely on telomerase-independent mechanisms to maintain their chromosome ends. The predominant “alternative lengthening of telomeres” pathway appears dependent on homology-directed repair (HDR) to maintain telomeric DNA. However, the molecular changes needed for cells to productively engage in telomeric HDR are poorly understood. To gain new insights into this transition, we monitored the state of telomeres during serial culture of fission yeast (Schizosaccharomyces pombe) lacking the telomerase recruitment factor Ccq1. Rad52 is loaded onto critically short telomeres shortly after germination despite continued telomere erosion, suggesting that recruitment of recombination factors is not sufficient to maintain telomeres in the absence of telomerase function. Instead, survivor formation coincides with the derepression of telomeric repeat-containing RNA (TERRA). In this context, degradation of TERRA associated with the telomere in the form of R-loops drives a severe growth crisis, ultimately leading to a novel type of survivor with linear chromosomes and altered cytological telomere characteristics, including the loss of the shelterin component Rap1 (but not the TRF1/TRF2 orthologue, Taz1) from the telomere. We demonstrate that deletion of Rap1 is protective in this context, preventing the growth crisis that is otherwise triggered by degradation of telomeric R-loops in survivors with linear chromosomes. These findings suggest that up-regulation of telomere-engaged TERRA or altered recruitment of shelterin components can support telomerase-independent telomere maintenance.
High interictal connectivity within the resection zone is associated with favorable post-surgical outcomes in focal epilepsy patients
Authors: Shah Preya , Bernabei John , Kini Lohith , Ashourvan Arian , Boccanfuso Jacqueline , Archer Ryan , Oechsel Kelly , Lucas Timothy H. , Bassett Danielle S. , Davis Kathryn A. , Litt Brian
Published: November 2018

Objective

Patients with drug-resistant focal epilepsy are often candidates for invasive surgical therapies. In these patients, it is necessary to accurately localize seizure-generators to ensure seizure freedom following intervention. While intracranial electroencephalography (iEEG) is the gold standard for mapping networks for surgery, this approach requires inducing and recording seizures, which may cause patient morbidity. The goal of this study is to evaluate the utility of mapping interictal (non-seizure) iEEG networks to identify targets for surgical treatment.

Methods

We analyze interictal iEEG recordings and neuroimaging from 27 focal epilepsy patients treated via surgical resection. We generate interictal functional networks by calculating pairwise correlation of iEEG signals across different frequency bands. We identify electrodes falling within surgically resected tissue (i.e. the resection zone), and compute node-level and edge-level synchrony in relation to the resection zone. We associate these metrics with post-surgical outcomes.

Results

Greater overlap between resected electrodes and highly synchronous electrodes is associated with favorable post-surgical outcomes. Additionally, good outcome patients have significantly higher connectivity localized within the resection zone compared to those with poorer postoperative seizure control. This finding persists following normalization by a spatially-constrained null model.

Conclusions

This study suggests that spatially-informed interictal network synchrony measures can distinguish between good and poor post-surgical outcomes. By capturing clinically relevant information during interictal periods, our method may ultimately reduce the need for prolonged invasive implants and provide insights into the pathophysiology of an epileptic brain. We discuss next steps for translating these findings into a prospectively useful clinical tool.
Multiplexed Profiling of Single-cell Extracellular Vesicles Secretion
Authors: Ji Yahui , Qi Dongyuan , Li Linmei , Su Haoran , Li Xiaojie , Luo Yong , Sun Bo , Zhang Fuyin , Lin Bingcheng , Liu Tingjiao , Lu Yao
Published: November 2018

Extracellular vesicles (EVs) are important intercellular mediators regulating health and disease. Conventional EVs surface marker profiling, which was based on population measurements, masked the cell-to-cell heterogeneity in the quantity and phenotypes of EVs secretion. Herein, by using spatially patterned antibodies barcode, we realized multiplexed profiling of single-cell EVs secretion from more than 1000 single cells simultaneously. Applying this platform to profile human oral squamous cell carcinoma (OSCC) cell lines led to deep understanding of previously undifferentiated single cell heterogeneity underlying EVs secretion. Notably, we observed the decrement of certain EV phenotypes (e.g. CD63+EVs) were associated with the invasive feature of both OSCC cell lines and primary OSCC cells. We also realized multiplexed detection of EVs secretion and cytokines secretion simultaneously from the same single cells to investigate multidimensional spectrum of intercellular communications, from which we resolved three functional subgroups with distinct secretion profiles by visualized clustering. In particular, we found EVs secretion and cytokines secretion were generally dominated by different cell subgroups. The technology introduced here enables comprehensive evaluation of EVs secretion heterogeneity at single cell level, which may become an indispensable tool to complement current single cell analysis and EV research.

Significance

Extracellular vesicles (EVs) are cell derived nano-sized particles medicating cell-cell communication and transferring biology information molecules like nucleic acids to regulate human health and disease. Conventional methods for EV surface markers profiling can’t tell the differences in the quantity and phenotypes of EVs secretion between cells. To address this need, we developed a platform for profiling an array of surface markers on EVs from large numbers of single cells, enabling more comprehensive monitoring of cellular communications. Single cell EVs secretion assay led to previously unobserved cell heterogeneity underlying EVs secretion, which might open up new avenues for studying cell communication and cell microenvironment in both basic and clinical research.
Genetic variants related to antihypertensive targets inform drug efficacy and side effects
Authors: Gill Dipender , Georgakis Marios K. , Koskeridis Fotios , Jiang Lan , Feng Qiping , Wei Wei-Qi , Theodoratou Evropi , Elliott Paul , Denny Joshua C. , Malik Rainer , Evangelou Evangelos , Dehghan Abbas , Dichgans Martin , Tzoulaki Ioanna
Published: November 2018

Background

Drug effects can be investigated through natural variation in the genes for their protein targets. We aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are amongst the most commonly used medications worldwide.

Methods

We identified genetic instruments for antihypertensive drug classes as variants in the gene for the corresponding target that associated with systolic blood pressure at genome-wide significance. To validate the instruments, we compared Mendelian randomisation (MR) estimates for drug effects on coronary heart disease (CHD) and stroke risk to randomised controlled trial (RCT) results. Phenome-wide association study (PheWAS) in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University Biobank (BioVU) and in observational analysis of the UK Biobank.

Findings

We identified suitable genetic instruments for beta-blockers (BBs) and calcium channel blockers (CCBs). MR estimates for their effect on CHD and stroke risk respectively were comparable to results from RCTs against placebo. PheWAS in the UK Biobank identified an association of the CCB genetic risk score (scaled to drug effect) with increased risk of diverticulosis (odds ratio [OR] 1.23, 95%CI 1.10-1.38), with a consistent estimate found in BioVU (OR 1.16, 95%CI 0.94-1.44). Association with diverticulosis was further supported in observational analysis of CCB use in the UK Biobank (OR 1.08, 95%CI 1.02-1.15).

Interpretation

We identified valid genetic instruments for BBs and CCBs. Using genetic and observational approaches, we highlighted a previously unreported potential detrimental effect of CCBs on risk of diverticulosis. This work serves as a proof of concept that investigation of genetic variants can offer a complementary approach to exploring the efficacy and side effects of anti-hypertensive medications.

Funding

Wellcome Trust.
Intense and sustained pain reduces cortical responses to auditory stimuli: implications for the interpretation of Heterotopic Noxious Conditioning Stimulation in humans
Authors: Torta DM , Jure FA , Andersen OK , Biurrun Manresa JA
Published: November 2018

Phasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (Heterotopic Noxious Conditioning Stimulation, HNCS). While this effect is thought to rely on a spino-bulbo-spinal mechanism in animals (Diffuse Noxious Inhibitory Controls, DNIC), the underlying neurophysiology in humans may further involve other pathways. In this study, we investigated the role of supraspinal mechanisms in HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the Cold Pressor Test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuliduringHNCS can be ascribed entirely to supraspinal mechanisms. High-density electroencephalography (EEG) was recorded during HNCS and auditory stimuli were administered in three blocks,before,during, andafterHNCS. Nociceptive Withdrawal Reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reducedduringHNCS. Moreover, the amplitude of the NWR was significantly diminishedduringHNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions to DNIC-like effects in humans is questionable. We conclude that the net effects of HCNS cannot be measured independently from attentional/cognitive influences.
Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy
Authors: Abbink Truus E.M. , Wisse Lisanne E. , Jaku Ermelinda , Thiecke Michiel J. , Voltolini-González Daniel , Fritsen Hein , Bobeldijk Sander , Braak Timo J. ter , Polder Emiel , Postma Nienke L. , Bugiani Marianna , Struijs Eduard A. , Verheijen Mark , Straat Nina , van der Sluis Sophie , Thomas Adri A.M. , Molenaar Douwe , van der Knaap Marjo S.
Published: November 2018

Vanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation under stress conditions. Mice with bi-allelic missense mutations in eIF2B recapitulate human VWM. VWM pathomechanisms are unclear. Using polysomal profiling to screen for mRNAs with altered translation we observed most prominent changes in expression of integrated stress response (ISR) mRNAs in brains of mutant compared to wild-type mice; expression levels correlated with disease severity. We substantiated these findings in VWM patients’ brains. ISRIB, an ISR inhibitor, normalized expression of mRNA markers, ameliorated white matter pathology and improved motor skills in VWM mice, thus showing that the ISR is central in VWM pathomechanisms and a viable target for therapy.

One Sentence Summary

ISRIB ameliorates ISR deregulation and clinical signs in VWM mice
Effects of childhood maltreatment on social cognition and brain functional connectivity in borderline personality disorder patients
Authors: Duque Xochitl , Alcalá-Lozano Ruth , González-Olvera Jorge J. , Garza-Villarreal Eduardo A. , Pellicer Francisco
Published: November 2018

Borderline personality disorder (BPD) is a chronic condition characterized by high levels of impulsivity, affective instability, and difficulty to establish and manage interpersonal relationships. This paper assessed differences in performance on social cognitive paradigms (MASC, RMTE) and how it related to child abuse. Specifically, it evaluated the relationship between performance on cognitive paradigms and baseline brain connectivity in patients with BPD, compared to healthy controls.

BPD patients had higher levels of childhood maltreatment, increased impulsivity and aggression, and more dissociative symptoms than control subjects. For the sexual abuse subdimension, there were no differences between the BPD and the control groups, but there was a negative correlation between MASC scores and total childhood maltreatment levels, as well as between physical abuse, physical negligence, and MASC. Both groups showed that the higher the level of childhood maltreatment, the lower the performance on the MASC social cognitive test. Further, in the BPD group, there was hypoconnectivity between the structures responsible for emotion regulation and social cognitive responses that have been described as part of the frontolimbic circuitry. The more serious the child abuse, the lower the connectivity.
Spike: A GPU Optimised Spiking Neural Network Simulator
Authors: Ahmad Nasir , Isbister James B. , Smithe Toby St. Clere , Stringer Simon M.
Published: November 2018

Spiking Neural Network (SNN) simulations require internal variables – such as the membrane voltages of individual neurons and their synaptic inputs – to be updated on a sub-millisecond resolution. As a result, a single second of simulation time requires many thousands of update calculations per neuron. Furthermore, increases in the scale of SNN models have, accordingly, led to manyfold increases in the runtime of SNN simulations. Existing solutions to this problem of scale include high performance CPU based simulators capable of multithreaded execution (“CPU parallelism”). More recent GPU based simulators have emerged, which aim to utilise GPU parallelism for SNN execution. We have identified several key speedups, which give GPU based simulators up to an order of magnitude performance increase over CPU based simulators on several benchmarks. We present the Spike simulator with three key optimisations: timestep grouping, active synapse grouping, and delay insensitivity. Combined, these optimisations massively increase the speed of executing a SNN simulation and produce a simulator which is, on a single machine, faster than currently available simulators.
The CspC pseudoprotease regulates germination of Clostridioides difficile spores in response to multiple environmental signals
Authors: Rohlfing Amy E. , Eckenroth Brian E. , Forster Emily R. , Kevorkian Yuzo , Lauren Donnelly M. , de la Puebla Hector Benito , Doublié Sylvie , Shen Aimee
Published: November 2018

The gastrointestinal pathogen, Clostridioides difficile, initiates infection when its metabolically dormant spore form germinates in the mammalian gut. While most spore-forming bacteria use transmembrane germinant receptors to sense nutrient germinants, C. difficile uses the soluble pseudoprotease, CspC, to detect bile salt germinants. To gain insight into CspC’s unique mechanism of action, we solved its crystal structure. Guided by this structure, we identified CspC mutations that confer either hypo- or hyper-sensitivity to bile salt germinant. Surprisingly, hyper-sensitive CspC variants exhibited bile salt-independent germination as well as increased sensitivity to amino acid and/or calcium co-germinants. Since the mechanism by which C. difficile spores sense co-germinants is unknown, our study provides the first evidence that CspC senses distinct classes of co-germinants in addition to bile salts. Since we observed that specific residues control CspC’s responsiveness to these different signals, CspC is critical for regulating C. difficile germination in response to multiple environmental signals.
Differential gene expression supports a resource-intensive, defensive role for colony production in the bloom-forming haptophyte, Phaeocystis globosa
Authors: Brisbina Margaret Mars , Mitaraia Satoshi
Published: November 2018

Phaeocystis globosa forms dense, monospecific blooms in temperate, northern waters. Blooms are usually dominated by the colonial morphotype—non-flagellated cells embedded in a secreted mucilaginous mass. Colonial Phaeocystis blooms significantly affect food-web structure and function and negatively impact fisheries and aquaculture, but factors initiating colony production remain enigmatic. Destructive P. globosa blooms have been reported in tropical and subtropical regions more recently and warm-water blooms could become more common with continued climate change and coastal eutrophication. We therefore assessed genetic pathways associated with colony production by investigating differential gene expression between colonial and solitary cells in a warm-water Phaeocystis globosa strain. Our results illustrate a transcriptional shift in colonial cells with most of the differentially expressed genes downregulated, supporting a reallocation of resources associated with colony production. Dimethylsulfide and acrylate production and pathogen interaction pathways were upregulated in colonial cells, suggesting a defensive role for colony production. We identify several protein kinase signaling pathways that may influence the transition between morphotypes, providing targets for future research into factors triggering colony production. This study provides novel insights into genetic mechanisms involved in Phaeocystis colony formation and provides new evidence supporting a defensive role for Phaeocystis colonies.
Deformed Alignment of Super-Resolution Images for Semi-flexible Structures in 3D
Authors: Shi Xiaoyu , Garcia Galo , Wang Yina , Reiter Jeremy , Huang Bo
Published: November 2018

Due to low labeling efficiency and structural heterogeneity in fluorescence-based single-molecule localization microscopy (SMLM), image alignment and quantitative analysis is often required to make accurate conclusions on the spatial relationships between proteins. Cryo-electron microscopy (EM) image alignment procedures have been applied to average structures taken with super-resolution microscopy. However, unlike cryo-EM, the much larger cellular structures analyzed by super-resolution microscopy are often heterogeneous, resulting in misalignment. And the light-microscopy image library is much smaller, which makes classification not realistic. To overcome these two challenges, we developed a method to deform semi-flexible ring-shaped structures and then align the 3D structures without classification. These algorithms can register semi-flexible structures with an accuracy of several nanometers in short computation time and with greatly reduced memory requirements. We demonstrated our methods by aligning experimental Stochastic Optical Reconstruction Microscopy (STORM) images of ciliary distal appendages and simulated structures. Symmetries, dimensions, and locations of protein complexes in 3D are revealed by the alignment and averaging for heterogeneous, tilted, and under-labeled structures.
Food web interaction strength distributions are conserved by greater variation between than within predator-prey pairs
Authors: Preston Daniel L. , Falke Landon P. , Henderson Jeremy S. , Novak Mark
Published: November 2018

Species interactions in food webs are usually recognized as dynamic, varying across species, space and time due to biotic and abiotic drivers. Yet food webs also show emergent properties that appear consistent, such as a skewed frequency distribution of interaction strengths (many weak, few strong). Reconciling these two properties requires an understanding of the variation in pairwise interaction strengths and its underlying mechanisms. We estimated stream sculpin feeding rates in three seasons at nine sites in Oregon to examine variation in trophic interaction strengths both across and within predator-prey pairs. We considered predator and prey densities, prey body mass, and abiotic factors as putative drivers of within-pair variation over space and time. We hypothesized that consistently skewed interaction strength distributions could result if individual interaction strengths show relatively little variation, or alternatively, if interaction strengths vary but shift in ways that conserve their overall frequency distribution. We show that feeding rate distributions remained consistently and positively skewed across all sites and seasons. The mean coefficient of variation in feeding rates within each of 25 focal species pairs across surveys was less than half the mean coefficient of variation seen across species pairs within a given survey. The rank order of feeding rates also remained relatively conserved across streams, seasons and individual surveys. On average, feeding rates on each prey taxon nonetheless varied by a hundredfold across surveys, with some feeding rates showing more variation in space and others in time. For most species pairs, feeding rates increased with prey density and decreased with high stream flows and low water temperatures. For nearly half of all species pairs, factors other than prey density explained the most variation, indicating that the strength of density dependence in feeding rates can vary greatly among a generalist predator’s prey species. Our findings show that although individual interaction strengths exhibit considerable variation in space and time, they can nonetheless remain relatively consistent, and thus predictable, compared to the even larger variation that occurs across species pairs. These insights help reconcile how the skewed nature of interaction strength distributions can persist in highly dynamic food webs.
species2vec: A novel method for species representation
Authors: Angelov Boyan
Published: November 2018

Word embeddings are omnipresent in Natural Language Processing (NLP) tasks. The same technology which defines words by their context can also define biological species. This study showcases this new method - species embedding (species2vec). By proximity sorting of 6761594 mammal observations from the whole world (2862 different species), we are able to create a training corpus for the skip-gram model. The resulting species embeddings are tested in an environmental classification task. The classifier performance confirms the utility of those embeddings in preserving the relationships between species, and also being representative of species consortia in an environment.
A new family of neural wiring receptors across bilaterians defined by phylogenetic, biochemical and structural evidence
Authors: Cheng Shouqiang , Park Yeonwoo , Kurleto Justyna D. , Jeon Mili , Zinn Kai , Thornton Joseph W. , Özkan Engin
Published: November 2018

The evolution of complex nervous systems was accompanied by the expansion of groups of protein families, most notably cell adhesion molecules, surface receptors and their ligands. These proteins mediate axonal guidance, synapse targeting, and other neuronal wiring-related functions. Recently, members of a set of thirty interacting cell surface proteins belonging to two newly defined families of the immunoglobulin superfamily (IgSF) in fruit flies were discovered to label different subsets of neurons in the brain and ventral nerve cord. They have been shown to be involved in synaptic targeting and morphogenesis, retrograde signaling, and neuronal survival. Here we show that these proteins, denoted as Dprs and DIPs, belong to a family of two and three-Ig domain molecules in bilaterians generally known for neuronal wiring functions. In protostomes, the ancestral Dpr/DIP gene has duplicated to form heterophilic partners, such as Dprs and DIPs, while in deuterostomes, they have evolved to create the IgLON family of neuronal receptors. In support of this phylogeny, we show that IgLONs interact with each other, and that their complexes can be broken by mutations designed using homology models based on Dpr and DIP structures. Similarly, the nematode orthologs ZIG-8 and RIG-5 can form heterophilic and homophilic complexes structurally matching Dpr-DIP and DIP-DIP complexes. The evolutionary, biochemical and structural relationships we demonstrate here provides insights into neural development and the rise of complexity in metazoans.

Significance Statement

Cell surface receptors assign and display unique identities to neurons, and direct proper and robust wiring of neurons to create functional neural circuits. Recent work has identified two new classes of receptors in fruit flies, called the Dpr and DIP families with 30 members, which interact in 38 pairwise combinations. These proteins are implicated in neural identity, wiring and survival in many parts of the fly nervous system. Here, using evolutionary, biochemical and structural evidence, we show that Dprs and DIPs are members of an ancient bilaterian family of receptors. Members of this family share functional roles relevant to wiring across species, and are likely crucial in the emergence of the bilaterian nervous systems common to vertebrate and invertebrate animals.
Developing and Evaluating Mappings of ICD-10 and ICD-10-CM Codes to PheCodes
Authors: Wu Patrick , Gifford Aliya , Meng Xiangrui , Li Xue , Campbell Harry , Varley Tim , Zhao Juan , Carroll Robert , Bastarache Lisa , Denny Joshua C , Theodoratou Evropi , Wei Wei-Qi
Published: November 2018

Background

The PheCode system was built upon the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) for phenome-wide association studies (PheWAS) in the electronic health record (EHR).

Objective

Here, we present our work on the development and evaluation of maps from ICD-10 and ICD-10-CM codes to PheCodes.

Methods

We mapped ICD-10 and ICD-10-CM codes to PheCodes using a number of methods and resources, such as concept relationships and explicit mappings from the Unified Medical Language System (UMLS), Observational Health Data Sciences and Informatics (OHDSI), Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT), and National Library of Medicine (NLM). We assessed the coverage of the maps in two databases: Vanderbilt University Medical Center (VUMC) using ICD-10-CM and the UK Biobank (UKBB) using ICD-10. We assessed the fidelity of the ICD-10-CM map in comparison to the gold-standard ICD-9-CM→PheCode map by investigating phenotype reproducibility and conducting a PheWAS.

Results

We mapped >75% of ICD-10-CM and ICD-10 codes to PheCodes. Of the unique codes observed in the VUMC (ICD-10-CM) and UKBB (ICD-10) cohorts, >90% were mapped to PheCodes. We observed 70-75% reproducibility for chronic diseases and <10% for an acute disease. A PheWAS with a lipoprotein(a) (LPA) genetic variant, rs10455872, using the ICD-9-CM and ICD-10-CM maps replicated two genotype-phenotype associations with similar effect sizes: coronary atherosclerosis (ICD-9-CM: P < .001, OR = 1.60 vs. ICD-10-CM: P < .001, OR = 1.60) and with chronic ischemic heart disease (ICD-9-CM: P < .001, OR = 1.5 vs. ICD-10-CM: P < .001, OR = 1.47).

Conclusions

This study introduces the initial “beta” versions of ICD-10 and ICD-10-CM to PheCode maps that will enable researchers to leverage accumulated ICD-10 and ICD-10-CM data for high-throughput PheWAS in the EHR.
53BP1 nuclear body-marked replication stress in a human mammary cell model of BRCA2 deficiency
Authors: Feng Weiran , Jasin Maria
Published: November 2018

BRCA2 deficiency causes genome instability and breast and ovarian cancer predisposition, but also paradoxically promotes cell lethality. The nature of the acute, detrimental consequences of BRCA2 loss is not fully understood. We recently generated BRCA2 conditional models from a non-transformed human mammary cell line, through allele-specific gene targeting using CRISPR-Cas9, which we now describe. With these models, we discovered that BRCA2 deficiency triggers a DNA under replication-53BP1 nuclear body formation-G1 arrest axis due to homologous recombination defects. In this Extra-view, we extend these findings to show that 53BP1 nuclear bodies are spatially linked with downstream p53 activation. Replication stress that leads to common fragile site expression to induce 53BP1 nuclear body formation is aggravated by the loss of BRCA2. Additionally, replication stress that does not selectively lead to common fragile site expression is also able to induce 53BP1 nuclear body formation in BRCA2-deficient cells, indicating lesions form more globally throughout the genome. Furthermore, compromising replication fork reversal by SMARCAL1 depletion restores replication fork protection but does not diminish the high replication stress in the BRCA2-deficient cells, further emphasizing that fork protection plays a minor role in these cells. These results further elucidate the causes and consequences of replication stresses in the face of BRCA2 inactivation, providing insight into the barriers that need to be overcome for cells to become tumorigenic.