bluuebunny/crossref_metadata_2025 huggingface dataset:
N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels
Authors: Alexander Veronica J , Xia Shuting , Hurh Eunju , Hughes Steven G , O’Dea Louis , Geary Richard S , Witztum Joseph L , Tsimikas Sotirios
Published: March 2019

Aims

Elevated apolipoprotein C-III (apoC-III) levels are associated with hypertriglyceridaemia and coronary heart disease. AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis.

Methods and results

The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation Phase 1/2a study in healthy volunteers (ages 18–65) with triglyceride levels ≥90 or ≥200 mg/dL. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously (sc) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months. In the single-dose cohorts treated with 10, 30, 60, 90, or 120 mg of AKCEA-APOCIII-LRx, median reductions of 0, −42%, −73%, −81%, and −92% in apoC-III, and −12%, −7%, −42%, −73%, and −77% in triglycerides were observed 14 days after dosing. In multiple-dose cohorts of 15 and 30 mg weekly and 60 mg every 4 weeks, median reductions of −66%, −84%, and −89% in apoC-III, and −59%, −73%, and −66% in triglycerides were observed 1 week after the last dose. Significant reductions in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, and increases in HDL-C were also observed. AKCEA-APOCIII-LRx was well tolerated with one injection site reaction of mild erythema, and no flu-like reactions, platelet count reductions, liver, or renal safety signals.

Conclusion

Treatment of hypertriglyceridaemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile. ClinicalTrials.gov Identifier: NCT02900027.
On the Outlying Eigenvalues of a Polynomial in Large Independent Random Matrices
Authors: Belinschi Serban T , Bercovici Hari , Capitaine Mireille
Published: March 2019

Given a selfadjoint polynomial $P(X,Y)$ in two noncommuting selfadjoint indeterminates, we investigate the asymptotic eigenvalue behavior of the random matrix $P(A_N,B_N)$, where $A_N$ and $B_N$ are independent Hermitian random matrices and the distribution of $B_N$ is invariant under conjugation by unitary operators. We assume that the empirical eigenvalue distributions of $A_N$ and $B_N$ converge almost surely to deterministic probability measures $\mu$ and $\nu$, respectively. In addition, the eigenvalues of $A_N$ and $B_N$ are assumed to converge uniformly almost surely to the support of $\mu$ and $\nu ,$ respectively, except for a fixed finite number of fixed eigenvalues (spikes) of $A_N$. It is known that almost surely the empirical distribution of the eigenvalues of $P(A_N,B_N)$ converges to a certain deterministic probability measure $\eta \ (\textrm{sometimes denoted}\ P^\square(\mu,\nu))$ and, when there are no spikes, the eigenvalues of $P(A_N,B_N)$ converge uniformly almost surely to the support of $\eta$. When spikes are present, we show that the eigenvalues of $P(A_N,B_N)$ still converge uniformly to the support of $\eta$, with the possible exception of certain isolated outliers whose location can be determined in terms of $\mu ,\nu ,P$, and the spikes of $A_N$. We establish a similar result when $B_N$ is replaced by a Wigner matrix. The relation between outliers and spikes is described using the operator-valued subordination functions of free probability theory. These results extend known facts from the special case in which $P(X,Y)=X+Y$.
Challenge of drug resistance in Pseudomonas aeruginosa: clonal spread of NDM-1-positive ST-308 within a tertiary hospital
Authors: Chew Ka Lip , Octavia Sophie , Ng Oon Tek , Marimuthu Kalisvar , Venkatachalam Indumathi , Cheng Bernadette , Lin Raymond T P , Teo Jeanette W P
Published: March 2019

Objectives

MDR Pseudomonas aeruginosa is a serious global threat to healthcare institutions. The mechanism by which drug resistance can be acquired is variable, but acquired carbapenemase production has been reported in P. aeruginosa. An investigation was performed to determine the rate and genomic epidemiology of New Delhi MBL (NDM) in β-lactam-non-susceptible isolates.

Methods

P. aeruginosa isolates from a tertiary hospital in Singapore between January 2015 and February 2018 were investigated for the presence of NDM genes.

Results

Out of 298 pan-β-lactam-non-susceptible isolates, 31 were found to be NDM positive (10.4%). WGS demonstrated that all 31 NDM-positive isolates were clonal, belonging to ST-308. blaNDM was chromosomally inserted within an integrative and conjugative element (ICE), ICETn43716385. The NDM-P. aeruginosa isolates possessed an extensive repertoire of both cell-associated [flagella, pili, alginate/biofilm, LPS, type III secretion system (T3SS) and type VI secretion system (T6SS)] and secreted virulence factors. Antibiograms revealed higher rates of drug resistance in NDM-positive isolates compared with their non-NDM counterparts. The NDM isolates remained 100% susceptible only to colistin.

Conclusions

The combination of chromosomal mutations, acquired resistance genes and virulence factors likely facilitated the persistent and ongoing spread of the ST-308 clade of P. aeruginosa within the hospital. Our study illustrates the particular threat of NDM-positive P. aeruginosa in a tertiary hospital setting in the era of antimicrobial resistance.
A Case of Surreptitious Glargine Overdose Confirmed by Insulin Pharmacokinetic Time Curves
Authors: Barmanray Rahul , Chiang Cherie Ying , Yeoh Kim , Yates Christopher James
Published: March 2019

Case

A 49-year-old man presented with recurrent altered conscious state suggestive of encephalitis. This was followed by an episode of severe hypoglycemia requiring protracted intravenous glucose administration. Comparing the pharmacokinetic time curves of serum insulin levels on two insulin immunoassays with different insulin analog cross-reactivity allowed the likely diagnosis of surreptitious glargine overdose to be made rapidly.

Discussion

The differing insulin analog cross-reactivity of serum insulin immunoassays, in this case the Abbott ARCHITECT and Roche Elecsys, allows the presence of insulin analog to be detected. Through comparison of time curves the characteristic signature of the specific causative insulin analog can be identified. This information confirms surreptitious insulin overdose in a timely manner, therefore avoiding the expensive and time-consuming investigations required to exclude alternate causes of severe hypoglycemia.
Preliminary Screening of Mosquito Spatial Distribution in Togo: With Special Focus on the Aedes (Diptera: Culicidae) Species
Authors: Thabet Hala S , Fawaz Emadeldin Y , Badziklou Kossi , Tag ElDin Reham A , Kaldas Rania M , Fahmy Nermeen T , Tamekloe Tsidi Agbeko , Kere-Banla Abiba , Diclaro Joseph W
Published: March 2019

The Togolese Republic has a tropical and humid climate which constitutes an ideal environment for mosquitoes to breed and transmit diseases. The Aedes mosquito is known to transmit yellow fever (YF), dengue, chikungunya, and Zika viruses in West Africa. Togo has been suffering from YF virus transmission, despite vaccination efforts. Unfortunately, there is scarcity in the data that reflect mosquito spatial distribution in Togo, specifically possible YF vectors. In the current study, mosquito surveillance efforts targeted areas with confirmed YF cases between July and August 2012. Indoor mosquitoes were collected using knockdown insecticide spraying, whereas Biogents (BG) traps were used to collect outdoor mosquito adults. Mosquito larval surveillance was conducted as well. In total, 17 species were identified. This investigation revealed the presence of medically important vectors in Togo, especially the Aedes aegypti (Linnaeus) (Diptera: Culicidae) which was collected in the four regions. Screening of all pools of female Aedes mosquitoes for YF, by real-time PCR, showed negative results. This is the first record for Coquillettidia flavocincta (Edwards) (Diptera: Culicidae) species in West Africa. This preliminary work serves as a baseline for further mosquito distribution studies in Togo.
Acupuncture Versus Cognitive Behavioral Therapy for Insomnia in Cancer Survivors: A Randomized Clinical Trial
Authors: Garland Sheila N , Xie Sharon X , DuHamel Kate , Bao Ting , Li Qing , Barg Frances K , Song Sarah , Kantoff Philip , Gehrman Philip , Mao Jun J
Published: March 2019

Background

Insomnia is a common and debilitating disorder experienced by cancer survivors. Although cancer survivors express a preference for using nonpharmacological treatment to manage insomnia, the comparative effectiveness between acupuncture and Cognitive Behavioral Therapy for Insomnia (CBT-I) for this disorder is unknown.

Methods

This randomized trial compared 8 weeks of acupuncture (n = 80) and CBT-I (n = 80) in cancer survivors. Acupuncture involved stimulating specific points on the body with needles. CBT-I included sleep restriction, stimulus control, cognitive restructuring, relaxation training, and education. We measured insomnia severity (primary outcome), pain, fatigue, mood, and quality of life posttreatment (8 weeks) with follow-up until 20 weeks. We used linear mixed-effects models for analyses. All statistical tests were two-sided.

Results

The mean age was 61.5 years and 56.9% were women. CBT-I was more effective than acupuncture posttreatment (P < .001); however, both acupuncture and CBT-I produced clinically meaningful reductions in insomnia severity (acupuncture: −8.31 points, 95% confidence interval = −9.36 to −7.26; CBT-I: −10.91 points, 95% confidence interval = −11.97 to −9.85) and maintained improvements up to 20 weeks. Acupuncture was more effective for pain at the end of treatment; both groups had similar improvements in fatigue, mood, and quality of life and reduced prescription hypnotic medication use. CBT-I was more effective for those who were male (P < .001), white (P = .003), highly educated (P < .001), and had no pain at baseline (P < .001).

Conclusions

Although both treatments produced meaningful and durable improvements, CBT-I was more effective and should be the first line of therapy. The relative differences in the comparative effectiveness between the two interventions for specific groups should be confirmed in future adequately powered trials to guide more tailored interventions for insomnia.
Latitude, distance offshore and local environmental features as modulators of zooplankton assemblages across the NE Atlantic Shelves Province
Authors: Fanjul Alvaro , Iriarte Arantza , Villate Fernando , Uriarte Ibon , Artiach Miguel , Atkinson Angus , Cook Kathryn
Published: March 2019

Contribution of latitude, distance offshore and environmental factors to variations in zooplankton assemblages across the Northeast Atlantic Shelves Province, from the Bay of Biscay [Bilbao 35 (B35) and Urdaibai 35 (U35)] to the English Channel (Plymouth L4; L4) and the North Sea (Stonehaven; SH), were assessed mainly by redundancy analysis. For coarse zooplankton groups latitude explained the main between-site differences, and meroplankton contributed more than holoplankton. Latitudinal differences were best indicated by contrasting abundances of cirripede larvae and doliolids (most abundant at the lowest latitude sites) and bryozoan and polychaete larvae (most abundant at the highest latitude site). Doliolids were best indicators of temperature-mediated latitudinal differences. The interaction between latitude and distance offshore or salinity and phytoplankton biomass explained smaller percentages of the variability. The main differences in copepod and cladoceran genera reflected the oceanic influence, with highest presence of Corycaeus and Oncaea at L4, likely related to the higher influence of off-shelf water intrusions, and neritic Acartia dominating at SH, U35 and B35. Podon and Evadne, which decreased from south to north, reflected latitude-related differences driven more by salinity than by temperature. Instances where a single species (e.g. Acartia clausi) dominated showed common relationships with temperature, consistent with a common thermal niche. Differences in co-generic species dominance between sites depicted the latitudinal gradient.
Short-term follow-up results of children with familial Mediterranean fever after cessation of colchicine: is it possible to quit?
Authors: Tanatar Ayşe , Karadağ Şerife Gül , Sönmez Hafize Emine , Çakan Mustafa , Aktay Ayaz Nuray
Published: March 2019

Objective

To define the characteristics of children expressing the FMF phenotype under colchicine until it was ceased and to compare the clinical features of patients requiring colchicine again with the patients who did not need colchicine.

Methods

Sixty-four of 1786 children with FMF in whom colchicine was stopped by the physician or patients/parents were enrolled. These patients were grouped as children who were in need of colchicine due to attacks and/or elevated acute phase reactants after cessation of colchicine (group 1) and children in whom colchicine was not necessary and not restarted (group 2).

Results

Colchicine was stopped in 59.4% by the physician and in 40.6% by the patient/parents. It was ceased at a median of 10.6 years of age (range 2.1–20.5) and attack- and inflammation-free periods of 18.2 months (range 6–148). The median follow-up of 64 patients after colchicine cessation was 37.4 months (range 6.4–154.7). It was restarted in 17 patients due to attacks (n = 11) or elevated acute phase reactants (n = 6). The age at cessation of the colchicine was lower (P = 0.04) and the duration of colchicine treatment until its cessation was shorter (P = 0.007) in group 1 compared with group 2.

Conclusion

Life-long colchicine treatment may not be required in all FMF patients. There are no current guidelines to determine in which patients it is safe to stop colchicine. We found that younger age during cessation and shorter duration of colchicine treatment lead to a higher risk of needing to restart colchicine.
Evaluating the implementation fidelity of a community-based intervention to promote hearing conservation among farm and rural youth
Authors: McCullagh Marjorie , Cohen Michael A , Koval Madison , Haberkorn Elizabeth , Wood Michelle
Published: March 2019

Noise-induced hearing loss is common among farm and rural youth. There is a lack of programs preparing this high-risk population to use hearing conservation strategies. Safety Days are 1-day workshops that teach 100,000 rural children safe farm practices in 400 sites across the USA annually. As part of a larger study for fourth graders, a hearing conservation lesson was delivered at 25 sites nationwide. However, the fidelity to the study-designed curriculum and quality of instruction was unknown. We examined whether community volunteers are capable of delivering, with adequate fidelity and quality, a planned intervention designed to increase use of hearing conservation strategies among farm and rural youth. We invited instructors (n = 22) to deliver a health lesson to fourth graders and provide lesson recordings. We developed instruments rating (i) fidelity of the teaching to the curriculum and (ii) quality of instruction. Initial instruments were modified based on the review for clarity, relevance, and conceptual fit; inter-rater reliabilities were .90 (content fidelity) and 1.00 (quality of instruction). Of seven recordings reviewed, mean fidelity to the planned curriculum was 1.51 (max score = 2), with nearly four fifths of lesson items fully addressed. Overall mean of rating of quality of instruction was 1.97 (out of 2). Fidelity to both content and quality of instruction was high. Results provide a model and support for use of community volunteers (with no special educational or experiential background) and fidelity testing as cost-effective strategies to provide sustainable programming for hearing conservation among farm and rural youth.
Valid and powerful group statistics for decoding accuracy: Information Prevalence Inference using the i-th order statistic (i-test)
Authors: Hirose Satoshi
Published: March 2019

In fMRI decoding studies using pattern classification, a “second-level” group statistical test is typically performed after “first-level” decoding analyses for individual participants. Neuroscientists often test the mean decoding accuracy across participants against the chance-level accuracy (e.g., one-sample Student t-test) to verify whether brain activation includes information about the label (i.e., cognitive content). However, Allefeld et al., (2016) notified that positive results for such tests only indicate that “there are some people in the population whose fMRI data carry information about the experimental condition.” Thus, such tests cannot provide inferences about the trend of the majority. They proposed an alternative method, in which prevalence inference is implemented. In this study, I extended their method and propose statistical test “information prevalence inference using the i-th order statistic (i-test)”. Compared with the method proposed in the previous study, i-test has high statistical power to provide an inference regarding major population trends. In i-test, the i-th lowest sample decoding accuracy (the i-th order statistic) is compared to the null distribution to test whether the proportion of the higher-than-chance decoding accuracy in the population (information prevalence) is higher than the threshold. Thus, a significant result of the i-test can be interpreted as “the majority of the population has information about the label in the brain.” Numerical calculation identified its high statistical power. Also, theoretical detail is provided, and the use of this method in an fMRI decoding study is demonstrated.

Allefeld, C., Görgen, K., Haynes, J.D., 2016. Valid population inference for information-based imaging: From the second-level t-test to prevalence inference. Neuroimage.
High-throughput quantitative detection of basal autophagy and autophagic flux using image cytometry
Authors: SenthilKumar Gopika , Skiba Justin H. , Kimple Randall J.
Published: March 2019

Quantitative assessment of changes in macro-autophagy is often performed through manual quantification of the number of LC3B foci in immunofluorescence microscopy images. This method is highly laborious, subject to image-field selection and foci-counting bias, and is not sensitive for analyzing changes in basal autophagy. Alternative methods such as flow cytometry and transmission electron microscopy require highly specialized, expensive instruments and time-consuming sample preparation. Immunoblots are prone to exposure-related variations and noise that prevent accurate quantification. We report a high-throughput, inexpensive, reliable, and objective method for studying basal level and flux changes in late-stage autophagy using image cytometry and acridine orange staining.

Methods summary

A high-throughput, inexpensive, reliable, and objective method for studying both basal autophagy and autophagic flux is reported. This approach uses acridine orange staining of late-stage autophagy and image cytometry to quantify autophagy.
Lateral pressure equalisation as a principle for designing support surfaces to prevent deep tissue pressure ulcers
Authors: Boyle Colin J. , Carpanen Diagarajen , Pandelani Thanyani , Higgins Claire A. , Masen Marc A. , Masouros Spyros D.
Published: March 2019

When immobile or neuropathic patients are supported by beds or chairs, their soft tissues undergo deformations that can cause pressure ulcers. Current support surfaces that redistribute under-body pressures at vulnerable body sites have not succeeded in reducing pressure ulcer prevalence. Here we show that adding a supporting lateral pressure can counter-act the deformations induced by under-body pressure, and that this ‘pressure equalisation’ approach is a more effective way to reduce ulcer-inducing deformations than current approaches based on redistributing under-body pressure.

A finite element model of the seated pelvis predicts that applying a lateral pressure to the soft tissue reduces peak von Mises stress in the deep tissue by a factor of 2.4 relative to a standard cushion — a greater effect than that achieved by using a more conformable cushion. The ratio of peak lateral pressure to peak under-body pressure was shown to regulate deep tissue stress better than under-body pressure alone. By optimising the magnitude and position of lateral pressure, tissue deformations can be reduced to that induced when suspended in a fluid.

Our results explain the lack of efficacy in current support surfaces, and suggest a new approach to designing and evaluating support surfaces: ensuring sufficient lateral pressure is applied to counter-act under-body pressure.
Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal
Authors: Madayag Aric C. , Gomez Devan , Anderson Eden M. , Ingebretson Anna E. , Thomas Mark J. , Hearing Matthew
Published: March 2019

Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the NAcSh and NAcC sub-regions in hopes of identifying excitatory plasticity that may contribute to differing facets of opioid addiction-related behavior. Three hours following an acute morphine injection (10 mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the shell and core regions, whereas only the frequency of events was elevated at D2-MSNs in the shell. In contrast, somatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100mg/kg) only enhanced mEPSC frequency at D2-MSNs in the shell 24 hrs following the final drug exposure. Further, drug re-exposure 10-14 days following a preference-inducing regimen of morphine produced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference – a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. While differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following exposure to relapse-linked stimuli, our findings indicate this plasticity has distinct behavioral consequences.

Compliance with Ethical Standards

The authors have no conflicts of interest to disclose. All authors have given their consent for manuscript submission. The research in the current study used mice single- or group-housed on a 12 h light/dark cycle with food and water available ad libitum with experiments run during the light portion. All experiments were approved by the University of Minnesota and Marquette University Institutional Animal Care and Use Committee. The following funding sources made the study possible: National Institute for Neurological Disorders and Stroke (P30 NS062158); National Institute on Drug Abuse grant K99 DA038706 (to M.H.), R00DA038706 (M.H.), R00DA038706-04S1 (A.C.M), R01DA019666 (M.J.T.), K02DA035459 (M.J.T.) and T32 DA007234 (A.E.I.).
ezTrack: An open-source video analysis pipeline for the investigation of animal behavior
Authors: Pennington Zachary T. , Dong Zhe , Bowler Regina , Feng Yu , Vetere Lauren M , Shuman Tristan , Cai Denise J.
Published: March 2019

Tracking small animal behavior by video is one of the most common tasks in the fields of neuroscience and psychology. Although commercial software exists for the execution of this task, commercial software often presents enormous cost to the researcher, and can also entail purchasing specific hardware setups that are not only expensive but lack adaptability. Moreover, the inaccessibility of the code underlying this software renders them inflexible. Alternatively, available open source options frequently require extensive model training and can be challenging for those inexperienced with programming. Here we present an open source and platform independent set of behavior analysis pipelines using interactive Python (iPython/Jupyter Notebook) that researchers with no prior programming experience can use. Two modules are described. One module can be used for the positional analysis of an individual animal across a session (i.e., location tracking), amenable to a wide range of behavioral tasks including conditioned place preference, water maze, light-dark box, open field, and elevated plus maze, to name but a few. A second module is described for the analysis of conditioned freezing behavior. For both modules, a range of interactive plots and visualizations are available to confirm that chosen parameters produce results that conform to the user’s approval. In addition, batch processing tools for the fast analysis of multiple videos is provided, and frame-by-frame output makes aligning the data with neural recording data simple. Lastly, options for cropping video frames to mitigate the influence of fiberoptic/electrophysiology cables, analyzing specified portions of time in a video, and defining regions of interest, can be implemented with ease.
Common DNA sequence variation influences 3-dimensional conformation of the human genome
Authors: Gorkin David U. , Qiu Yunjiang , Hu Ming , Fletez-Brant Kipper , Liu Tristin , Schmitt Anthony D. , Noor Amina , Chiou Joshua , Gaulton Kyle J , Sebat Jonathan , Li Yun , Hansen Kasper D. , Ren Bing
Published: March 2019

The 3-dimensional (3D) conformation of chromatin inside the nucleus is integral to a variety of nuclear processes including transcriptional regulation, DNA replication, and DNA damage repair. Aberrations in 3D chromatin conformation have been implicated in developmental abnormalities and cancer. Despite the importance of 3D chromatin conformation to cellular function and human health, little is known about how 3D chromatin conformation varies in the human population, or whether DNA sequence variation between individuals influences 3D chromatin conformation. To address these questions, we performed Hi-C on Lymphoblastoid Cell Lines (LCLs) from 20 individuals. We identified thousands of regions across the genome where 3D chromatin conformation varies between individuals and found that this conformational variation is often accompanied by variation in gene expression, histone modifications, and transcription factor (TF) binding. Moreover, we found that DNA sequence variation influences several features of 3D chromatin conformation including loop strength, contact insulation, contact directionality and density of localciscontacts. We mapped hundreds of Quantitative Trait Loci (QTLs) associated with 3D chromatin features and found evidence that some of these same variants are associated at modest levels with other molecular phenotypes as well as complex disease risk. Our results demonstrate that common DNA sequence variants can influence 3D chromatin conformation, pointing to a more pervasive role for 3D chromatin conformation in human phenotypic variation than previously recognized.
FIND: Identifying Functionally and Structurally Important Features in Protein Sequences with Deep Neural Networks
Authors: Murali Ranjani , Hemp James , Orphan Victoria , Bisk Yonatan
Published: March 2019

The ability to correctly predict the functional role of proteins from their amino acid sequences would significantly advance biological studies at the molecular level by improving our ability to understand the biochemical capability of biological organisms from their genomic sequence. Existing methods that are geared towards protein function prediction or annotation mostly use alignment-based approaches and probabilistic models such as Hidden-Markov Models. In this work we introduce a deep learning architecture (FunctionIdentification withNeuralDescriptions orFIND) which performs protein annotation from primary sequence. The accuracy of our methods matches state of the art techniques, such as protein classifiers based on Hidden Markov Models. Further, our approach allows for model introspection via a neural attention mechanism, which weights parts of the amino acid sequence proportionally to their relevance for functional assignment. In this way, the attention weights automatically uncover structurally and functionally relevant features of the classified protein and find novel functional motifs in previously uncharacterized proteins. While this model is applicable to any database of proteins, we chose to apply this model to superfamilies of homologous proteins, with the aim of extracting features inherent to divergent protein families within a larger superfamily. This provided insight into the functional diversification of an enzyme superfamily and its adaptation to different physiological contexts. We tested our approach on three families (nitrogenases, cytochromebd-type oxygen reductases and heme-copper oxygen reductases) and present a detailed analysis of the sequence characteristics identified in previously characterized proteins in the heme-copper oxygen reductase (HCO) superfamily. These are correlated with their catalytic relevance and evolutionary history. FIND was then applied to discover features in previously uncharacterized members of the HCO superfamily, providing insight into their unique sequence features. This modeling approach demonstrates the power of neural networks to recognize patterns in large datasets and can be utilized to discover biochemically and structurally important features in proteins from their amino acid sequences.

Author summary
Deep learning-based imaging classification identified cingulate island sign in dementia with Lewy bodies
Authors: Iizuka Tomomichi , Fukasawa Makoto , Kameyama Masashi
Published: March 2019

abstract

The differentiation of dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD) using brain perfusion single photon emission tomography is important but has been a challenge because these conditions have common features. The cingulate island sign (CIS) is the most recently identified specific feature of DLB for a differential diagnosis. The present study aimed to examine the usefulness of deep learning-based imaging classification for the diagnoses of DLB and AD. We also investigated whether CIS was focused by the deep convolutional neural network (CNN) during differentiation.

Brain perfusion single photon emission tomography images were acquired from 80 patients each with DLB and with AD and 80 individuals with normal cognition (NL). The CNN was trained on brain surface perfusion images. Gradient-weighted class activation mapping (Grad-CAM) was applied to the CNN for visualization of the features that the trained CNN focused on.

Binary classifications between DLB and NL, DLB and AD and AD and NL were 94.69%, 87.81% and 94.38% accurate, respectively. The CIS ratios closely correlated with softmax output scores for DLB-AD discrimination (DLB/AD scores). The Grad-CAM highlighted CIS in the DLB discrimination. Visualization of learning process by guided Grad-CAM revealed that CIS became more focused by the CNN as the training progressed. DLB/AD score was significantly associated with three core-features of DLB.

Deep learning-based imaging classification was useful not only for objective and accurate differentiation of DLB from AD but also for predicting clinical features of DLB. The CIS was identified as a specific feature during DLB classification. The visualization of specific features and learning process could have important implications for the potential of deep learning to discover new imaging features.
Population fragmentation leads to morpho-functional variation in British red squirrels (Sciurus vulgaris)
Authors: Cox Philip G. , Morris Philip J.R. , Kitchener Andrew C.
Published: March 2019

It is well-known that population fragmentation and isolation can lead to rapid morphological and functional divergence, with the effect being particularly well-documented in rodents. Here, we investigated whether such a phenomenon could be identified in the Eurasian red squirrel (Sciurus vulgaris), which was once widespread across the majority of Great Britain, but suffered a severe population decline across the 20thcentury, leaving a highly fragmented distribution. The aim was to test for morphological and biomechanical variation of the mandible between the remaining British red squirrel populations. Linear and geometric morphometric methods were used to analyse shape in a sample of over 250 squirrel mandibles from across the UK and Germany. Canonical variates analysis identified significant shape differences between most British red squirrel populations, but particularly between squirrels from Formby and those from other populations. Linear measurements showed that Formby red squirrels have a significantly lower mechanical advantage of the temporalis muscle, indicating that they are less efficient at gnawing. We suggest that this difference may be related to past supplemental feeding of Formby squirrels with peanuts, which are less mechanically resistant than food items that occur naturally in the diet of British red squirrels.
Relationship between faecal microbiota and plasma metabolome in rats fed NK603 and MON810 GM maize from the GMO90+ study
Authors: Mesnage Robin , Le Roy Caroline I. , Biserni Martina , Salles Bernard , Antoniou Michael N.
Published: March 2019

Safety concerns arising from the consumption of foods derived from genetically modified (GM) crops remains a highly debated and controversial subject. We report here a faecal microbiota compositional analysis in Wistar rats from the GMO90+ study, which fed glyphosate-tolerant NK603 (+/− Roundup application during cultivation) and Bt toxin MON810 GM maize for 6 months (at 11 and 33% composition of the feed) in comparison to their closest non-GM isogenic lines. We first integrated the faecal microbiota compositional data with results from plasma metabolomics to establish a baseline allowing us to understand which bacterial species can influence host metabolism.CoriobacteriaceaeandAcetatifactorsignificantly predicted plasma metabolic profile in males, whileBifidobacteriumandRuminococcuswere able to predict female plasma metabolites. We then investigated the differences in fecal microbiota composition between group of rats fed MON810 or NK603 GM maize varieties in comparison to their respective isogenic lines. Bacterial community richness was not altered by the test diets. There were no statistically significant differences in taxa abundance in the rat faecal microbiota that we could attribute to the consumption of either MON810 or NK603 GM maize varieties. In conclusion, we show that the consumption of the widely cultivated GM maize varieties NK603 and MON810 even up to 33% of the total diet had no effect on the status of the faecal microbiota compared to non-GM near isogenic lines.
Just how big is intraspecific trait variation in basidiomycete wood fungal fruit bodies?
Authors: Dawson Samantha K. , Jönsson Mari
Published: March 2019

As the use of functional trait approaches is growing in fungal ecology, there is a corresponding need to understand trait variation. Much of trait theory and statistical techniques are built on the assumption that interspecific variation is larger than intraspecific variation. This allows the use of mean trait values for species, which the vast majority of trait studies adopt. We examined the size of intra- vs. inter-specific variation in two wood fungal fruit body traits: size and density. Both coefficients of variation (CV) and Trait Probability Density analyses were used to quantify trait variation. We found that intraspecific variation in fruit body density was more than twice as variable as interspecific variation, and fruit body size was hugely variable (CVs averaged 190%), although interspecific variation was larger. Further, there was a very high degree of overlap in the trait space of species, indicating that there may be little niche partitioning at the species level. These findings show that intraspecific variation is highly important and should be accounted for when using trait approaches to understand fungal ecology. More data on variation of other fungal traits is also desperately needed to ascertain whether the high level of variation found here is typical for fungi. While the need to measure individuals does reduce the ability to generalise at the species level, it does not negate the usefulness of fungal trait measurements. There are two reasons for this: first, the ecology of most fungal species remains poorly known and trait measurements address this gap; and secondly, if trait overlap between species more generally is as much as we found here, then individual measurements may be more helpful than species identity for untangling fungal community dynamics.
Initiation of chromosome replication controls both division and replication cycles in E. coli through a double-adder mechanism
Authors: Witz Guillaume , van Nimwegen Erik , Julou Thomas
Published: March 2019

Living cells proliferate by completing and coordinating two essential cycles, a division cycle that controls cell size, and a DNA replication cycle that controls the number of chromosomal copies in the cell. Despite lacking dedicated cell cycle control regulators such as cyclins in eukaryotes, bacteria such as E. coli manage to tightly coordinate those two cycles across a wide range of growth conditions, including situations where multiple nested rounds of replication progress simultaneously. Various cell cycle models have been proposed to explain this feat, but it has been impossible to validate them so far due to a lack of experimental tools for systematically testing their different predictions. Recently new insights have been gained on the division cycle through the study of the structure of fluctuations in growth, size, and division in individual cells. In particular, it was found that cell size appears to be controlled by an adder mechanism, i.e. the added volume between divisions is held approximately constant and fluctuates independently of growth rate and cell size at birth. However, how replication initiation is regulated and coupled to cell size control remains unclear, mainly due to scarcity of experimental measurements on replication initiation at the single-cell level. Here, we used time-lapse microscopy in combination with microfluidics to directly measure growth, division and replication in thousands of single E. coli cells growing in both slow and fast growth conditions. In order to compare different phenomenological models of the cell cycle, we introduce a statistical framework which assess their ability to capture the correlation structure observed in the experimental data. Using this in combination with stochastic simulations, our data indicate that, instead of thinking of the cell cycle as running from birth to division, the cell cycle is controlled by two adder mechanisms starting at the initiation of replication: the added volume since the last initiation event controls the timing of both the next division event and the next replication initiation event. Interestingly the double-adder mechanism identified in this study has recently been found to explain the more complex cell cycle of mycobacteria, suggesting shared control strategies across species.
Augmented Interval List: a novel data structure for efficient genomic interval search
Authors: Feng Jianglin , Ratan Aakrosh , Sheffield Nathan C.
Published: March 2019

Motivation

Genomic data is frequently stored as segments or intervals. Because this data type is so common, interval-based comparisons are fundamental to genomic analysis. As the volume of available genomic data grows, developing efficient and scalable methods for searching interval data is necessary.

Results

We present a new data structure, the augmented interval list (AIList), to enumerate intersections between a query interval q and an interval set R. An AIList is constructed by first sorting R as a list by the interval start coordinate, then decomposing it into a few approximately flattened components (sublists), and then augmenting each sublist with the running maximum interval end. The query time for AIList is O(log2N + n + m), where n is the number of overlaps between R and q, N is the number of intervals in the set R, and m is the average number of extra comparisons required to find the n overlaps. Tested on real genomic interval datasets, AIList code runs 5 - 18 times faster than standard high-performance code based on augmented interval-trees (AITree), nested containment lists (NCList), or R-trees (BEDTools). For large datasets, the memory-usage for AIList is 4% - 60% of other methods. The AIList data structure, therefore, provides a significantly improved fundamental operation for highly scalable genomic data analysis.

Availability

An implementation of the AIList data structure with both construction and search algorithms is available at code.databio.org/AIList.
Genome sequence of the euryhaline Javafish medaka, Oryzias javanicus: a small aquarium fish model for studies on adaptation to salinity
Authors: Takehana Yusuke , Zahm Margot , Cabau Cédric , Klopp Christophe , Roques Céline , Bouchez Olivier , Donnadieu Cécile , Barrachina Celia , Journot Laurent , Kawaguchi Mari , Yasumasu Shigeki , Ansai Satoshi , Naruse Kiyoshi , Inoue Koji , Shinzato Chuya , Schartl Manfred , Guiguen Yann , Herpin Amaury
Published: March 2019

Background

The genus Oryzias is constituted of 35 medaka-fish species each exhibiting various ecological, morphological and physiological peculiarities and adaptations. Beyond of being a comprehensive phylogenetic group for studying intra-genus evolution of several traits like sex determination, behaviour, morphology or adaptation through comparative genomic approaches, all medaka species share many advantages of experimental model organisms including small size and short generation time, transparent embryos and genome editing tools for reverse and forward genetic studies. The Java medaka, Oryzias javanicus, is one of the two species of medaka perfectly adapted for living in brackish/sea-waters. Being an important component of the mangrove ecosystem, O. javanicus is also used as a valuable marine test-fish for ecotoxicology studies. Here, we sequenced and assembled the whole genome of O. javanicus, and anticipate this resource will be catalytic for a wide range of comparative genomic, phylogenetic and functional studies.

Findings

Complementary sequencing approaches including long-read technology and data integration with a genetic map allowed the final assembly of 908 Mbp of the O. javanicus genome. Further analyses estimate that the O. javanicus genome contains 33% of repeat sequences and has a heterozygosity of 0.96%. The achieved draft assembly contains 525 scaffolds with a total length of 809.7 Mbp, a N50 of 6.3 Mbp and a L50 of 37 scaffolds. We identified 21454 expressed transcripts for a total transcriptome size of 57, 146, 583 bps.

Conclusions

We provide here a high-quality draft genome assembly of the euryhaline Javafish medaka, and give emphasis on the evolutionary adaptation to salinity.
Two gut microbes are necessary and sufficient for normal cognition in Drosophila melanogaster
Authors: DeNieu Michael , Mounts Kristin , Manier Mollie
Published: March 2019

It is widely accepted that the gut microbiome can affect various aspects of brain function, including anxiety, depression, learning, and memory. However, we know little about how individual microbial species contribute to communication along the gut-brain axis. Vertebrate microbiomes are comprised of hundreds of species, making it difficult to systematically target individual microbes and their interactions. Here, we use Drosophila melanogaster as a simple model organism to tease apart individual and combined effects of gut microbes on cognition. We used an aversive phototactic suppression assay to show that two dominant gut commensals in our lab stock, Lactobacillus and Acetobacter, are necessary and sufficient for normal learning and short-term memory relative to flies with a conventional microbiome. We also demonstrate that microbes did not affect their hosts’ ability to detect the aversive learning stimulus (quinine), suggesting that our results were due to decreased cognition and not sensory deficits. We thus establish Drosophila as a model for elucidating mechanisms of gut-brain communication at the level of individual bacterial species.
Differential impacts of the head onPlatynereis dumeriliiperipheral circadian rhythms
Authors: Arboleda Enrique , Zurl Martin , Tessmar-Raible Kristin
Published: March 2019

Background

The marine bristle wormPlatynereis dumeriliiis a useful functional model system for the study of the circadian clock and its interplay with others, e.g. circalunar clocks. The focus has so far been on the worm’s head. However, behavioral and physiological cycles in other animals typically arise from the coordination of circadian clocks located in the brain and in peripheral tissues. Here we focus on peripheral circadian rhythms and clocks, revisit and expand classical circadian work on the worm’s chromatophores, investigate locomotion as read-out and include molecular analyses.

Results

We establish that different pieces of the trunk exhibit synchronized, robust oscillations of core circadian clock genes. These circadian core clock transcripts are under strong control of the light-dark cycle, quickly losing synchronized oscillation under constant darkness, irrespective of the absence or presence of heads. Different wavelengths are differently effective in controlling the peripheral molecular synchronization. We have previously shown that locomotor activity is under circadian clock control. Here we show that upon decapitation it still follows the light-dark cycle, but does not free-run under constant darkness. We also observe the rhythmicity of pigments in the worm’s individual chromatophores, confirming that chromatophore size changes follow a circadian pattern. These size changes continue under constant darkness, but cannot be re-entrained by light upon decapitation.

Conclusions

Here we provide the first basic characterization of the peripheral circadian clock ofPlatynereis dumerilii. In the absence of the head, light is essential as a major synchronization cue for peripheral molecular and locomotor circadian rhythms. Circadian changes in chromatophore size can however continue for several days in the absence of light/dark changes and the head. Thus, the dependence on the head depends on the type of peripheral rhythm studied. These data show that peripheral circadian rhythms and clocks should be considered when investigating the interactions of clocks with different period lengths, a notion likely also true for other organisms with circadian and non-circadian clocks.