bluuebunny/crossref_metadata_2025 huggingface dataset:
An unbiased, efficient sleep–wake detection algorithm for a population with sleep disorders: change point decoder
Authors: Cakmak Ayse S , Da Poian Giulia , Willats Adam , Haffar Ammer , Abdulbaki Rami , Ko Yi-An , Shah Amit J , Vaccarino Viola , Bliwise Donald L , Rozell Christopher , Clifford Gari D
Published: February 2020

Study Objectives

The usage of wrist-worn wearables to detect sleep–wake states remains a formidable challenge, particularly among individuals with disordered sleep. We developed a novel and unbiased data-driven method for the detection of sleep–wake and compared its performance with the well-established Oakley algorithm (OA) relative to polysomnography (PSG) in elderly men with disordered sleep.

Methods

Overnight in-lab PSG from 102 participants was compared with accelerometry and photoplethysmography simultaneously collected with a wearable device (Empatica E4). A binary segmentation algorithm was used to detect change points in these signals. A model that estimates sleep or wake states given the changes in these signals was established (change point decoder, CPD). The CPD’s performance was compared with the performance of the OA in relation to PSG.

Results

On the testing set, OA provided sleep accuracy of 0.85, wake accuracy of 0.54, AUC of 0.67, and Kappa of 0.39. Comparable values for CPD were 0.70, 0.74, 0.78, and 0.40. The CPD method had sleep onset latency error of −22.9 min, sleep efficiency error of 2.09%, and underestimated the number of sleep–wake transitions with an error of 64.4. The OA method’s performance was 28.6 min, −0.03%, and −17.2, respectively.

Conclusions

The CPD aggregates information from both cardiac and motion signals for state determination as well as the cross-dimensional influences from these domains. Therefore, CPD classification achieved balanced performance and higher AUC, despite underestimating sleep–wake transitions. The CPD could be used as an alternate framework to investigate sleep–wake dynamics within the conventional time frame of 30-s epochs.
Cerebral grey matter density is associated with neuroreceptor and neurotransporter availability: A combined PET and MRI study
Authors: Manninen Sandra , Karjalainen Tomi , Tuominen Lauri J. , Hietala Jarmo , Kaasinen Valtteri , Joutsa Juho , Rinne Juha , Nummenmaa Lauri
Published: February 2020

Positron emission tomography (PET) can be used forin vivomeasurement of specific neuroreceptors and transporters using radioligands, while voxel-based morphometric analysis of magnetic resonance images allows automated estimation of local grey matter densities. However, it is not known how regional neuroreceptor or transporter densities are reflected in grey matter densities. Here, we analyzed brain scans retrospectively from 325 subjects and compared grey matter density estimates with three different neuroreceptors and transporter availabilities. µ-opioid receptors (MORs) were measured with [11C]carfentanil (162 scans), dopamine D2 receptors with [11C]raclopride (91 scans) and serotonin transporters (SERT) with [11C]MADAM (72 scans). The PET data were modelled with simplified reference tissue model. Voxel-wise correlations between binding potential and grey matter density images were computed. Regional binding of all the used radiotracers was associated with grey matter density in region and ligand-specific manner independently of subjects’ age or sex. These data show that grey matter density and MOR and D2R neuroreceptor / SERT availability are correlated, with effect sizes (r2) ranging from 0.04 to 0.69. This suggests that future studies comparing PET outcome measure different groups (such as patients and controls) should take grey matter density differences between the groups into account.
An Evaluation of the Efficacy of Preclinical Models of Lung Cancer Drugs
Authors: Pan Elizabeth , Bogumil David , Cortessis Victoria , Yu Sherrie , Nieva Jorge
Published: February 2020

Background

Preclinical cell models are the mainstay in the early stages of drug development. We sought to explore the preclinical data that differentiated successful from failed therapeutic agents in lung cancer.

Methods

134 failed lung cancer drugs and 27 successful lung cancer drugs were identified. Preclinical data were evaluated. The outcome variable for cell model experiments was the half maximal inhibitory concentration (IC50), and for murine model experiments was tumor growth inhibition (TGI). A logistic regression was performed on quartiles (Q) of IC50s and TGIs.

Results

We compared odds of approval among drugs defined by IC50 and TGI quartile. Compared to drugs with preclinical cell experiments in highest IC50 quartile (Q4, IC50 345.01-100,000nM), those in Q3 differed little, but those in the lower two quartiles had better odds of being approved. However, there was no significant monotonic trend identified (P-trend 0.4). For preclinical murine models, TGI values ranged from −0.3119 to 1.0000, with a tendency for approved drugs to demonstrate poorer inhibition than failed drugs. Analyses comparing success of drugs according to TGI quartile produced interval estimates too wide to be statistically meaningful, although all point estimates accord with drugs in Q2-Q4 (TGI 0.5576-0.7600, 0.7601-0.9364, 0.9365-1.0000) having lower odds of success than those in Q1 (−0.3119-0.5575).

Conclusion

There does not appear to be a significant linear trend between preclinical success and drug approval, and therefore published preclinical data does not predict success of therapeutics in lung cancer. Newer models with predictive power would be beneficial to drug development efforts.
DREAM: A Toolbox to Decode Rhythms of the Brain System
Authors: Gong Zhu-Qing , Gao Peng , Jiang Chao , Xing Xiu-Xia , Dong Hao-Ming , White Tonya , Castellanos F. Xavier , Li Hai-Fang , Zuo Xi-Nian
Published: February 2020

Rhythms of the brain are generated by neural oscillations across multiple frequencies, which can be observed with multiple modalities. Following the natural log linear law of frequency distribution, these oscillations can be decomposed into distinct frequency intervals associated with specific physiological processes. This perspective on neural oscillations has been increasingly applied to study human brain function and related behaviors. In practice, relevant signals are commonly measured as a discrete time series, and thus the sampling period and number of samples determine the number and ranges of decodable frequency intervals. However, these limits have been often ignored by researchers who instead decode measured oscillations into multiple frequency intervals using a fixed sample period and numbers of samples. One reason for such misuse is the lack of an easy-to-use toolbox to implement automatic decomposition of frequency intervals. We report on a toolbox with a graphical user interface for achieving local and remote decoding rhythms of the brain system (DREAM) which is accessible to the public via GitHub. We provide worked examples of DREAM used to investigate frequency-specific performance of both neural (spontaneous brain activity) and neurobehavioral (in-scanner head motion) oscillations. DREAM analyzed the head motion oscillations and found that younger children moved their heads more than older children across all five frequency intervals whereas boys moved more than girls in the age interval from 7 to 9 years. It is interesting that the higher frequency bands contains more head movements, and showed stronger age-motion associations but the weaker sex-motion interactions. Using the fast functional magnetic resonance imaging data from the Human Connectome Project, DREAM mapped the amplitude of these neural oscillations into multiple frequency bands and evaluated their test-retest reliability. A novel result indicated that the higher frequency bands exhibited more reliable amplitude measurements, implying more inter-individual variability of the amplitudes for the higher frequency bands. In summary, these findings demonstrated the applicability of DREAM for frequency-specific human brain mapping as well as the assessments on their measurement reliability and validity.
Distinct neural ensemble response statistics are associated with recognition and discrimination of natural sound textures
Authors: Zhai X. , Khatami F. , Sadeghi M. , He F. , Read H.L. , Stevenson I.H. , Escabí M.A.
Published: February 2020

The perception of sound textures, a class of natural sounds defined by statistical sound structure such as fire wind, and rain, has been proposed to arise through the integration of time-averaged summary statistics. Where and how the auditory system might encode these summary statistics to create internal representations of these stationary sounds, however, is unknown. Here, using natural textures and synthetic variants with reduced statistics, we show that summary statistics modulate the correlations between frequency organized neuron ensembles in the awake rabbit inferior colliculus. These neural ensemble correlation statistics capture high-order sound structure and allow for accurate neural decoding in a single trial recognition task with evidence accumulation times approaching 1 s. In contrast, the average activity across the neural ensemble (neural spectrum) provides a fast (tens of ms) and salient signal that contributes primarily to texture discrimination. Intriguingly, perceptual studies in human listeners reveals analogous trends: the sound spectrum is integrated quickly and serves as salient discrimination cue while high-order sound statistics are integrated slowly and contribute substantially more towards recognition. The findings suggest statistical sound cues such as the sound spectrum and correlation structure are represented by distinct response statistics in auditory midbrain ensembles, and that these neural response statistics may have dissociable roles and time scales for the recognition and discrimination of natural sounds.

SIGNIFICANCE STATEMENT

Being able to recognize and discriminate natural sounds, such as from a running stream, a crowd clapping, or ruffling leaves is a critical task of the normal functioning auditory system. Humans can easily perform such tasks, yet they can be particularly difficult for the hearing impaired and they challenge our most sophisticated computer algorithms. This difficulty is attributed to the complex physical structure of such natural sounds and the fact they are not unique: they vary randomly in a statistically defined manner from one excerpt to the other. Here we provide the first evidence, to our knowledge, that the central auditory system is able to encode and utilize statistical sound cues for natural sound recognition and discrimination behaviors.
Does offspring sex ratio differ between urban and forest populations of great tits (Parus major)?
Authors: Ágh Nóra , Pipoly Ivett , Szabó Krisztián , Vincze Ernő , Bókony Veronika , Seress Gábor , Liker András
Published: February 2020

Since male and female offspring may have different costs and benefits, parents may use sex ratio adjustment to increase their fitness under different environmental conditions. Urban habitats provide poorer conditions for nestling development in many birds. Therefore, we investigated whether great tits (Parus major) produce different brood sex ratios in urban and natural habitats. We determined the sex of nestlings of 126 broods in two urban and two forest habitats between 2012 and 2014 by molecular sexing. We found that brood sex ratio did not differ significantly between urban and forest habitats either at egg-laying or near fledging. Male offspring were larger than females in both habitats. This latter result suggests that male offspring may be more costly to raise than females, yet our findings suggest that urban great tits do not produce more daughters despite the unfavourable breeding conditions. This raises the possibility that other aspects of urban life, such as better post-fledging survival, might favour males and thereby compensate for the extra energetic costs of producing male offspring.
Interaction of intraocular pressure and ganglion cell function in open angle glaucoma
Authors: Al-Nosairy K. O. , Van den Bosch J.J.O.N. , Pennisi V. , Thieme H. , Mansouri K , Choritz L. , Hoffmann M. B.
Published: February 2020

Purpose

To test the feasibility of simultaneous steady-state pattern electroretinogram (PERG) and intraocular pressure (IOP) measurements with an IOP sensor and to test a model for IOP manipulation during lateral decubitus positioning (LDP) and its impact on the PERG.

Design

A prospective, observational study.

Methods

15 healthy controls and 15 treated glaucoma patients participated in the study. 8 patients had an intraocular IOP sensor (eyemate-IO®, Implandata Ophthalmic Products GmbH) in the right eye (GLAIMP) and 7 had no sensor and with glaucoma in the left eye. (1) We tested the feasibility of simultaneous IOP and PERG recordings by comparing PERGs with and without simultaneous IOP-read out in GLAIMP. (2) All participants were positioned in the following order: sitting1 (S1), right LDP (LDR), sitting2 (S2), left LDP (LDL) and sitting3 (S3). For each position, PERG amplitudes and IOP were determined with rebound tonometry (Icare® TA01i) in all participants without the IOP sensor.

Results

Electromagnetic intrusions of IOP sensor readout onto steady-state PERG-recordings had, due to different frequency ranges, no relevant effect on PERG amplitudes. IOP and PERG measures were affected by LDP, e.g., IOP was increased during LDRvs S1 in the lower eyes of GLAIMPand controls (P < 0.001 and P < 0.05, respectively) and PERG amplitude was decreased (P < 0.05 and P < 0.01, respectively).

Conclusions

During LDP, IOP and PERG measurements changed more in the lower eye. IOP changes induced by LDP may be a model for studying the interaction of IOP and ganglion cell function.
Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia
Authors: De Cicco Silvia , Ivanyuk Dina , Haq Wadood , Panagiotakopoulou Vasiliki , Arsić Aleksandra , Schöndorf David , Yu Cong , Perez Maria-Jose , Cassatella Ruggiero Pio , Jakobi Meike , Schneiderhan-Marra Nicole , Nikić-Spiegel Ivana , Gasser Thomas , Deleidi Michela
Published: February 2020

Increasing evidence suggests a role for interferons (IFNs) in neurodegeneration. Parkinson’s disease (PD) associated kinase LRRK2 has been implicated in IFN type II (IFN) response in infections and nigral neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ still remains unclear. Here, we employed dopaminergic (DA) neurons and microglia differentiated from patient induced pluripotent stem cells to unravel the role of IFN-γ in LRRK2-PD. We show that IFN-γ induces LRRK2 expression in both DA neurons and microglial cells. LRRK2-G2019S, the most common PD-associated mutation, sensitizes DA neurons to IFN-γ by decreasing AKT phosphorylation. IFN-γ suppresses NFAT activity in both neurons and microglia and synergistically enhances LRRK2-induced defects of NFAT activation. Furthermore, LRRK2-G2019S negatively regulates NFAT via calcium and microtubule dynamics. Importantly, we uncover functional consequences of the reduction of NFAT activity in both cell types, namely defects of neurite elongation and alteration of microglial activation profile and motility. We propose that synergistic IFN-γ/LRRK2 activation serves as a direct link between inflammation and neurodegeneration in PD.
Csmd2 interacts with Dab1 and is Required in Reelin-Mediated Neuronal Maturation
Authors: Gutierrez Mark A , Dwyer Brett E , Franco Santos J
Published: February 2020

Reelin is a glycoprotein secreted by Cajal-Retzius cells to regulate development of the cerebral cortex. Reelin binding to its receptors on immature neurons initiates a signaling cascade through the downstream adaptor protein, Dab1. Defects in this signaling mechanism result in perturbed neuronal migration, reductions in dendrite complexity, and deficits in synapse development and function. How Reelin controls neuronal migration and brain lamination have been extensively investigated over the years, but the pathways that regulate dendrite and spine development downstream of Reelin and Dab1 have yet to be fully elucidated. Here, we have identified a novel interaction between Dab1 and Csmd2, a synaptic transmembrane protein required for dendrite and dendritic spine development in forebrain excitatory neurons. We demonstrate that Csmd2 contains an NPxY motif on its intracellular region, through which Dab1 interacts with Csmd2. Interestingly, we find that this NPxY consensus motif is not required for Csmd2 to localize at the postsynaptic densities of spiny neurons. Rather, the introduction of an NPxY mutant form of Csmd2 results in a significant overproduction of immature, filopodia-like dendritic spines in maturing neurons. Moreover, we show that knockdown ofCsmd2mRNA expression in immature developing neurons abolishes the ability of Reelin to promote dendrite elaboration and dendritic spine maturation. This suggests that the Csmd2-Dab1 interaction may be a requirement of Reelin/Dab1 signaling to mediate the structural maturation of neurons. Together, these results point toward a role of Csmd2 in the Reelin/Dab1 signaling axis that promotes the development of dendrites and dendritic spines in maturing neurons.

Summary Statement

How Reelin controls neuronal maturation remains to be understood. We demonstrate that the synaptic protein Csmd2 interacts with the Reelin-associated adaptor protein Dab1. We also determine that Reelin requires Csmd2 to regulate structural development and maturation of forebrain neurons.
Learning for angling: an advanced learning capability for avoidance of angling gear in red sea bream juveniles
Authors: Takahashi Kohji , Masuda Reiji
Published: February 2020

Angling has been the cause of mortality for fish since ancient. The avoidance learning for angling gear could be considered as a survival strategy against the mortality by angling. Whereas some studies indicated the possibility of avoidance learning for angling gear, most studies investigated the avoidance learning by using groups of fish, in which it is difficult to reveal the process and mechanisms of the learning. The present study elucidated the avoidance learning for angling gear by experiment of single fish in a tank using red sea breamPagrus majorjuveniles. Individuals with only once or twice of experience for angling avoided angling gear while showing the feeding motivation for pellets, representing avoidance learning for the angling gear. Most of the experienced individuals avoided the krill attached with a fishing line, but not krill and pellets near the angling gear. Feeding rate for prey on a fishing line at two month after the angling trial demonstrated that approximately half of fish kept the memory for angling gear. A series of experiment for angling gear elucidated that red sea bream juveniles are equipped with considerable learning capability for angling gear, suggesting a cognitive evolution for angling.
A Prokaryotic Membrane Sculpting BAR Domain Protein
Authors: Phillips Daniel A. , Zacharoff Lori A. , Hampton Cheri M. , Chong Grace W. , Malanoski Anthony P. , Metskas Lauren Ann , Xu Shuai , Bird Lina J. , Eddie Brian J. , Jensen Grant J. , Drummy Lawrence F. , El-Naggar Mohamed Y. , Glaven Sarah M.
Published: February 2020

Bin/Amphiphysin/RVS (BAR) domain proteins belong to a superfamily of coiled-coil proteins influencing membrane curvature in eukaryotes and are associated with vesicle biogenesis, vesicle-mediated protein trafficking, and intracellular signaling. Here we report the first prokaryotic BAR domain protein, BdpA, fromShewanella oneidensisMR-1, known to produce redox-active membrane vesicles and micrometer-scale outer membrane extensions (OMEs). BdpA is required for uniform size distribution of membrane vesicles and scaffolding OMEs into a consistent diameter and curvature. Cryogenic transmission electron microscopy reveals a strain lacking BdpA produces lobed, disordered OMEs rather than membrane tubes produced by the wild type strain. Overexpression of BdpA promotes OME formation during conditions where they are less common. Heterologous expression results in OME production inMarinobacter atlanticusandEscherichia coli. Based on the ability of BdpA to alter membrane curvaturein vivo, we propose that BdpA and its homologs comprise a newly identified class of prokaryotic BAR (P-BAR) domains.
Degradation of white birch shelterbelts by attack of white-spotted longicorn beetle in central Hokkaido, northern Japan
Authors: Masaka Kazuhiko , Wakita Yohichi , Iwasaki Kenta , Hayamizu Masato
Published: February 2020

Widespread decline of white birch shelterbelts was observed in central Hokkaido, northern Japan. Many exit holes bored by adults of the white-spotted longicorn beetle have been found at the bases of the trunks of trees in these stands. The number of adult longicorn beetle exit holes (Nholes) of dead standing trees tended to be greater than that of living trees.Nholestended to increase with increasingDBH, and there was a negative relationship betweenNholesand tree vigor. We found a size-dependent lethal threshold inNholes. A resonance-measurement device (RMD) for diagnosing the level of wood defection inside the trunk was also tested. The RMD examination together with the lethal threshold inNholescan be a useful tool for the diagnosis of white birch trees. We estimatedNholesof dead standing trees with aDBHof 25 cm in each plot (ND25) to compare the severity of infestation among plots. Logistic regression analysis revealed that 50% of stands will be degraded ifND25= 25.0. Thus, the degradation could also be evaluated byNholes.
Altered beta-band oscillations and connectivity underlie detail-oriented visual processing in autism
Authors: Ronconi Luca , Vitale Andrea , Federici Alessandra , Pini Elisa , Molteni Massimo , Casartelli Luca
Published: February 2020

Sensory and perceptual anomalies have been increasingly recognized as core phenotypic markers for autism spectrum disorders (ASD). A neurophysiological characterization of these anomalies is of utmost importance to understand more complex behavioural manifestations within the spectrum. The present study employed electroencephalography (EEG) to test whether detail-oriented visual perception, a recognized hallmark of ASD, is associated with altered neural oscillations and functional connectivity in beta (and alpha) frequency bands, considering their role in feedback and top-down reentrant signalling in the typical population. A sample of children with diagnosis of ASD (N=18) and typically developing peers (TD; N=20) performed a visual crowding task, where they had to discriminate a peripheral target letter surrounded by flankers at different distances, together with a control condition with no flankers. In TD participants the amplitude of the target-locked N1 component and its cortical sources was significantly modulated as a function of visual crowding, whereas such modulation was absent in the ASD group, suggesting that their visual scene analysis takes place without a flexible neural computation. The comparison between groups showed a decreased activity in the ASD group in occipital, infero-temporal and inferior/middle frontal regions in conditions requiring detail-oriented perception as opposed to conditions requiring the discrimination of target in isolation. Moreover, in TD participants detail-oriented perception was associated with an event-related beta power reduction (15-30 Hz), which was not evident in the ASD group. A data-driven functional connectivity analysis highlighted in the ASD sample an increased connectivity in the beta frequency range between occipital and infero-temporal regions. Notably, individual hyperconnectivity indexes correlated to less severe ASD symptomatology and to a diminished detail-oriented perception, suggesting a potential compensatory mechanism. Overall, these results show that altered communication in the beta frequency band may explain atypical perception in ASD, reflecting aberrant feedback connectivity within the visual system with potential cascade effects in visual scene parsing and higher-order functions.
Temporal expectation hastens decision onset but does not affect evidence quality
Authors: van den Brink Ruud L. , Murphy Peter R. , Desender Kobe , de Ru Nicole , Nieuwenhuis Sander
Published: February 2020

The ability to predict the timing of forthcoming events, known as temporal expectation, has a strong impact on human information processing. Although there is growing consensus that temporal expectations enhance the speed and accuracy of perceptual decisions, it remains unclear whether they affect the decision process itself, or non-decisional (sensory / motor) processes. Here, healthy human participants (N = 21; 18 female) used predictive auditory cues to anticipate the timing of low-contrast visual stimuli they were required to detect. Modelling of the behavioral data using a prominent sequential sampling model indicated that temporal expectations speeded up non-decisional processes but had no effect on decision formation.

Electrophysiological recordings confirmed and extended this result: temporal expectations hastened the onset of a neural signature of decision formation, but had no effect on its build-up rate. Anticipatory alpha-band power was modulated by temporal expectation, and co-varied with intrinsic trial-by-trial variability in behavioral and neural signatures of the onset latency of the decision process. These findings highlight how temporal predictions optimize our interaction with unfolding sensory events.

SIGNIFICANCE STATEMENT

Temporal expectation enhances performance, but the locus of this effect remains debated. Here, we contrasted the two dominant accounts: enhancement through (1) expedited decision onset, or (2) an increase in the quality of sensory evidence. We manipulated expectations about the onset of a dim visual target using a temporal cueing paradigm, and probed the locus of the expectation effect with two complementary approaches: drift diffusion modeling of behavior, and estimation of the onset and progression of the decision process from a supramodal accumulation-to-bound signal in simultaneously measured EEG signals. Behavioral modeling and neural data provided strong, converging evidence for an account in which temporal expectations enhance perception by speeding up decision onset, without affecting evidence quality.
Synchronous nonmonotonic changes in functional connectivity and white matter integrity in a rat model of sporadic Alzheimer’s disease
Authors: Pereira Catarina Tristão , Diao Yujian , Yin Ting , da Silva Analina R , Lanz Bernard , Pierzchala Katarzyna , Poitry-Yamate Carole , Jelescu Ileana O
Published: February 2020

Brain glucose hypometabolism has been singled out as an important contributor and possibly main trigger to Alzheimer’s disease (AD). Intracerebroventricular injections of streptozotocin (icv-STZ) cause brain glucose hypometabolism without systemic diabetes. Here, a first-time longitudinal study of brain glucose metabolism, functional connectivity and white matter microstructure was performed in icv-STZ rats using PET and MRI. Histological markers of pathology were tested at an advanced stage of disease. STZ rats exhibited altered functional connectivity and intra-axonal damage and demyelination in brain regions typical of AD, in a temporal pattern of acute injury, transient recovery/compensation and chronic degeneration. In the context of sustained glucose hypometabolism, these nonmonotonic trends – also reported in behavioral studies of this animal model as well as in human AD – suggest a compensatory mechanism, possibly recruiting ketone bodies, that allows a partial and temporary repair of brain structure and function. The early acute phase could thus become a valuable therapeutic window to strengthen the recovery phase and prevent or delay chronic degeneration, to be considered both in preclinical and clinical studies of AD. In conclusion, this work reveals the consequences of brain insulin resistance on structure and function, highlights signature nonmonotonic trajectories in their evolution and proposes potent MRI-derived biomarkers translatable to human AD and diabetic populations.
Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet
Authors: Schlezinger JJ , Puckett H , Oliver J , Nielsen G , Heiger-Bernays W , Webster TF
Published: February 2020

Humans are exposed to per- and polyfluoroalkyl substances (PFAS) in their drinking water, food, air, dust in their homes, and by direct use of consumer products. Increased concentrations of serum total cholesterol and low density lipoprotein cholesterol are among the endpoints best supported by epidemiology. The objectives of this study were to generate a new model for examining PFAS-induced dyslipidemia and to conduct molecular studies to better define mechanism(s) of action. We tested the hypothesis that PFOA exposure at a human-relevant level dysregulates expression of genes controlling cholesterol homeostasis in livers of mice expressing human PPARα (hPPARα). Female and male hPPARα and PPARα null mice were fed a diet based on the “What we eat in America” analysis and exposed to perfluorooctanoic acid (PFOA) in drinking water (8 µM) for 6 weeks. This resulted in a serum PFOA concentration of 48 μg/ml. PFOA increased liver mass, which was associated with histologically-evident lipid accumulation. PFOA induced PPARα and constitutive androstane receptor target gene expression in liver. Expression of genes in four pathways regulating cholesterol homeostasis were also measured. PFOA decreased expression ofHmgcrin a PPARα-dependent manner. PFOA decreased expression ofLdlrandCyp7a1in a PPARα-independent manner.Apobexpression was not changed. Gene expression in females appeared to be more sensitive to PFOA exposure than in males. This novel study design (hPPARα mice, American diet, long term exposure) generated new insight on the effects of PFOA on cholesterol regulation in the liver and the role of hPPARα.
Selection and subsequent physiological characterisation of industrialSaccharomyces cerevisiaestrains during continuous growth at sub- and- supra optimal temperatures
Authors: Lip Ka Ying Florence , García-Ríos Estéfani , Costa Carlos E. , Guillamón José Manuel , Domingues Lucília , Teixeira José , van Gulik Walter M.
Published: February 2020

A phenotypic screening of 12 industrial yeast strains and the well-studied laboratory strain CEN.PK113-7D at cultivation temperatures between 12 °C and 40 °C revealed significant differences in maximum growth rates and temperature tolerance. TwoSaccharomyces cerevisiaestrains, one performing best at sub-, and the other at supra-optimal temperatures, plus the laboratory strain, were selected for further physiological characterization in well-controlled bioreactors. The strains were grown in anaerobic chemostats, at a fixed specific growth rate of 0.03 h-1and sequential batch cultures at 12, 30, and 39 °C. We observed significant differences in biomass and ethanol yields on glucose, biomass protein and storage carbohydrate contents, and biomass yields on ATP between strains and cultivation temperatures. Increased temperature tolerance coincided with higher energetic efficiency of cell growth, indicating that temperature intolerance is a result of energy wasting processes, such as increased turnover of cellular components (e.g. proteins) due to temperature induced damage.
Redox-active cysteines in TGACG-BINDING FACTOR 1 (TGA1) do not play a role in salicylic acid- or pathogen-induced expression of TGA1-regulated target genes inArabidopsis thaliana
Authors: Budimir Jelena , Treffon Katrin , Nair Aswin , Thurow Corinna , Gatz Christiane
Published: February 2020

Salicylic acid (SA) is an important signaling molecule of the plant immune system.

SA biosynthesis is indirectly modulated by the closely related transcription factors TGA1 (TGACG-BINDING FACTOR 1) and TGA4. They activate expression ofSARD1(SYSTEMIC ACQUIRED RESISTANCE DEFICIENT1), the gene product of which regulates the key SA biosynthesis geneICS1(ISOCHORISMATE SYNTHASE 1).

Since TGA1 interacts with the SA receptor NPR1 (NON EXPRESSOR OF PATHOGENESIS-RELATED GENES 1) in a redox-dependent manner and since the redox state of TGA1 is altered in SA-treated plants, TGA1 was assumed to play a role in the NPR1-dependent signaling cascade. Here we identified 193 out of 2090 SA-induced genes that require TGA1/TGA4 for maximal expression after SA treatment. One robustly TGA1/TGA4-dependent gene encodes for the SA hydroxylase DLO1 (DOWNY MILDEW RESISTANT 6-LIKE OXYGENASE 1) suggesting an additional regulatory role of TGA1/TGA4 in SA catabolism.

Expression of TGA1/TGA4-dependent genes in mock/SA-treated or Pseudomonas-infected plants was rescued in thetga1 tga4double mutant after introduction of a mutant genomicTGA1fragment encoding a TGA1 protein without any cysteines. Thus, the functional significance of the observed redox modification of TGA1 in SA-treated tissues has remained enigmatic.

SIGNIFICANCE STATEMENT

Previous findings demonstrating a redox-dependent interaction between transcription factor TGA1 and NPR1 attracted considerable attention. Here we show that TGA1 can act in the NPR1- and SA-dependent signaling cascade, but that its SA-regulated redox-active cysteines do not affect its function in this process.
Expression and purification of African Swine Fever virus p72 trimers as subunit vaccine candidate
Authors: Meng Kaiwen , Zhang Yueping , Zhu Wenzhuang , Xiang Ye , Meng Geng
Published: February 2020

The authors have withdrawn this manuscript because the result is invalid. We intend to revise it on our technical approach and interpretation of the results. The authors do not wish for this manuscript to be cited as a reference for this project. Please contact the corresponding author if you have any questions.
Microbial trend analysis for common dynamic trend, group comparison and classification in longitudinal microbiome study
Authors: Wang Chan , Hu Jiyuan , Blaser Martin J. , Li Huilin
Published: February 2020

Motivation

The human microbiome is inherently dynamic and its dynamic nature plays a critical role in maintaining health and driving disease. With an increasing number of longitudinal microbiome studies, scientists are eager to learn the comprehensive characterization of microbial dynamics and their implications to the health and disease-related phenotypes. However, due to the challenging structure of longitudinal microbiome data, few analytic methods are available to characterize the microbial dynamics over time.

Results

We propose a microbial trend analysis (MTA) framework for the high-dimensional and phylogenetically-based longitudinal microbiome data. In particular, MTA can perform three tasks: 1) capture the common microbial dynamic trends for a group of subjects on the community level and identify the dominant taxa; 2) examine whether or not the microbial overall dynamic trends are significantly different in groups; 3) classify an individual subject based on its longitudinal microbial profiling. Our extensive simulations demonstrate that the proposed MTA framework is robust and powerful in hypothesis testing, taxon identification, and subject classification. Our real data analyses further illustrate the utility of MTA through a longitudinal study in mice.

Conclusions

The proposed MTA framework is an attractive and effective tool in investigating dynamic microbial pattern from longitudinal microbiome studies.
Synteny-guided resolution of gene trees clarifies the functional impact of whole genome duplications
Authors: Parey Elise , Louis Alexandra , Cabau Cédric , Guiguen Yann , Crollius Hugues Roest , Berthelot Camille
Published: February 2020

Whole genome duplications (WGD) have major impacts on the evolution of species, as they produce new gene copies contributing substantially to adaptation, isolation, phenotypic robustness, and evolvability. They result in large, complex gene families with recurrent gene losses in descendant species that sequence-based phylogenetic methods fail to reconstruct accurately. As a result, orthologs and paralogs are difficult to identify reliably in WGD-descended species, which hinders the exploration of functional consequences of WGDs. Here we present SCORPiOs, a novel method to reconstruct gene phylogenies in the context of a known WGD event. WGDs generate large duplicated syntenic regions, which SCORPiOs systematically leverages as a complement to sequence evolution to infer the evolutionary history of genes. We applied SCORPiOs to the 320-million-year-old WGD at the origin of teleost fish. We find that almost one in four teleost gene phylogenies in the Ensembl database (3,391) are inconsistent with their syntenic contexts. For 70% of these gene families (2,387), we were able to propose an improved phylogenetic tree consistent with both the molecular substitution distances and the local syntenic information. We show that these synteny-guided phylogenies are more congruent with the species tree, with sequence evolution and with expected expression conservation patterns than those produced by state-of-the-art methods. Finally, we show that synteny-guided gene trees emphasize contributions of WGD paralogs to evolutionary innovations in the teleost clade.
An injectable meta-biomaterial
Authors: Béduer A. , Bonini F. , Verheyen C. , Burch P. , Braschler T.
Published: February 2020

We present a novel type of injectable biomaterial with an elastic softening transition. The material enablesin-vivoshaping, followed by induction of 3D stable vascularized tissue adopting the desired shape. We establish the necessary geometrical and physical parameters by extensive numerical simulation. Irregular particle shape dramatically enhances yield strain forin-vivostability against deformation, while friction and porosity provide the elastic softening transition as an emergent meta-material property. Accordingly, we synthesize our injectable meta-biomaterial as a suspension of irregularly fragmented, highly porous sponge-like microgels. The meta-biomaterial exhibits both high yield strain, and the desired novel elastic softening transition forin-situshaping and unprecedented dynamic matching of adipose tissue mechanics.In vivo, predetermined shapes can be sculpted manually after subcutaneous injection in mice. The 3D shape is maintained during excellent host tissue integration into the particle pore space. The meta-biomaterial sustains vascularized connective tissue to the end of one-year follow-up.
A litmus test for harmonized mosquito monitoring across Europe and Africa
Authors: Graziosi Ignazio , Aranda Carles , Balestrino Fabrizio , Bellini Romeo , Busquets Núria , Coulibaly Mammadou , Crisanti Andrea , Diallo Diawo , Diallo Mawlouth , Gaye Alioune , Guelbeogo Moussa , Ignjatović-Ćupina Aleksandra , Napp Sebastián , N’Falé Sagnon , Petrić Dušan , Pollegioni Paola , Simoni Alekos , Zgomba Marija , Müller Ruth
Published: February 2020

The accelerating rate of outbreaks from mosquito borne diseases are urging the development of updated and effective tools for the surveillance of insect populations and their larval habitats. Harmonized field protocols help to build a comprehensive picture on species-specific vector ecology and generate important knowledge for implementing coordinated mosquito surveillance programs at regional scales and across continents. In this study, we test the efficiency and potential barriers of available harmonized protocols from earlier EU project VectorNet. As a kind of litmus test for such protocols, we specifically aim to capture the ecoregional variation of breeding site characteristics and population density of five mosquito vectors in Europe and Africa. As expected, the five species considered show different aquatic habitat preferences.Culex pipiens, Aedes albopictusin Europe andAe. aegyptiin Africa select breeding habitats within specific volume classes, whileAnopheles gambiaeandAn. coluzziimay select breeding habitats based on seasonal availability. Population densities in aquatic habitats greatly varied across species and countries, but larval production sites ofAe. albopictusgenerate populations with higher ratio of pupae compared to the other species. This result underlines the fundamental ecological difference between the selected vector species disregarding of the ecoregion. Mean water temperatures had limited variation across species and higher among countries. Understanding the ecology of native and non-native mosquito vectors is key in evaluating transmission risks for diseases such as West Nile, chikungunya and dengue fevers, zika and malaria. The available harmonized field protocols are a valuable tool for achieving homogeneous mosquito surveillance in Europe and Africa.
Proteomics Using Protease Alternatives to Trypsin Benefits from Sequential Digestion with Trypsin
Authors: Dau Therese , Bartolomucci Giulia , Rappsilber Juri
Published: February 2020

Trypsin is the most used enzyme in proteomics. Nevertheless, proteases with complementary cleavage specificity have been applied in special circumstances. In this work, we analyzed the characteristics of five protease alternatives to trypsin for protein identification and sequence coverage when applied toS. pombewhole cell lysates. The specificity of the protease heavily impacted on the number of proteins identified. Proteases with higher specificity let to the identification of more proteins than proteases with lower specificity. However, AspN, GluC, chymotrypsin and proteinase K largely benefited from being paired with trypsin in sequential digestion, as had been shown by us for elastase before. In the most extreme case, pre-digesting with trypsin improves the number of identified proteins for proteinase K by 731 %. Trypsin pre-digestion also improved the protein identifications of other proteases, AspN (+62 %), GluC (+80 %) and chymotrypsin (+21 %). Interestingly, the sequential digest with trypsin and AspN yielded even higher number of protein identifications than digesting with trypsin alone.
Plasticity of the glutamate transporter EAAT2 on striatal astrocytes regulates flexibility in behavior
Authors: Boender Arjen J. , Tonini Raffaella
Published: February 2020

Modulation of striatal circuits is necessary for behavioral flexibility and confers the ability to adapt to environmental changes. Striatal astrocytes contribute to circuit neuromodulation by controlling the activity of ambient neurotransmitters. In particular, extracellular glutamate levels are tightly controlled by the astrocytic glutamate transporter EAAT2, thereby influencing synaptic functioning and neural network activity. While disturbances in EAAT2 have been related to neurological dysfunctions, it remains unclear if environmental cues influence this protein’s function to specifically shape action control.

In this study, we investigate the relationship between experience-dependent plasticity of EAAT2 expression and action inflexibility that follows overtraining for an instrumental task. We find that task overtraining is associated with the upregulation of EAAT2 in the lateral part of the dorsal striatum (DLS). Interfering with EAAT2 upregulation by chemogenetic activation of astrocytic Gq signaling or by transientin vivoknockdown of EAAT2 in the DLS restores behavioral flexibility. Astrocytes are emerging as critical regulators of striatal functions, and by demonstrating that plasticity of EAAT2 expression in the DLS shapes behavior, this work provides novel mechanistic insights into how flexibility in action control is regulated.
GAMIBHEAR: whole-genome haplotype reconstruction from Genome Architecture Mapping data
Authors: Markowski Julia , Kempfer Rieke , Kukalev Alexander , Irastorza-Azcarate Ibai , Loof Gesa , Kehr Birte , Pombo Ana , Rahmann Sven , Schwarz Roland F
Published: February 2020

Motivation

Genome Architecture Mapping (GAM) was recently introduced as a digestion- and ligation-free method to detect chromatin conformation. Orthogonal to existing approaches based on chromatin conformation capture (3C), GAM’s ability to capture both inter- and intra-chromosomal contacts from low amounts of input data makes it particularly well suited for allele-specific analyses in a clinical setting. Allele-specific analyses are powerful tools to investigate the effects of genetic variants on many cellular phenotypes including chromatin conformation, but require the haplotypes of the individuals under study to be known a-priori. So far however, no algorithm exists for haplotype reconstruction and phasing of genetic variants from GAM data, hindering the allele-specific analysis of chromatin contact points in non-model organisms or individuals with unknown haplotypes.

Results

We present GAMIBHEAR, a tool for accurate haplotype reconstruction from GAM data. GAMIBHEAR aggregates allelic co-observation frequencies from GAM data and employs a GAM-specific probabilistic model of haplotype capture to optimise phasing accuracy. Using a hybrid mouse embryonic stem cell line with known haplotype structure as a benchmark dataset, we assess correctness and completeness of the reconstructed haplotypes, and demonstrate the power of GAMIBHEAR to infer accurate genome-wide haplotypes from GAM data.

Availability

GAMIBHEAR is available as an R package under the open source GPL-2 license athttps://bitbucket.org/schwarzlab/gamibhear

Maintainer:julia.markowski@mdc-berlin.de
Selfish mitochondria exploit nutrient status across different levels of selection
Authors: Gitschlag Bryan L. , Tate Ann T. , Patel Maulik R.
Published: February 2020

Cooperation and cheating are widespread evolutionary strategies. Competition can simultaneously favor cheating within groups and cooperation between groups. Selfish or cheater mitochondrial DNA (mtDNA) mutants proliferate within hosts while being selected against at the level of host fitness. How does environment govern competition between cooperators and cheaters across different selection levels? Focusing on food availability, we address this question using heteroplasmicCaenorhabditis elegans. We show that by promoting germline development, nutrient status provides the niche space for mtDNA variants to compete. However, the within-host advantage of selfish mtDNA requires additional conditions, namely the FoxO transcription factor DAF-16. During food scarcity, DAF-16 mitigates the host fitness cost of the selfish mtDNA. We conclude that food availability, and resilience to food scarcity, govern selfish mtDNA dynamics across the levels of selection. Our study integrates an evolutionary framework with experimentation to identify cellular mechanisms underlying the multilevel selection that characterizes cheater dynamics.