bluuebunny/crossref_metadata_2025_split huggingface dataset:
Properties and unbiased estimation ofF- andD-statistics in samples containing related and inbred individuals
Authors: Mughal Mehreen R. , DeGiorgio Michael 
Published: November 2020

AbstractThe PattersonF- andD-statistics are commonly-used measures for quantifying population relationships and for testing hypotheses about demographic history. These statistics make use of allele frequency information across populations to infer different aspects of population history, such as population structure and introgression events. Inclusion of related or inbred individuals can bias such statistics, which may often lead to the filtering of such individuals. Here we derive statistical properties of theF- andD-statistics, including their biases due to finite sample size or the inclusion of related or inbred individuals, their variances, and their corresponding mean squared errors. Moreover, for those statistics that are biased, we develop unbiased estimators and evaluate the variances of these new quantities. Comparisons of the new unbiased statistics to the originals demonstrates that our newly-derived statistics often have lower error across a wide population parameter space. Furthermore, we apply these unbiased estimators using several global human populations with the inclusion of related individuals to highlight their application on an empirical dataset. Finally, we implement these unbiased estimators in open-source software packagefunbiasedfor easy application by the scientific community.
Mapping the contents of consciousness during musical imagery
Authors: Regev Mor , Halpern Andrea R. , Owen Adrian M. , Patel Aniruddh D. , Zatorre Robert J. 
Published: November 2020

AbstractHumans can internally represent auditory information without an external stimulus. When imagining music, how similar are unfolding neural representations to those during the original perceived experience? Can rhythmic motion influence the neural representation of music during imagery as during perception? Participants first memorized six one-minute-long instrumental musical pieces with high accuracy. Functional MRI data were collected during: 1) silent imagery of melodies to the beat of a visual metronome; 2) same but while tapping to the beat; and 3) passive listening. During imagery, inter-subject comparison showed that melody-specific temporal response patterns were reinstated in right associative auditory cortices. When tapping accompanied imagery, the melody-specific neural patterns were extended to associative cortices bilaterally. These results indicate that the specific contents of conscious experience are encoded similarly during imagery and perception in the dynamic activity of auditory cortices. Furthermore, rhythmic motion can enhance the reinstatement of neural patterns associated with the experience of complex sounds, in keeping with models of motor to sensory influences in auditory processing.
Unilateral acoustic degradation delays attentional separation of competing speech
Authors: Kraus Frauke , Tune Sarah , Ruhe Anna , Obleser Jonas , Wöstmann Malte 
Published: November 2020

AbstractHearing loss is often asymmetric, such that hearing thresholds differ substantially between the two ears. The extreme case of such asymmetric hearing is single-sided deafness. A unilateral cochlear implant (CI) on the more severely impaired ear is an effective treatment to restore hearing. The interactive effects of unilateral acoustic degradation and spatial attention to one sound source in multi-talker situations are at present unclear. Here, we simulated some features of listening with a unilateral CI in young, normal-hearing listeners (N= 22) who were presented with 8-band noise-vocoded speech to one ear and intact speech to the other ear. Neural responses were recorded in the electroencephalogram (EEG) to obtain the spectro-temporal response function (sTRF) to speech. Listeners made more mistakes when answering questions about vocoded (versus intact) attended speech. At the neural level, we asked how unilateral acoustic degradation would impact the attention-induced amplification of tracking target versus distracting speech. Interestingly, unilateral degradation did not per se reduce the attention-induced amplification but instead delayed it in time: Speech encoding accuracy, modelled on the basis of the sTRF, was significantly enhanced for attended versus ignored intact speech at earlier neural response latencies (<~250 ms). This attentional enhancement was not absent but delayed for vocoded speech. These findings suggest that attentional selection of unilateral, degraded speech is feasible, but induces delayed neural separation of competing speech, which might explain listening challenges experienced by unilateral CI users.
The role of alpha-helix on the structure-targeting drug design of amyloidogenic proteins
Authors: Tempra Carmelo , La Rosa Carmelo , Lolicato Fabio 
Published: November 2020

AbstractThe most accredited hypothesis links the toxicity of amyloid proteins to their harmful effects on membrane integrity through the formation of prefibrillar-transient oligomers able to disrupt cell membranes. However, damage mechanisms necessarily assume a first step in which the amyloidogenic protein transfers from the aqueous phase to the membrane hydrophobic core. This determinant step is still poorly understood. However, according to our lipid-chaperon hypothesis, free lipids in solution play a crucial role in facilitating this footfall. Free phospholipid concentration in the aqueous phase acts as a switch between ion channel-like pore and fibril formation, so that high free lipid concentration in solution promotes pore and repress fibril formation. Conversely, low free lipids in the solution favor fibril and repress pore formation. This behavior is due to the formation of stable lipid-protein complexes. Here, we hypothesize that the helix propensity is a fundamental requirement to fulfill the lipid-chaperon model. The alpha-helix region seems to be responsible for the binding with amphiphilic molecules fostering the proposed mechanism. Indeed, our results show the dependency of protein-lipid binding from the helical structure presence. When the helix content is substantially lower than the wild type, the contact probability decreases. Instead, if the helix is broadening, the contact probability increases. Our findings open a new perspective for in silico screening of secondary structure-targeting drugs of amyloidogenic proteins.
Legionella pneumophilaLegC7 effector protein drives aberrant ER:endosome fusion in yeast
Authors: Glueck Nathan K. , O’Brien Kevin M. , Starai Vincent J. 
Published: November 2020

AbstractLegionella pneumophilais a facultative intracellular bacterial pathogen, causing the severe form of pneumonia known as Legionnaires’ disease.Legionellaactively alters host organelle trafficking through the activities of ‘effector’ proteins secreted via a TypeIVB secretion system, in order to construct the bacteria-laden Legionella-containing vacuole (LCV) and prevent lysosomal degradation. The LCV is derived from membrane derived from host ER, secretory vesicles, and phagosomes, although the precise molecular mechanisms that drive its synthesis remain poorly understood. In an effort to characterize thein vivoactivity of the LegC7/YlfA SNARE-like effector protein fromLegionellain the context of eukaryotic membrane trafficking in yeast, we find that LegC7 interacts with the Emp46p/Emp47p ER-to-Golgi glycoprotein cargo adapter complex, alters ER morphology, and induces aberrant ER:endosome fusion, as measured by visualization of ER cargo degradation, reconstitution of split-GFP proteins, and enhanced oxidation of the ER lumen. LegC7-dependent toxicity, disruption of ER morphology, and ER:endosome fusion events were dependent upon endosomal VPS class C tethering complexes and the endosomal t-SNARE, Pep12p. This work establishes a model in which LegC7 functions to recruit host ER material to the bacterial phagosome during infection by inducing membrane fusion, potentially through interaction with host membrane tethering complexes and/or cargo adapters.
Individual and combined effects of Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) on striato-cortical connectivity in the human brain
Authors: Wall Matthew B. , Freeman Tom P. , Hindocha Chandni , Demetriou Lysia , Ertl Natalie , Freeman Abigail M. , Jones Augustus PM , Lawn Will , Pope Rebecca , Mokrysz Claire , Solomons Daniel , Statton Ben , Walker Hannah R. , Yamamori Yumeya , Yang Zixu , Yim Jocelyn L.L. , Nutt David J. , Howes Oliver D. , Curran H. Valerie , Bloomfield Michael 
Published: November 2020

AbstractCannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have somewhat opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Across two placebo-controlled, double-blind studies, we examine the effects of THC, CBD, and THC+CBD on the functional connectivity of striatal sub-divisions (associative, limbic, and sensorimotor) using resting-state functional Magnetic Resonance Imaging (fMRI) and seed-based functional connectivity analyses. Study 1 (N=17; inhaled 8mg THC, 8mg THC+10mg CBD, placebo) showed strong disruptive effects of both THC and THC+CBD conditions on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum, which was alleviated in the THC+CBD condition such that it did not differ from placebo. In Study 2 (N=23, oral 600mg CBD, placebo) CBD increased connectivity in the associative network, but relatively minor decreases/disruptions were found in the limbic and sensorimotor. In conclusion, THC strongly disrupts striato-cortical networks, and this effect is selectively mitigated in the limbic striatum when co-administered with CBD. When administered alone, 600mg oral CBD has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis related disorders, and the development of cannabinoid therapeutics.
The Pump-Leak/Donnan ion homeostasis strategies of skeletal muscle fibers and neurons
Authors: Joos Béla , Morris Catherine E 
Published: November 2020

ABSTRACTSkeletal muscle fibers (SMFs) and neurons are low and high duty-cycle excitable cells constituting exceptionally large and extraordinarily small fractions of vertebrate bodies. The immense ClC-1-based chloride-permeability (PCl) of SMFs has thwarted understanding of their Pump-Leak/Donnan (P-L/D) ion homeostasis. After formally defining P-L/D set-points and feedbacks, we therefore devise a simple yet demonstrably realistic model for SMFs. Hyper-stimulated, it approximates rodent fibers’ ouabain-sensitive ATP-consumption. Size-matched neuron-model/SMF-model comparisons reveal steady-states occupying two ends of an energetics/resilience P-L/D continuum. Excitable neurons’ costly vulnerable process is Pump-Leak dominated. Electrically-reluctant SMFs’ robust low-cost process is Donnan dominated: collaboratively, Donnan effectors and [big PCl] stabilize Vrest, while SMFs’ exquisitely small PNa minimizes ATP-consumption, thus maximizing resilience. “Classic” excitable cell homeostasis ([small PCl][big INaleak]), de rigueur for electrically-agile neurons, is untenable for vertebrates’ (including humans’) major tissue. Vertebrate bodies evolved thanks to syncytially-efficient SMFs using a Donnan dominated ([big PCl][small INaleak]) ion homeostatic strategy.
Donnan dominated ion homeostasis and the longevity of ischemic Na+-loaded dystrophic skeletal muscle
Authors: Morris Catherine E , Wheeler Joshua J , Joos Béla 
Published: November 2020

ABSTRACTThe inherited muscle-wasting disease, Duchenne muscular dystrophy (DMD), renders skeletal muscle fibers (SMFs) Na+-overloaded, ischemic, membrane-damaged, cation-leaky, depolarized, and prone to myogenic firing. DMD fibers nevertheless survive up to 3 decades before succumbing to Ca2+-necrosis. The Ca2+-necrosis is explicable, the longevity is not. Modeling here shows that SMFs’ ion homeostasis strategy, a low-cost resilient Pump-Leak/Donnan feedback process we term “Donnan dominated”, underpins that longevity. Together, SMFs’ huge chloride-permeability and tiny sodium-permeability minimize excitability and pump costs, facilitating the outsized SMF pump-reserve that lets DMD fibers withstand deep ischemia and leaky channels. We illustrate how, as these impairments intensify, patients’ chronic Na+-overload (now non-invasively evident via Na23-MRI) would change. In simulations, prolonged excitation (→physiological Na+-overloading) and/or intense ischemia (→too little Na+-pumping) and accumulated bleb-damage (→too much Na+-leaking) eventually trigger Ca2+-overloading conditions. Our analysis implies an urgent need to identify SMFs’ pivotal small PNa, thereby opening new therapeutic remediation routes.
mTORC1 activity is supported by spatial association with focal adhesions
Authors: Rabanal-Ruiz Yoana , Byron Adam , Wirth Alexander , Madsen Ralitsa , Sedlackova Lucia , Hewitt Graeme , Nelson Glyn , Stingele Julian , Wills Jimi C. , Zhang Tong , Zeug André , Fässler Reinhard , Vanhaesebroeck Bart , Maddocks Oliver D.K. , Ponimaskin Evgeni , Carroll Bernadette , Korolchuk Viktor I. 
Published: November 2020

AbstractThe mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery1–4. Here we show that translocation of lysosomes towards the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, are necessary for both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.
A multi-modal machine learning approach towards predicting patient readmission
Authors: Mohanty Somya D. , Lekan Deborah , McCoy Thomas P. , Jenkins Marjorie , Manda Prashanti 
Published: November 2020

AbstractHealthcare costs that can be attributed to unplanned readmissions are staggeringly high and negatively impact health and wellness of patients. In the United States, hospital systems and care providers have strong financial motivations to reduce readmissions in accordance with several government guidelines. One of the critical steps to reducing readmissions is to recognize the factors that lead to readmission and correspondingly identify at-risk patients based on these factors. The availability of large volumes of electronic health care records make it possible to develop and deploy automated machine learning models that can predict unplanned readmissions and pinpoint the most important factors of readmission risk. While hospital readmission is an undesirable outcome for any patient, it is more so for medically frail patients. Here, we develop and compare four machine learning models (Random Forest, XGBoost, CatBoost, and Logistic Regression) for predicting 30-day unplanned readmission for patients deemed frail (Age ≥ 50). Variables that indicate frailty, comorbidities, high risk medication use, demographic, hospital and insurance were incorporated in the models for prediction of unplanned 30-day readmission. Our findings indicate that CatBoost outperforms the other three models (AUC 0.80) and prior work in this area. We find that constructs of frailty, certain categories of high risk medications, and comorbidity are all strong predictors of readmission for elderly patients.
ATP signaling in the integrative neural center ofAplysia californica
Authors: Györi János , Kohn Andrea B. , Romanova Daria Y. , Moroz Leonid L. 
Published: November 2020

AbstractATP and its ionotropic P2X receptors are components of one of the most ancient signaling systems. However, little is known about the distribution and function of purinergic transmission in invertebrates. Here, we cloned, expressed, and pharmacologically characterized P2X receptors in the sea slugAplysia californica– the prominent model in cellular and system neuroscience. These functional P2X receptors were successfully expressed inXenopusoocytes and displayed activation by ATP (EC50=306 μM) with two-phased kinetics as well as Na+-dependence. The ATP analog, Bz-ATP, was a less effective agonist (~20%) than ATP, and PPADS was a more potent inhibitor of the P2X receptors than the suramin. We showed that P2X receptors are uniquely expressed withinAplysia’s cerebral bioenergetic center (also known as F-cluster). Using RNA-seq, we found that the F-cluster contains more than a dozen unique secretory peptides, including three insulins, interleukins, and potential toxins, as well as ecdysone-type receptors and a district subset of ion channels. This structure is one of the most prominent integrative centers in the entire CNS and remarkably different from the morphologically similar neurosecretory center (bag cluster) involved in egg-laying behavior. Using RNA-seq, we also characterized the expression of P2X receptors across more than a dozenAplysiaperipheral tissues and developmental stages. We showed that P2X receptors are predominantly expressed in chemosensory structures and during early cleavage stages. The localization and pharmacology of P2X receptors inAplysiahighlight the evolutionary conservation of bioenergetic sensors and chemosensory purinergic transmission across animals. This study also provides a foundation to decipher homeostatic mechanisms in development and neuroendocrine systems.Graphical AbstractWe show that ATP and its ligand-gated P2X receptors are essential signaling components within both the chemosensory systems and the unique integrative neurosecretory center, present in the CNS of the sea slugAplysia– a prominent model in neuroscience. Expression and pharmacology of P2X receptors inAplysiaconfirms the preservation of evolutionary conserved bioenergetic sensors across animals and provide new tools to decipher homeostatic mechanisms in neuro-endocrine systems in general.
Oxytocin receptors in the nucleus accumbens shell are necessary for the onset of maternal behavior in post-parturient mice
Authors: Witchey Shannah , Caldwell Heather K. 
Published: November 2020

AbstractOxytocin (Oxt) signaling via its receptor, the Oxt receptor (Oxtr), is important to the onset of mammalian maternal care. Specifically, evidence suggests that Oxt signaling around the time of parturition underlies the critical shift in how pups are perceived, i.e. from aversive stimuli to rewarding stimuli. Previous work from our lab has found that both Oxtr knockout (−/−) mice and forebrain-specific Oxtr knockout (FB/FB) are more likely than controls to abandon their first litters. Based on these data, we hypothesized that this observed pup abandonment phenotype was due to a failure of the brain to “switch” to a more maternal state. In order to identify where in the brain Oxt signaling contributes to the onset of maternal care we performed three experiments. In Experiment 1, virgin Oxtr FB/FB females were assessed for genotypic differences in maternal behavior and c-Fos expression following maternal sensitization was quantified. In Experiment 2, c-Fos expression was quantified in Oxtr −/− and Oxtr FB/FB females following parturition. In Experiment 3, based on our findings from Experiment 2, the Oxtr in the nucleus accumbens shell (NAcc) was genetically deleted in female Oxtr floxed mice (Oxtr Flox/Flox) mice using a Cre recombinase expressing adeno-associated virus. In Experiment 1, sensitized virgin Oxtr FB/FB females had significantly lower retrieval latencies on the first day of testing and reduced c-Fos expression in the dorsal lateral septum compared to controls. In Experiment 2, increased c-Fos expression was observed in the NAcc shell of both Oxtr −/− and Oxtr FB/FB dams as compared to controls. In Experiment 3, virally mediated knockout of the Oxtr in the NAcc shell completely disrupted the onset of maternal care. Thus, by genetically deleting Oxtr expression in the NAcc the pup abandonment phenotype previously observed in Oxtr −/− and Oxtr FB/FB dams was recreated. Taken together, these data suggest that in post-parturient mice, Oxtr expression in the NAcc shell is critical to the onset of maternal behavior.
A single bacterial sulfatase is required for metabolism of colonic mucinO-glycans and intestinal colonization by a symbiotic human gut bacterium
Authors: Luis Ana S. , Jin Chunsheng , Pereira Gabriel Vasconcelos , Glowacki Robert W. P. , Gugel Sadie , Singh Shaleni , Byrne Dominic P. , Pudlo Nicholas , London James A , Baslé Arnaud , Reihill Mark , Oscarson Stefan , Eyers Patrick A. , Mirjam Czjzek , Michel Gurvan , Barbeyron Tristan , Yates Edwin A , Hansson Gunnar C. , Karlsson Niclas G. , Cartmell Alan , Martens Eric C. 
Published: November 2020

SummaryHumans have co-evolved with a dense community of microbial symbionts that inhabit the lower intestine. In the colon, secreted mucus creates a physical barrier that separates these microbes from the intestinal epithelium. Some gut bacteria are able to utilize mucin glycoproteins, the main mucus component, as a nutrient source. However, it remains unclear which bacterial enzymes initiate the degradation of the highly complexO-glycans found in mucins. In the colon, these glycans are heavily sulfated, but the specific sulfatases that are active on colonic mucins have not been identified. Here, we show that sulfatases are essential to the utilization of colonic mucinO-glycans by the human gut symbiontBacteroides thetaiotaomicron. We have characterized the activity of 12 different sulfatases encoded by this species, showing that these enzymes collectively are active on all of the known sulfate linkages in colonicO-glycans. Crystal structures of 3 enzymes provide mechanistic insight into the molecular basis of substrate-specificity. Unexpectedly, we found that a single sulfatase is essential for utilization of sulfatedO-glycansin vitroand also plays a major rolein vivo. Our results provide insight into the mechanisms of mucin degradation by gut bacteria, an important process for both normal microbial gut colonization and diseases such as inflammatory bowel disease (IBD). Sulfatase activity is likely to be a keystone step in bacterial mucin degradation and inhibition of these enzymes may therefore represent a viable therapeutic path for treatment of IBD and other diseases.