bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dopamine D2 receptors modulate intrinsic properties and synaptic transmission of parvalbumin interneurons in the mouse primary motor cortex
Authors: Cousineau Jérémy , Lescouzères Léa , Taupignon Anne , Delgado-Zabalza Lorena , Valjent Emmanuel , Baufreton Jérôme , Bon-Jégo Morgane Le 
Published: October 2019

AbstractDopamine (DA) plays a crucial role in the control of motor and higher cognitive functions such as learning, working memory and decision making. The primary motor cortex (M1), which is essential for motor control and the acquisition of motor skills, receives dopaminergic inputs in its superficial and deep layers from the midbrain. However, the precise action of DA and DA receptor subtypes on the cortical microcircuits of M1 remains poorly understood. The aim of this work was to investigate how DA, through the activation of D2 receptors (D2R), modulates the cellular and synaptic activity of M1 parvalbumin-expressing interneurons (PVINs) which are crucial to regulate the spike output of pyramidal neurons (PNs). By combining immunofluorescence, ex vivo electrophysiology, pharmacology and optogenetics approaches, we show that D2R activation increases neuronal excitability of PVINs and GABAergic synaptic transmission between PVINs and PNs in layer V of M1. Our data reveal a mechanism through which cortical DA modulates M1 microcircuitry and might participate in the acquisition of motor skills.Significance StatementPrimary motor cortex (M1), which is a region essential for motor control and the acquisition of motor skills, receives dopaminergic inputs from the midbrain. However, precise action of dopamine and its receptor subtypes on specific cell types in M1 remained poorly understood. Here, we demonstrate in M1 that dopamine D2 receptors (D2R) are present in parvalbumin interneurons (PVINs) and their activation increases the excitability of the PVINs, which are crucial to regulate the spike output of pyramidal neurons (PNs). Moreover the activation of the D2R facilitates the GABAergic synaptic transmission of those PVINs on layer V PNs. These results highlight how cortical dopamine modulates the functioning of M1 microcircuit which activity is disturbed in hypo- and hyperdopaminergic states.
Regulatory dynamic enzyme-cost flux balance analysis: A unifying framework for constraint-based modeling
Authors: Liu Lin , Bockmayr Alexander 
Published: October 2019

AbstractIntegrated modeling of metabolism and gene regulation continues to be a major challenge in computational biology. While there exist approaches like regulatory flux balance analysis (rFBA), dynamic flux balance analysis (dFBA), resource balance analysis (RBA) or dynamic enzyme-cost flux balance analysis (deFBA) extending classical flux balance analysis (FBA) in various directions, there have been no constraint-based methods so far that allow predicting the dynamics of metabolism taking into account both macromolecule production costs and regulatory events.In this paper, we introduce a new constraint-based modeling framework named regulatory dynamic enzyme-cost flux balance analysis (r-deFBA), which unifies dynamic modeling of metabolism, cellular resource allocation and transcriptional regulation in a hybrid discrete-continuous setting.With r-deFBA, we can predict discrete regulatory states together with the continuous dynamics of reaction fluxes, external substrates, enzymes, and regulatory proteins needed to achieve a cellular objective such as maximizing biomass over a time interval. The dynamic optimization problem underlying r-deFBA can be reformulated as a mixed-integer linear optimization problem, for which there exist efficient solvers.
Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank
Authors: Abul-Husn Noura S. , Soper Emily R. , Odgis Jacqueline A. , Cullina Sinead , Bobo Dean , Moscati Arden , Rodriguez Jessica E. ,   CBIPM Genomics Team,   Regeneron Genetics Center, Loos Ruth J.F. , Cho Judy H. , Belbin Gillian M. , Suckiel Sabrina A. , Kenny Eimear E. 
Published: October 2019

AbstractPathogenic variants inBRCA1andBRCA2(BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant positive individuals in the general population are unaware of their risk, and little is known about the prevalence of pathogenicBRCA1/2variants in non-European populations. We investigatedBRCA1/2prevalence and impact using exome sequencing and electronic health record (EHR) data from 30,223 adult participants of the BioMeBiobank in New York City. There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. In sub-populations defined by genetic ancestry, the highest prevalence was in individuals of Ashkenazi Jewish (AJ; 1 in 49), Filipino and Southeast Asian (1 in 81), and Non-AJ European (1 in 103) descent. Among 218 variant positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1c.5266dupC and c.68_69delAG, andBRCA2c.5946delT), 7 had a Puerto Rican founder variant (BRCA2c.3922G>T), and 25 had one of 19 other founder variants. Non-European populations were more likely to harborBRCA1/2variants that were not classified in ClinVar, or that had uncertain or conflicting evidence for pathogenicity. Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion African genetic ancestry and the likelihood of harboring aBRCA1/2variant with uncertain or conflicting evidence for pathogenicity. Based on EHR and participant questionnaire data, ∼28% of variant positive individuals had a personal history, and ∼45% a personal or family history ofBRCA1/2-associated cancers. Approximately 27% of variant positive individuals had evidence of prior clinical genetic testing forBRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (38%) than those with other pathogenic variants (19%). These findings deepen our knowledge aboutBRCA1/2variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.
Response modality-dependent abstract choice representations for vibrotactile comparisons
Authors: Wu Yuan-hao , Velenosi Lisa A. , Blankenburg Felix 
Published: October 2019

AbstractPrevious electrophysiological studies in monkeys and humans suggest that premotor regions are the primary loci for the encoding of perceptual choices during vibrotactile comparisons. However, these studies employed paradigms wherein choices were inextricably linked with the physical properties of the stimuli and action selection. It raises the question what brain regions represent choices at a more abstract level, independent of the sensorimotor components of the task. To address this question, we used fMRI-MVPA and a variant of the vibrotactile frequency discrimination task which enabled the isolation of choice-related signals from those related to stimulus properties and selection of the manual decision reports. We identified the left, contralateral dorsal premotor cortex (PMd) and intraparietal sulcus (IPS) as carrying information about abstract choices. Notably, our previous work using an oculomotor variant of the task also reported abstract choice representation in intraparietal and premotor regions. However, the informative premotor cluster was centered in the frontal eye fields rather than in the PMd, providing empirical support for a response effector-dependent organization of abstract choice representation in the context of vibrotactile comparisons. Considering our results together with findings from recent studies in animals, we speculate that the premotor region likely serves as a temporary storage site for information necessary for the specification of concrete manual movements, while the IPS might be more directly involved in the computation of choice.
Inserting small molecules across membrane mixtures: Insight from the potential of mean force
Authors: Centi Alessia , Dutta Arghya , Parekh Sapun H. , Bereau Tristan 
Published: October 2019

ABSTRACTSmall solutes have been shown to alter the lateral organization of cell membranes and reconstituted phospholipid bilayers; however, the mechanisms by which these changes happen are still largely unknown. Traditionally, both experiment and simulation studies have been restricted to testing only a few compounds at a time, failing to identify general molecular descriptors or chemical properties that would allow extrapolating beyond the subset of considered solutes. In this work, we probe the competing energetics of inserting a solute in different membrane environments by means of the potential of mean force. We show that these calculations can be used as a computationally-efficient proxy to establish whether a solute will stabilize or destabilize domain phase separation. Combined with umbrella sampling simulations and coarse-grained molecular dynamics simulations, we are able to screen solutes across a wide range of chemistries and polarities. Our results indicate that, for the system under consideration, preferential partitioning and therefore effectiveness in altering membrane phase separation are strictly linked to the location of insertion in the bilayer (i.e., midplane or interface). Our approach represents a fast and simple tool for obtaining structural and thermodynamic insight into the partitioning of small molecules between lipid domains and its relation to phase separation, ultimately providing a platform for identifying the key determinants of this process.SIGNIFICANCEIn this work we explore the relationship between solute chemistry and the thermodynamics of insertion in a mixed lipid membrane. By combining a coarse-grained resolution and umbrella-sampling simulations we efficiently sample conformational space to study the thermodynamics of phase separation. We demonstrate that measures of the potential of mean force—a computationally-efficient quantity—between different lipid environments can serve as a proxy to predict a compound’s ability to alter the thermodynamics of the lipid membrane. This efficiency allows us to set up a computational screening across many compound chemistries, thereby gaining insight beyond the study of a single or a handful of compounds.
Affinity-based polymers provide long-term immunotherapeutic drug delivery across particle size ranges optimal for macrophage targeting
Authors: Rohner Nathan A. , Purdue Linda , von Recum Horst A. 
Published: October 2019

AbstractLong term drug delivery to specific arms of the immune system can be technically challenging to provide limited off-target toxicity as well as prolonged delivery and specific cellular targeting given the limits of current drug delivery systems. In this work, we demonstrate the robustness of a cyclodextrin (CD) polymer platform that can extend immunomodulatory drug delivery via affinity interactions to promote long-term, sustained release at multiple size scales. The parameter space of synthesis variables (pre-incubation and stirring speed) and post-synthesis grinding effects on resulting particle diameter were characterized. We demonstrate that polymerized CD forms exhibit size-independent release profiles of the small molecule drug lenalidomide (LND) and can provide similar drug delivery profiles as macro-scale CD polymer disks. CD polymer microparticles and nanoparticles demonstrated no significant cytotoxicity as compared to the base CD macromonomer when co-incubated with fibroblasts. Uptake of ground CD nanoparticles was significantly higher following incubation with RAW 264.7 macrophages in culture over originally synthesized, larger CD microparticles. Thus, the affinity/structure properties afforded by polymerized CD allow particle size to be modified to affect cellular uptake profiles independently of drug release rate for applications in cell-targeted drug delivery.
Pseudomonas aeruginosa lasRmutant fitness in microoxia is supported by an Anr-regulated oxygen-binding hemerythrin
Authors: Clay Michelle E. , Hammond John H. , Zhong Fangfang , Chen Xiaolei , Kowalski Caitlin H. , Lee Alexandra J. , Porter Monique S. , Greene Casey S. , Pletneva Ekaterina V. , Hogan Deborah A. 
Published: October 2019

AbstractPseudomonas aeruginosastrains with loss-of-function mutations in the transcription factor are frequently encountered in the clinic and the environment. Among the characteristics common to LasR-defective (LasR-) strains is increased activity of the transcription factor Anr, relative to their LasR+ counterparts, in low oxygen conditions. One of the Anr-regulated genes that was highly induced in the LasR-strains encoded a putative oxygen-binding hemerythrin encoded byPA14_42860(PA1673) which we namedmhrfor microoxic hemerythrin. PurifiedP. aeruginosaMhr protein contained the predicted di-iron center and binds oxygen with aKdof 1 µM. Both Anr and Mhr were necessary for fitness inlasR+ andlasRmutant strains in colony biofilms grown in microoxic conditions, and the effects were more striking in thelasRmutant. Among genes in the Anr regulon,mhrwas most closely co-regulated with the Anr-controlled high affinity cytochromecoxidase genes and in the absence of high affinity cytochromecoxidase activity, deletion ofmhrno longer caused a fitness disadvantage suggesting that Mhr works in concert with microoxic respiration. We demonstrate that Anr and Mhr contribute to LasR-strain fitness even in the normoxic biofilm conditions, and metabolomics data indicate that in alasRmutant, expression of Anr-regulatedmhrleads to differences in metabolism in cells grown on LB and artificial sputum medium. Together these data indicate that increased Anr activity in microoxically-grownlasRmutants confers an advantage in part for its regulation of the O2binding protein Mhr.SignificancePseudomonas aeruginosa, a versatile bacterium that both lives in environmental habitats and causes life-threatening opportunistic infections, uses quorum sensing to coordinate gene expression with cell density. ThelasRgene, which encodes a quorum sensing regulator, is often deleteriously mutated in clinical isolates. Interestingly, LasR-strains have high activity of the oxygen-sensitive transcription factor Anr in microoxic conditions. This report identifies and characterizes an Anr-regulated microoxic hemerythrin that reversibly binds oxygen. We showed bothanrandmhrare critical to fitness in microoxia, and these genes uniquely benefit LasR-strains in normoxia. Our findings enrich our understanding of the success ofP. aeruginosaas a pulmonary resident through its propensity to lose LasR functionality in the context of low-oxygen infection environments.
A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation
Authors: Johnson Erik C.B. , Dammer Eric B. , Duong Duc M. , Ping Lingyan , Zhou Maotian , Yin Luming , Higginbotham Lenora A. , Guajardo Andrew , White Bartholomew , Troncoso Juan C. , Thambisetty Madhav , Montine Thomas J. , Lee Edward B. , Trojanowski John Q. , Beach Thomas G. , Reiman Eric M. , Haroutunian Vahram , Wang Minghui , Schadt Eric , Zhang Bin , Dickson Dennis W. , Ertekin-Taner Nilufer , Golde Todd E. , Petyuk Vladislav A. , De Jager Philip L. , Bennett David A. , Wingo Thomas S. , Rangaraju Srikant , Hajjar Ihab , Shulman Joshua M. , Lah James J. , Levey Allan I. , Seyfried Nicholas T. 
Published: October 2019

AbstractOur understanding of the biological changes in the brain associated with Alzheimer’s disease (AD) pathology and cognitive impairment remains incomplete. To increase our understanding of these changes, we analyzed dorsolateral prefrontal cortex of control, asymptomatic AD, and AD brains from four different centers by label-free quantitative mass spectrometry and weighted protein co-expression analysis to obtain a consensus protein co-expression network of AD brain. This network consisted of 13 protein co-expression modules. Six of these modules correlated with amyloid-β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These six modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community-based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module. This module was enriched in AD genetic risk factors, and was also highly enriched in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from the sugar metabolism module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. In this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.
Novel two-stage processes for optimal chemical production in microbes
Authors: Raj Kaushik , Venayak Naveen , Mahadevan Radhakrishnan 
Published: October 2019

AbstractMicrobial metabolism can be harnessed to produce a broad range of industrially important chemicals. Often, three key process variables: Titer, Rate and Yield (TRY) are the target of metabolic engineering efforts to improve microbial hosts toward industrial production. Previous research into improving the TRY metrics have examined the efficacy of having distinct growth and production stages to achieve enhanced productivity. However, these studies assumed a switch from a maximum growth to a maximum production phenotype. Hence, phenotypes with intermediate growth and chemical production for the growth and production stages of two-stage processes are yet to be explored. The impact of reduced growth rates on substrate uptake adds to the need for intelligent choice of operating points while designing two-stage processes. In this work, we develop a computational framework that scans the phenotypic space of microbial metabolism to identify ideal growth and production phenotypic targets, to achieve optimal TRY targets. Using this framework, with Escherichia coli as a model organism, we compare two-stage processes that use dynamic pathway regulation, with one-stage processes that use static intervention strategies, for different bioprocess objectives. Our results indicate that two-stage processes with intermediate growth during the production stage always result in optimal TRY values even in cases where substrate uptake is limited due to reduced growth during chemical production. By analyzing the flux distributions for the production enhancing strategies, we identify key reactions and reaction subsystems that require perturbation to achieve a production phenotype for a wide range of metabolites in E. coli. Interestingly, flux perturbations that increase phosphoenolpyruvate and NADPH availability are enriched among these production phenotypes. Furthermore, reactions in the pentose phosphate pathway emerge as key control nodes that function together to increase the availability of precursors to most products in E. coli. The inherently modular nature of microbial metabolism results in common reactions and reaction subsystems that need to be regulated to modify microbes from their target of growth to the production of a diverse range of metabolites. Due to the presence of these common patterns in the flux perturbations, we propose the possibility of a universal production strain.
Potential function of CbuSPL and gene encoding its interacting protein during flowering in Catalpa bungei
Authors: Wang Zhi , Zhu Tianqing , Fan Erqin , Lu Nan , Ouyang Fangqun , Wang Nan , Yang Guijuan , Kong Lisheng , Qu Guanzheng , Zhang Shougong , Ma Wenjun , Wang Junhui 
Published: October 2019

Abstract“Bairihua”, a variety of the Catalpa bungei, has a large amount of flowers and a long flowering period which make it an excellent material for flowering researches in trees. SPL is one of the hub genes that regulate both flowering transition and development. Here, a SPL homologues CbuSPL9 was cloned using degenerate primers with RACE. Expression studies during flowering transition in Bairihua and ectopic expression in Arabidopsis showed that CbuSPL9 was functional similarly with its Arabidopsis homologues. In the next step, we used Y2H to identify the proteins that could interact with CbuSPL9. HMGA, an architectural transcriptional factor, was identified and cloned for further research. BiFC and BLI showed that CbuSPL9 could form a heterodimer with CbuHMGA in the nucleus. The expression analysis showed that CbuHMGA had a similar expression trend to that of CbuSPL9 during flowering in “Bairihua”. Intriguingly, ectopic expression of CbuHMGA in Arabidopsis would lead to aberrant flowers, but did not effect flowering time. Taken together, our results implied a novel pathway that ChuSPL9 regulated flowering development, but not flowering transition, with the participation of ChuHMGA. Further investments need to be done to verify the details of this pathway.
Measures of repetition suppression in the Fusiform Face Area are inflated by co-occurring effects of statistically learned visual associations
Authors: Rostalski Sophie-Marie , Amado Catarina , Kovács Gyula , Feuerriegel Daniel 
Published: October 2019

AbstractRepeated presentation of a stimulus leads to reductions in measures of neural responses. This phenomenon, termed repetition suppression (RS), has recently been conceptualized using models based on predictive coding, which describe RS as due to expectations that are weighted toward recently-seen stimuli. To evaluate these models, researchers have manipulated the likelihood of stimulus repetition within experiments. They have reported findings that are inconsistent across hemodynamic and electrophysiological measures, and difficult to interpret as clear support or refutation of predictive coding models. We instead investigated a different type of expectation effect that is apparent in stimulus repetition experiments: the difference in one’s ability to predict the identity of repeated, compared to unrepeated, stimuli. In previous experiments that presented pairs of repeated or alternating images, once participants had seen the first stimulus image in a pair, they could form specific expectations about the repeated stimulus image. However they could not form such expectations for the alternating image, which was often randomly chosen from a large stimulus set. To assess the contribution of stimulus predictability effects to previously observed RS, we measured BOLD signals while presenting pairs of repeated and alternating faces. This was done in contexts whereby stimuli in alternating trials were either i.) predictable through statistically learned associations between pairs of stimuli or ii.) chosen randomly and therefore unpredictable. We found that RS in the right FFA was much larger in trials with unpredictable compared to predictable alternating faces. This was primarily due to unpredictable alternating stimuli evoking larger BOLD signals than predictable alternating stimuli. We show that imbalances in stimulus predictability across repeated and alternating trials can greatly inflate measures of RS, or even mimic RS effects. Our findings also indicate that stimulus-specific expectations, as described by predictive coding models, may account for a sizeable portion of observed RS effects.