bluuebunny/crossref_metadata_2025 huggingface dataset:
Club Cell Protein, CC10, Attenuates Acute Respiratory Distress Syndrome Induced by Smoke Inhalation
Authors: Lopez Ernesto , Fujiwara Osamu , Nelson Christina , Winn Melissa E. , Clayton Richard S. , Cox Robert A. , Hawkins Hal K. , Andersen Clark R. , Wade Charles E. , Hariprakasha Humcha , Prough Donald S. , Pilon Aprile L. , Enkhbaatar Perenlei
Published: May 2019

Objectives:

To evaluate the dose effects of Recombinant human Club cell 10-kDa protein (rhCC10) on lung function in a well-characterized ovine model of acute respiratory distress syndrome (ARDS) induced by smoke inhalation injury (SII); specifically, the potential of rhCC10 protein to control the inflammatory response and protect pulmonary tissue and function following SII.

Design:

Randomized, controlled, prospective, and large animal translational studies.

Setting:

University large animal intensive care unit.

Subjects:

Thirty-six adult female sheep were surgically prepared and allocated into five groups (Sham (no SII), n = 6; 1 mg/kg/d CC10, n = 8; 3 mg/kg/d CC10, n = 7; 10 mg/kg/d CC10, n = 8; Control SII, n = 7).

Interventions:

All groups except the sham group were subjected to SII with cooled cotton smoke. Then, the animals were placed on a ventilator, treated with 1, 3, and 10 mg/kg/d of intravenous rhCC10 or vehicle, divided evenly into two administrations per day every 12 h, fluid resuscitated, and monitored for 48 h in a conscious state.

Measurements and main results:

The group treated with 10 mg/kg/d rhCC10 attenuated changes in the following variables: PaO2/FiO2 ratio, oxygenation index, and peak inspiratory pressure; neutrophil content in the airway and myeloperoxidase levels; obstruction of the large and small airways; systemic leakage of fluid and proteins, and pulmonary edema.

Conclusions:

In this study, high-dose rhCC10 significantly attenuated ARDS progression and lung dysfunction and significantly reduced systemic extravasation of fluid and proteins, normalizing fluid balance. Based on these results, rhCC10 may be considered a novel therapeutic option for the treatment of SII-induced ARDS.
Emerging pharmacological therapies in fragile X syndrome and autism
Authors: Yamasue Hidenori , Aran Adi , Berry-Kravis Elizabeth
Published: May 2019

Purpose of review

Research on the pathophysiology of syndromic autism spectrum disorder (ASD) has contributed to the uncovering of mechanisms in nonsyndromic ASD. The current review aims to compare recent progress in therapeutics development for ASD with those for fragile X syndrome (FXS), the most frequent monogenic form of ASD.

Recent findings

Although candidates such as oxytocin, vasopressin, and cannabinoids are being tested as novel therapeutics, it remains difficult to focus on a specific molecular target of drug development for ASD core symptoms. As the pathophysiology of FXS has been well described as having a causal gene, fragile X mental retardation-1, development of therapeutic agents for FXS is focused on specific molecular targets, such as metabotropic glutamate receptor 5 and GABAB receptor.

There is a large unmet medical need in ASD, a heterogeneous and clinically defined behavioral syndrome, owing to its high prevalence in the general population, lifelong cognitive and behavioral deficits, and no established treatment of ASD core symptoms, such as deficits in social communication and restrictive repetitive behaviors. The molecular pathogenesis of nonsyndromic ASD is largely undefined. Lessons from initial attempts at targeted treatment development in FXS, and new designs resulting from these lessons, will inform trials in nonsyndromic ASD for development of therapeutics for its core symptoms.
Curcumin as Add-On to Antipsychotic Treatment in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Miodownik Chanoch , Lerner Vladimir , Kudkaeva Natalie , Lerner Paul P. , Pashinian Artashez , Bersudsky Yuly , Eliyahu Ronen , Kreinin Anatoly , Bergman Joseph
Published: May 2019

Background

Introduction of old and new generations of antipsychotics leads to significant improvements in the positive symptoms of schizophrenia. However, negative symptoms remain refractory to conventional trials of antipsychotic therapy. Recently, there were several open clinical human trials with curcumin. Curcumin is a natural polyphenol, which has a variety of pharmacological activities, including antioxidative and neuroprotective effects. The studies showed that curcumin improved the negative symptoms of schizophrenia. The purpose of our study was to examine the efficacy of curcumin as an add-on agent to regular antipsychotic medications in patients with chronic schizophrenia.

Methods

Thirty-eight patients with chronic schizophrenia were enrolled in a 24-week, double-blind, randomized, placebo-controlled study. The subjects were treated with either 3000 mg/d curcumin or placebo combined with antipsychotics from January 2015 to February 2017. The outcome measures were the Positive and Negative Symptoms Scale (PANSS) and the Calgary Depression Scale for Schizophrenia.

Results

Analysis of variance showed significant positive changes in both groups from baseline to the end of the study in all scales of measurement. There was a significant response to curcumin within 6 months in total PANSS (P = 0.02) and in the negative symptoms subscale (P = 0.04). There were no differences in the positive and general PANSS subscales, and the Calgary Depression Scale for Schizophrenia scores between the treatment and placebo groups. No patient complained of any adverse effect.

Conclusions

The promising results of curcumin as an add-on to antipsychotics in the treatment of negative symptoms may open a new and safe therapeutic option for the management of schizophrenia. However, these results should be replicated in further studies.

ClinicalTrials.gov Identifier: NCT 02298985
A Spatiomolecular Map of the Striatum
Authors: Märtin Antje , Calvigioni Daniela , Tzortzi Ourania , Fuzik Janos , Wärnberg Emil , Meletis Konstantinos
Published: May 2019

The striatum is organized into two major outputs formed by striatal projection neuron (SPN) subtypes with distinct molecular identities. In addition, the histochemical division into patch and matrix compartments represents an additional spatial organization, proposed to mirror a functional specialization in a motor-motivation dimension. To map the molecular diversity of SPNs in the context of the patch and matrix division, we genetically labeled mu-opioid receptor (Oprm1) expressing striatal neurons and performed single-nucleus RNA sequencing (snRNA-seq). This allowed us to establish new molecular definitions of the patch-matrix compartments, resulting in a molecular code for mapping patch SPNs at the cellular level. In addition, Oprm1 expression labeled exopatch SPNs, which we found to be molecularly distinct from both patch as well as neighboring matrix SPNs, thereby forming a separate molecular entity. At the cell-type level, we found an unexpected SPN diversity, leading to the identification of a new Col11a1+ striatonigral SPN type. At the tissue level, we found that mapping the spatial expression of a number of markers revealed new definitions of spatial domains in the striatum, which were conserved in the non-human primate brain. Interestingly, the spatial markers were cell-type independent and instead represented a spatial code that was found across all SPNs within a spatially restricted domain. This spatiomolecular map establishes a formal system for targeting and studying the striatal subregions and SPNs subtypes, beyond the classical striatonigral and striatopallidal division.
Unicellular Cyanobacteria Exhibit Light-Driven, Oxygen-Tolerant, Constitutive Nitrogenase Activity Under Continuous Illumination
Authors: Young James , Gu Liping , Hildreth Michael , Zhou Ruanbao
Published: May 2019

Cyanobacteria have played a profound role in shaping the biosphere, most notably through the Great Oxygenation Event (GOE) with the advent of photosynthesis1. Cyanobacteria also contribute to global primary production through biological nitrogen fixation (BNF) using nitrogenase2,3, an oxygen-labile enzyme complex that evolutionarily predates the GOE4. Current literature reports nitrogenase activity in unicellular cyanobacteria is protected from oxygen through diurnal separation of photosynthesis and BNF5. However, historic conditions of continuous-light and warm temperature at polar latitudes during the Triassic and Cretaceous may have created a selective advantage amongst unicellular cyanobacteria for non-temporal mechanisms of maintaining nitrogenase activity in the presence of oxygen. Here we report constitutive nitrogenase activity concurrent with a net-gain of oxygen through photosynthesis in a continuous-light adapted culture of the unicellular cyanobacteria, Cyanothece sp. ATCC 51142. Nitrogenase activity in the adapted culture exhibited dependence on light and an increased resilience to artificially raised oxygen-tension compared to traditional culture. We predict cyanobacteria closely related to Cyanothece sp. ATCC 51142 also possess this physiology and found an accessory predicted proteome with functional relevance. This work provides a model of light-driven, oxygen-tolerant, constitutive nitrogenase activity and suggests this physiology may be conserved in closely related unicellular diazotrophic cyanobacteria with implications for primary production in polar ecosystems and potential biotechnological application in sustainable agriculture production.
Harvesting-induced evolution of collective risk-taking behavior and changes to the circadian system in a fish
Authors: Sbragaglia Valerio , López-Olmeda Jose Fernando , Frigato Elena , Bertolucci Cristiano , Arlinghaus Robert
Published: May 2019

Intensive and trait-selective harvesting of fish and wildlife can cause evolutionary changes in a range of life-history and behavioural traits. These changes might in turn alter the circadian system both at behavioral and molecular levels, with knock-on effects on daily physiological processes and behavioural outputs. We examined the evolutionary impact of size-selective mortality on collective risk-taking behavior and the circadian system in a model fish species. We exposed zebrafish (Danio rerio) to either large or small size-selective mortality relative to a control over five generations, followed by eight generations during which harvesting halted to remove maternal effects. Large size-selective mortality typical of many fisheries and specialized predators targeting larger size classes decreased collective risk-taking behavior compared to controls. The opposite occurred in response to small size-selective mortality typical of specialized fisheries and most gape-limited predators. The evolutionary changes in risk-taking behavior were linked to daily activity rhythms in response to small size-selective mortality, while no changes were observed in response to large size-selective mortality. We also found changes in the molecular circadian core clockwork in response to both size selective mortality treatments. These changes disappeared in the clock output pathway, resulting in similar transcription profiles of both size-selected lines. The results suggest a switch downstream to the molecular circadian core clockwork, leading to overall similar daily activity patterns across selection lines. Our experimental harvest left an evolutionary legacy in collective risktaking behavior and relatedly in the circadian system, both at behavioral and molecular levels. Changes to risk-sensitive behavior of exploited organisms can have far-reaching consequences for how space and time is used and may also affect catchability and natural predation.
Binaural Beats through the auditory pathway: from brainstem to connectivity patterns
Authors: Perez Hector D Orozco , Dumas Guillaume , Lehmann Alexandre
Published: May 2019

Binaural beating is a perceptual auditory illusion occurring when presenting two neighboring frequencies to each ear separately. Binaural beats have been attributed to several controversial claims regarding their ability to modulate brain activity and mood, in both the scientific literature and the marketing realm. Here, we sought to address those questions in a robust fashion using a single-blind, sham-controlled protocol. To do so, we characterized responses to theta and gamma binaural beats and “sham” stimulation (monaural beats) across four distinct levels: subcortical and cortical entrainment, scalp-level Functional Connectivity and self-reports. Both stimuli elicited standard subcortical responses at the pure tone frequencies of the stimulus (i.e., Frequency Following Response), and entrained the cortex at the beat frequency (i.e., Auditory Steady State Response). Furthermore, Functional Connectivity patterns were modulated differentially by both kinds of stimuli, with binaural beats being the only one eliciting cross-frequency activity. Despite this, we did not find any mood modulation related to our experimental manipulation. Our results provide evidence that binaural beats elicit cross frequency connectivity patterns, but weakly entrain the cortex when compared to a sham stimulus. Whether these patterns have an impact in cognitive performance or other mood measurements remains to be seen.

Significance Statement

Binaural beats have been a source of speculation and debate in the scientific community. Our study addresses pseudo-scientific marketing claims and approaches them using proper experimental control and state-of-the-art signal processing techniques. Here we show that binaural beats can both entrain the cortex and elicit specific connectivity patterns. Regardless of this, our sham condition was able to entrain the cortex more strongly, and both binaural beats and the sham condition failed to regulate mood. All in all, though binaural beats weakly entrain cortical activity and elicit complex patterns of connectivity, the functional significance (if any) of these patterns remains an open question.
Myosin II Tension Sensors Visualize Force Generation within the Actin Cytoskeleton in Living Cells
Authors: Hart Ryan G. , Kota Divya , Li Fangjia , Ramallo Diego , Price Andrew J. , Otterpohl Karla L. , Smith Steve J. , Dunn Alexander R. , Liu Jing , Chandrasekar Indra
Published: May 2019

Type II myosin motors generate cytoskeletal forces that are central to cell division, embryogenesis, muscle contraction, and many other cellular functions. However, at present there is no method that can directly measure the forces generated by myosins in living cells. Here we describe a Förster resonance energy transfer (FRET)-based tension sensor that can measure forces generated by Nonmuscle Myosin IIB (NMIIB) in living cells with piconewton (pN) sensitivity. Fluorescence lifetime imaging microscopy (FLIM)-FRET measurements indicate that the forces generated by NMIIB exhibit significant spatial and temporal heterogeneity, with inferred tensions that vary widely in different regions of the cell. This initial report highlights the potential utility of myosin-based tension sensors in elucidating the roles of cytoskeletal contractility in a wide variety of contexts.
Evidence for shared conceptual representations for sign and speech
Authors: Evans Samuel , Price Cathy , Diedrichsen Jörn , Gutierrez-Sigut Eva , MacSweeney Mairéad
Published: May 2019

Do different languages evoke different conceptual representations? If so, greatest divergence might be expected between languages that differ most in structure, such as sign and speech. Unlike speech bilinguals, hearing sign-speech bilinguals use languages conveyed in different modalities. We used functional magnetic resonance imaging and representational similarity analysis (RSA) to quantify the similarity of semantic representations elicited by the same concepts presented in spoken British English and British Sign Language in hearing, early sign-speech bilinguals. We found shared representations for semantic categories in left posterior middle and inferior temporal cortex. Despite shared category representations, the same spoken words and signs did not elicit similar neural patterns. Thus, contrary to previous univariate activation-based analyses of speech and sign perception, we show that semantic representations evoked by speech and sign are only partially shared. This demonstrates the unique perspective that sign languages and RSA provide in understanding how language influences conceptual representation.
Pontoscolex corethrurus:a Homeless Invasive Tropical Earthworm?
Authors: Ortíz-Ceballos Angel I. , Ortiz-Gamino Diana , Andrade-Torres Antonio , Pérez-Rodríguez Paulino , López-Ortega Maurilio
Published: May 2019

The presence of earthworm species in crop fields is as old as agriculture itself. The earthwormsPontoscolex corethrurus(invasive) andBalanteodrilus pearsei(native) are associated with the emergence of agriculture and sedentism in the region Amazon and Maya, respectively. Both species have shifted their preference from their natural habitat to the cropland niche; however, they contrast in terms of intensification of agricultural land use (anthropic impact to the symbiotic soil microbiome).P. corethrurusinhabits conventional agroecosystems (pesticides, herbicides, and fertilizers are applied to soil), whileB. pearseithrives in traditional agroecosystems (biological management of soil); that is,P. corethrurushas not yet been recorded in soils whereB. pearseidwells. The demographic behavior of these two earthworm species was assessed in the laboratory over 100 days, according to their origin (OE;P. corethrurusandB. pearsei) food quality (FQ; soil only, maize stubble, andMucuna pruriens), and soil moisture (SM; 25, 33, and 42%). The results showed that OE, FQ, SM, and the OE x FQ interaction were highly significant for the survival, growth, and reproduction of earthworms.P. corethrurusshowed a lower survival rate (> mortality).P. corethrurussurvivors fed a diet of low-to-intermediate nutritional quality (soil and corn stalks, respectively) showed a greater capacity to grow and reproduce; however, it was surpassed by the native earthworm when fed a high-quality diet (M. pruriens). Besides,P. corethrurusdisplayed a low cocoon hatching (emergence of juveniles). These results suggest that the presence of the invasive species was associated with the absence of natural mutualistic bacteria (gut, nephridia, and cocoons), and with a negative interaction with the soil microbiota where the native species dwells. These results are consistent with the absence ofP. corethrurusin milpa and pasture-type agricultural niches managed by peasants (agroecologists) to grow food regularly a biological management of soil. The results reported here and the published information jointly (e.g., designation of the neotype and ambiguity of the place of origin) jointly suggest thatP. corethrurusis an invasive species that is neither wild nor domesticated, that is, its eco-evolutionary phylogeny needs to be derived based on its symbionts.
Genetic characterization of a recombinant myxoma virus leap into the Iberian hare (Lepus granatensis)
Authors: Águeda-Pinto Ana , de Matos Ana Lemos , Abrantes Mário , Kraberger Simona , Risalde Maria A. , Gortázar Christian , McFadden Grant , Varsani Arvind , Esteves Pedro J.
Published: May 2019

Myxomatosis is a lethal disease of wild European and domestic rabbits (Oryctolagus cuniculus) caused by a Myxoma virus (MYXV) infection, a leporipoxvirus that is found naturally in someSylvilagusrabbit species in South America and California. The introduction of MYXV in the early 1950s into feral European rabbit populations in Australia and Europe demonstrate the best documented field example of host-virus coevolution following a cross-species transmission. Recently, a new cross-species jump of MYXV has been suggested in both Great Britain and Spain, where European brown hares (Lepus europaeus) and Iberian hares (Lepus granatensis) were found dead with lesions consistent with those observed in myxomatosis. To investigate the possibility of a new cross-species transmission event by MYXV, tissue samples collected from a wild Iberian hare found dead in Spain (Toledo region) were analyzed and deep sequenced. Our results report a new MYXV strain (MYXV Toledo) in the tissues of this species. The genome of this new strain encodes three disrupted genes (M009L,M036LandM152R) and a novel 2.8 KB recombinant region that resulted from an insertion of four novel poxviral genes towards the 5’ end of its genome. From the open reading frames inserted into the MYXV Toledo strain, a new orthologue of a poxvirus host range gene family member was identified which is related to the MYXV geneM064R. Overall, we confirmed the identity of a new MYXV strain in Iberian hares that we hypothesize was able to more effectively counteract the host defenses in hares and start an infectious process in this new host.
A comprehensive plasma metabolomics dataset for a cohort of mouse knockouts within the international mouse phenotyping consortium
Authors: Barupal Dinesh K , Zhang Ying , Shen Tong , Fan Sili , Roberts Bryan S , Fitzgerald Patrick , Wancewicz Benjamin , Valdiviez Luis , Wohlgemuth Gert , Byram Gregory , Choy YingYng , Haffner Bennett , Showalter Megan R. , Vaniya Arpana , Bloszies Clayton S , Folz Jacob S , Kind Tobias , Fiehn Oliver
Published: May 2019

Mouse knockouts allow studying gene functions. Often, multiple phenotypes are impacted when a gene is inactivated. The International Mouse Phenotyping Consortium (IPMC) has generated thousands of mouse knockouts and catalogued their phenotype data. We have acquired metabolomics data from 220 plasma samples of 30 mouse gene knockouts and corresponding wildtype mice from IMPC. To acquire comprehensive metabolomics data, we have used liquid chromatography (LC) combined with mass spectrometry (MS) for detecting polar and lipophilic compounds in an untargeted approach. We have also used targeted methods to measure bile acids, steroids and oxylipins. In addition, we have used gas chromatography GC-TOFMS for measuring primary metabolites. The metabolomics dataset reports 832 unique structurally identified metabolites from 124 chemical classes as determined by ChemRICH software. The GCMS and LCMS raw data files, intermediate and finalized data matrices, R-Scripts, annotation databases and extracted ion chromatograms are provided in this data descriptor. The dataset can be used for subsequent studies to link genetic variants with molecular mechanisms and phenotypes.

Data Set

The dataset is available at the MetabolomicsWorkbench repository (accession ID: ST001154)

Data Set License

license under which the data set is made available (CC0).
Proteomics Standards Initiative Extended FASTA Format (PEFF)
Authors: Binz Pierre-Alain , Shofstahl Jim , Vizcaíno Juan Antonio , Barsnes Harald , Chalkley Robert J. , Menschaert Gerben , Alpi Emanuele , Clauser Karl , Eng Jimmy K. , Lane Lydie , Seymour Sean L. , Sánchez Luis Francisco Hernández , Mayer Gerhard , Eisenacher Martin , Perez-Riverol Yasset , Kapp Eugene A. , Mendoza Luis , Baker Peter R. , Collins Andrew , Van Den Bossche Tim , Deutsch Eric W.
Published: May 2019

Mass spectrometry-based proteomics enables the high-throughput identification and quantification of proteins, including sequence variants and post-translational modifications (PTMs), in biological samples. However, most workflows require that such variations be included in the search space used to analyze the data, and doing so remains challenging with most analysis tools. In order to facilitate the search for known sequence variants and PTMs, the Proteomics Standards Initiative (PSI) has designed and implemented the PSI Extended FASTA Format (PEFF). PEFF is based on the very popular FASTA format but adds a uniform mechanism for encoding substantially more metadata about the sequence collection as well as individual entries, including support for encoding known sequence variants, PTMs, and proteoforms. The format is very nearly backwards compatible, and as such, existing FASTA parsers will require little or no changes to be able to read PEFF files as FASTA files, although without supporting any of the extra capabilities of PEFF. PEFF is defined by a full specification document, controlled vocabulary terms, a set of example files, software libraries, and a file validator. Popular software and resources are starting to support PEFF, including the sequence search engine Comet and the knowledge bases neXtProt and UniProtKB. Widespread implementation of PEFF is expected to further enable proteogenomics and top-down proteomics applications by providing a standardized mechanism for encoding protein sequences and their known variations. All the related documentation, including the detailed file format specification and example files, are available athttp://www.psidev.info/peff.
The swim-up technique separates bovine sperm by metabolic rates, motility and tail length
Authors: Magdanz Veronika , Boryshpolets Sergii , Ridzewski Clara , Eckel Barbara , Reinhardt Klaus
Published: May 2019

Swim-up is a sperm purification method that is being used daily in andrology labs around the world as a simple step forin vitrosperm selection. This method accumulates the most motile sperm in the upper fraction and leaves sperm with low or no motility in the lower fraction but the underlying reasons are not fully understood. In this article, we compare metabolic rate, motility and sperm tail length of bovine sperm cells of the upper and lower fraction. The metabolic assay platform reveals oxygen consumption rates and extracellular acidification rates simultaneously and thereby delivers the metabolic rates in real time. Our study confirms the upper fraction of bull sperm has improved motility compared to the cells in the lower fraction and shows higher metabolic rates. This pattern was consistent across media of two different levels of viscosity. Sperm with longer flagella are selected in the upper fraction. We conclude that the motility-based separation of the swim-up technique is based on metabolic differences. Metabolic assays could serve as additional or alternative, label-free method to evaluate sperm quality, which is likely particularly useful in cases of asthenozoospermia and teratospermia. Furthermore, metabolic measurements of sperm cells can reveal differences in metabolic pathways in different environments.
Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease
Authors: Bender Sébastien , Ayala Maria Victoria , Bonaud Amélie , Javaugue Vincent , Carrion Claire , Oblet Christelle , Rinsant Alexia , Quellard Nathalie , Kaaki Sihem , Oruc Zeliha , Boyer François , Paquet Agnès , Pons Nicolas , Hervé Bastien , Ashi Mohamad Omar , Jaccard Arnaud , Delpy Laurent , Touchard Guy , Cogné Michel , Bridoux Frank , Sirac Christophe
Published: May 2019

Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells. High free LC levels were achieved after backcrossing with mice presenting increased plasma cell differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on plasma cells demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.
In vivo functional diversity of midbrain dopamine neurons within identified axonal projections
Authors: Farassat Navid , Costa Kauê M. , Albert Stefan , Kovacheva Lora , Shin Josef , Somayaji Mahalakshmi , Schneider Gaby , Roeper Jochen
Published: May 2019

The functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and synaptic connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and juxtacellular labelling in mouse brain to create the first single cell-resolved in vivo functional topography of the midbrain DA system. We identified surprising differences in burst firing among those DA neurons projecting to dorsolateral striatum, which were organized along the medio-lateral substantia nigra (SN) axis. Furthermore, burst properties also differentiated DA neurons in the medial SN that projected either to dorsal or ventral striatum. In contrast, DA neurons projecting to lateral shell of nucleus accumbens displayed identical firing properties, irrespective of whether they were located in the SN or ventral tegmental area (VTA), thus breaching classical anatomical boundaries. Finally, we found robust differences in mean firing rates and pause durations among VTA DA neurons projecting to either lateral or medial shell of nucleus accumbens. Together, our data set establishes a high-resolution functional landscape of midbrain DA neurons, which will facilitate the identification of selective functions and pathophysiological changes within the midbrain DA system.
Multilevel selection in groups of groups
Authors: Pruitt Jonathan N. , Fisher David N. , Costa-Pereira Raul , Pinter-Wollman Noa
Published: May 2019

Natural selection occurs at many levels. We evaluated selection acting on collectives at a level of multilevel selection analysis not yet quantified: within and between clusters of groups. We did so by monitoring the performance of natural colonies of social spiders with contrasting foraging aggressiveness in clusters of various sizes. Within-clusters, growth rates were suppressed when colonies were surrounded by more rival groups, conveying that competition is greater. When colonies were surrounded by few rivals, the more aggressive colonies in a cluster were more successful. In contrast, relatively non-aggressive colonies performed better when surrounded by many rivals. Patterns of selection between-clusters depended on the performance metric considered, but cluster-wide aggressiveness was always favored in small clusters. Together, selection both within-and between natural clusters of colonies was detectable, but highly contingent on the number of competing colonies.
Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk
Authors: Kremen William S. , Panizzon Matthew S. , Elman Jeremy A. , Granholm Eric L. , Andreassen Ole A. , Dale Anders M. , Gillespie Nathan A. , Gustavson Daniel E. , Logue Mark W. , Lyons Michael J. , Neale Michael C. , Reynolds Chandra A. , Whitsel Nathan , Franz Carol E.
Published: May 2019

Pathological changes in Alzheimer’s disease (AD) begin decades before dementia onset. Because locus coeruleus tau pathology is the earliest occurring AD pathology, targeting indicators of locus coeruleus (dys)function may improve midlife screening for earlier identification of AD risk. Pupillary responses during cognitive tasks are driven by the locus coeruleus and index cognitive effort. Several findings suggest task-associated pupillary response as an early marker of AD risk. Requiring greater effort suggests being closer to one’s compensatory capacity, and adults with mild cognitive impairment (MCI) have greater pupil dilation during digit span tasks than cognitively normal individuals, despite equivalent task performance. Higher AD polygenic risk scores (AD-PRSs) are associated with increased odds of MCI and tau positivity. We hypothesized that AD-PRSs would be associated with pupillary responses in cognitively normal middle-aged adults. We demonstrated that pupillary responses during digit span tasks were heritable (h2=.30-.36) in 1119 men ages 56-66. We then examined associations between AD-PRSs and pupillary responses in a cognitively normal subset who all had comparable span capacities (n=539). Higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit recall) cognitive load condition; Cohen’s d=.36 for the upper versus lower quartile of the AD-PRS distribution. Results held up after controlling for APOE genotype. The results support pupillary response—and by inference, locus coeruleus dysfunction—as a genetically-mediated biomarker of early MCI/AD risk. In some studies, cognition predicted disease progression earlier than biomarkers. Pupillary responses might improve screening and early identification of genetically at-risk individuals even before cognitive performance declines.
When do individuals maximize their inclusive fitness?
Authors: Lehmann Laurent , Rousset François
Published: May 2019

Adaptation is often described in behavioral ecology as individuals maximizing their inclusive fitness. Under what conditions does this hold and how does this relate to the gene-centered perspective of adaptation? We unify and extend the literature on these questions to class-structured populations. We demonstrate that the maximization (in the best-response sense) of class-specific inclusive fitness obtains in uninvadable population states (meaning that all deviating mutant go extinct). This defines a genuine actor-centered perspective on adaptation. But this inclusive fitness is assigned to all bearers of a mutant allele in a given class and depends on distributions of demographic and genetic contexts. These distributions, in turn, usually depend on events in previous generations and are thus not under individual control. This prevents, in general, from envisioning individuals themselves as autonomous fitness-maximizers, each with its own inclusive fitness. For weak selection, however, the dependence on earlier events can be neglected. We then show that each individual in each class appears to maximize its own inclusive fitness when all other individuals exhibit fitness-maximizing behavior. This defines a genuine individual-centered perspective of adaptation and justifies formally, as a first-order approximation, the long-heralded view of individuals appearing to maximize their own inclusive fitness.
Single-cell chromatin accessibility analysis of mammary gland development reveals cell state transcriptional regulators and cellular lineage relationships
Authors: Chung Chi-Yeh , Ma Zhibo , Dravis Christopher , Preissl Sebastian , Poirion Olivier , Luna Gidsela , Hou Xiaomeng , Giraddi Rajshekhar R. , Ren Bing , Wahl Geoffrey M.
Published: May 2019

It has only recently become possible to obtain single-cell level resolution of the epigenetic changes that occur during organ development. We reasoned that precision single-cell chromatin accessibility mapping of mammary gland development could provide needed insight into the epigenetic reprogramming and transcriptional regulators involved in normal mammary gland development. Here, we provide the first single-cell resource of chromatin accessibility for murine mammary development from the peak of fetal mammary stem cell (fMaSC) functional activity in late embryogenesis to the differentiation of adult basal and luminal cells. We find that the chromatin landscape within individual cells predicts both gene accessibility and transcription factor activity, and we present a web application as a scientific resource for facilitating future analyses. Strikingly, these single-cell chromatin profiling data reveal that fMaSCs can be separated into basal-like and luminal-like lineages, providing evidence of early lineage segregation prior to birth. Such distinctions were not evident in analyses of single-cell transcriptomic data.
A VEGF reaction-diffusion mechanism that selects variable densities of endothelial tip cells
Authors: Bedell W. , Stroock A. D.
Published: May 2019

The patterned differentiation of endothelial cells into tip and stalk cells represents an important step in the process of angiogenic sprouting. Vascular biologists hypothesize that changes in the density and overall structure of the vasculature can be traced in part to changes in the number of tip cells selected in the endothelium prior to sprout formation. However, the dominant hypotheses for tip cell selection invoke lateral inhibition via Notch; this juxtacrine mechanism predicts that a fixed fraction of endothelial cells become tip cells through a pattern-forming instability. Here, we present and analyze a hypothetical mechanism for tip cell selection that is based on endothelial competition for diffusible vascular endothelial growth factor (VEGF); this mechanism predicts that variable densities of tip cells emerge depending on the local (paracrine) production rate of VEGF. First, we hypothesize a network of VEGF signaling and trafficking based on previous experimental findings that could allow internalization of VEGF to occur with positive feedback. We formalize the hypothesis into a set of nonlinear ordinary differential equations and perform linear stability analysis to elucidate a general criterion for tip cell pattern formation under the mechanism. We use numerical integration to explore the nonlinear dynamics and final steady-states of tip cell patterns under this mechanism; the observed density of tip cells can be tuned from 10% to 84%. We conclude with proposals of future experiments and computational studies to explore how competitive consumption of diffusible VEGF may play a role in determining vascular structure.

Statement of Significance

The patterned differentiation of endothelial cells into tip and stalk cells represents an important step in the process of blood vessel growth. Vascular biologists hypothesize that changes in the density and overall structure of the vasculature can be traced in part to changes in the number of tip cells selected during angiogenesis. However, the dominant hypotheses for tip cell selection predict that a locally fixed fraction of endothelial cells become tip cells following stimulation by vascular endothelial growth factor (VEGF). Here, we present and analyze a hypothetical mechanism for tip cell selection based on endothelial competition for diffusible VEGF; this mechanism predicts that variable densities of tip cells emerge depending on the local production rate of VEGF.
Distinguishing “self” from “other” in a dynamic synchronization task with an adaptive virtual partner
Authors: Fairhurst Merle T. , Janata Petr , Keller Peter E.
Published: May 2019

For precise interpersonal coordination, some degree of merging a sense of self with other is required. In group music making, one may want to be in “sync” with one’s ensemble and, if playing a similar instrument, one can assume a degree of temporal and acoustic overlap. However, to what extent is self-other merging optimal? An incorrect balance of segregation and integration of self and other information would result in a lack of interpersonal cohesion or a disruption of self-agency. Using an interactive finger-tapping task with a virtual partner and functional MRI, we explored neural differences between self-other merging and distinction. Varying both the level of adaptivity of a virtual partner and the quality of self-related auditory feedback, we show that the predictability of the other and availability of distinguishable, self-related information improve performance and demonstrate how dynamic interactions vary one’s sense of agency. From neuroimaging data, we identify regions that are more active when self and other are distinct, including the TPJ. Conversely, we observe activity in the cerebellum, EBA and SMA when self and other blur. These findings suggest that a certain degree of self-other distinction at sensorimotor, experiential, and neurophysiological levels is required to maintain successful interpersonal coordination.
Insights about variation in meiosis from 31,228 human sperm genomes
Authors: Bell Avery Davis , Mello Curtis J. , Nemesh James , Brumbaugh Sara A. , Wysoker Alec , McCarroll Steven A.
Published: May 2019

Meiosis, while critical for reproduction, is also highly variable and error prone: crossover rates vary among humans and individual gametes, and chromosome nondisjunction leads to aneuploidy, a leading cause of miscarriage. To study variation in meiotic outcomes within and across individuals, we developed a way to sequence many individual sperm genomes at once. We used this method to sequence the genomes of 31,228 gametes from 20 sperm donors, identifying 813,122 crossovers, 787 aneuploid chromosomes, and unexpected genomic anomalies. Different sperm donors varied four-fold in the frequency of aneuploid sperm, and aneuploid chromosomes gained in meiosis I had 36% fewer crossovers than corresponding non-aneuploid chromosomes. Diverse recombination phenotypes were surprisingly coordinated: donors with high average crossover rates also made a larger fraction of their crossovers in centromere-proximal regions and placed their crossovers closer together. These same relationships were also evident in the variation among individual gametes from the same donor: sperm with more crossovers tended to have made crossovers closer together and in centromere-proximal regions. Variation in the physical compaction of chromosomes could help explain this coordination of meiotic variation across chromosomes, gametes, and individuals.
An Electrophysiological Marker of Arousal Level in Humans
Authors: Lendner Janna D. , Helfrich Randolph F. , Mander Bryce A. , Romundstad Luis , Lin Jack J. , Walker Matthew P. , Larsson Pal G. , Knight Robert T.
Published: May 2019

Deep non-rapid eye movement sleep (NREM) – also called slow wave sleep (SWS) – and general anesthesia are prominent states of reduced arousal linked to the occurrence of slow oscillations in the electroencephalogram (EEG). Rapid eye movement (REM) sleep, however, is also associated with a diminished arousal level, but is characterized by a desynchronized, ‘wake-like’ EEG. This observation challenges the notion of oscillations as the main physiological mediator of reduced arousal. Using intracranial and surface EEG recordings in four independent data sets, we establish the 1/f spectral slope as an electrophysiological marker that accurately delineates wakefulness from anesthesia, SWS and REM sleep. The spectral slope reflects the non-oscillatory, scale-free measure of neural activity and has been proposed to index the local balance between excitation and inhibition. Taken together, these findings reconcile the long-standing paradox of reduced arousal in both REM and NREM sleep and provide a common unifying physiological principle — a shift in local Excitation/ Inhibition balance — to explain states of reduced arousal such as sleep and anesthesia in humans.

Significance Statement

The clinical assessment of arousal levels in humans depends on subjective measures such as responsiveness to verbal commands. While non-rapid eye movement (NREM) sleep and general anesthesia share some electrophysiological markers, rapid eye movement sleep (REM) is characterized by a ‘wake-like’ electroencephalogram. Here, we demonstrate that non-oscillatory, scale-free electrical brain activity — recorded from both scalp electroencephalogram and intracranial recordings in humans — reliably tracks arousal levels during both NREM and REM sleep as well as under general anesthesia with propofol. Our findings suggest that non-oscillatory brain activity can be used effectively to monitor vigilance states.
Regulated spindle orientation buffers tissue growth in the epidermis
Authors: Morrow Angel , Underwood Julie , Seldin Lindsey , Hinnant Taylor , Lechler Terry
Published: May 2019

Tissue homeostasis requires a balance between progenitor cell proliferation and loss. Mechanisms that maintain this robust balance are needed to avoid tissue loss or overgrowth. Here we demonstrate that regulation of spindle orientation/asymmetric cell divisions is one mechanism that is used to buffer changes in proliferation and tissue turnover in mammalian skin. Genetic and pharmacologic experiments demonstrate that asymmetric cell divisions were increased in hyperproliferative conditions and decreased under hypoproliferative conditions. Further, active K-Ras also increased the frequency of asymmetric cell divisions. Disruption of spindle orientation in combination with constitutively active K-Ras resulted in massive tissue overgrowth. Together, these data highlight the essential roles of spindle orientation in buffering tissue homeostasis in response to perturbations.
Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations
Authors: Gordon Aaron , Grønborg-Forsingdal Annika , Klewe Ib Vestergaard , Nielsen Jacob , Didriksen Michael , Werge Thomas , Geschwind Daniel
Published: May 2019

Genetic risk for psychiatric illness is complex, so identification of shared molecular pathways where distinct forms of genetic risk might coincide is of substantial interest. A growing body of genetic and genomic studies suggest that such shared molecular pathways exist across disorders with different clinical presentations, such as schizophrenia and autism spectrum disorder (ASD). But how this relates to specific genetic risk factors is unknown. Further, whether some of the molecular changes identified in brain relate to potentially confounding antemortem or post-mortem factors is difficult to prove. We analyzed the transcriptome from the cortex and hippocampus of three mouse lines modeling human copy number variants (CNVs) associated with schizophrenia and ASD: Df(h15q13)/+, Df(h22q11)/+, and Df(h1q21)/+ which carry the 15q13.3 deletion, 22q11.2 deletion, and 1q21.1 deletion, respectively. Although we found very little overlap of differential expression at the level of individual genes, gene network analysis identified two modules of co-expressed genes that were dysregulated across all three mouse models. One module observed in both cortex and hippocampus was associated with neuronal energetics and firing rate, and overlapped with changes identified in post mortem human brain from SCZ and ASD patients. These data highlight aspects of convergent gene expression in mouse models harboring major risk alleles, and strengthen the connection between neuronal energetic dysfunction and neuropsychiatric disorders in humans.