bluuebunny/crossref_metadata_2025 huggingface dataset:
Provider Preference in Exam Room Layout Design and Computing
Authors: Read Jacob M. , Weiler Dustin T. , Satterly Tyler , Soares Catarina , Saleem Jason J.
Published: December 2019

Background The introduction of the electronic health record (EHR) has had a significant impact on provider–patient interactions, particularly revolving around patient-centeredness. More research is needed to understand the provider perspective of this interaction.

Objectives Our objective was to obtain provider feedback on a new exam room design compared with the one already in use with respect to the computing layout, which included a wall-mounted monitor for ease of (re)-positioning. An additional objective was to understand elements of exam room design and computing that were highly valued.

Methods Semistructured interviews were conducted with 28 providers from several health care organizations. Interviews were audio recorded and transcribed for analysis. We used an inductive coding approach to abstract recurrent themes from the data.

Results Our analysis revealed several themes organized around exam room layout, exam room computing, and provider workflow. We report frequency of occurrence of the coded data for computer accessories, computing usefulness, computer mobility, documentation habits, form factor, layout preference, patient interaction, screen sharing, and work habits.

Conclusion Providers in our study preferred exam room design to promote flexibility, mobility, and body orientation directed toward the patient. Providers also expressed the need for exam room design to support varying work habits and preferences, including whether to share the computer screen or not.
Formative Usability Testing Reduces Severe Blood Product Ordering Errors
Authors: Orenstein Evan W. , Boudreaux Jeanne , Rollins Margo , Jones Jennifer , Bryant Christy , Karavite Dean , Muthu Naveen , Hike Jessica , Williams Herb , Kilgore Tania , Carter Alexis B. , Josephson Cassandra D.
Published: December 2019

Background Medical errors in blood product orders and administration are common, especially for pediatric patients. A failure modes and effects analysis in our health care system indicated high risk from the electronic blood ordering process.

Objectives There are two objectives of this study as follows:

(1) To describe differences in the design of the original blood product orders and order sets in the system (original design), new orders and order sets designed by expert committee (DEC), and a third-version developed through user-centered design (UCD).

(2) To compare the number and type of ordering errors, task completion rates, time on task, and user preferences between the original design and that developed via UCD.

Methods A multidisciplinary expert committee proposed adjustments to existing blood product order sets resulting in the DEC order set. When that order set was tested with front-line users, persistent failure modes were detected, so orders and order sets were redesigned again via formative usability testing. Front-line users in their native clinical workspaces were observed ordering blood in realistic simulated scenarios using a think-aloud protocol. Iterative adjustments were made between participants. In summative testing, participants were randomized to use the original design or UCD for five simulated scenarios. We evaluated differences in ordering errors, time on task, and users' design preference with two-sample t-tests.

Results Formative usability testing with 27 providers from seven specialties led to 18 changes made to the DEC to produce the UCD. In summative testing, error-free task completion for the original design was 36%, which increased to 66% in UCD (30%, 95% confidence interval [CI]: 3.9–57%; p = 0.03). Time on task did not vary significantly.

Conclusion UCD led to substantially different blood product orders and order sets than DEC. Users made fewer errors when ordering blood products for pediatric patients in simulated scenarios when using the UCD orders and order sets compared with the original design.
Effect of age on binaural integration using dichotic digit test in Kannada
Authors: Jain Chandni , Parmeshwara Keerthi Sringari , Chinnaraj Geetha
Published: December 2019

Objecitve:

The present study aimed to compare the effect of age on binaural integration in younger and older adults with normal hearing using dichotic digit test in Kannada.

Materials and methods:

Two groups of participants with normal hearing sensitivity sensitivity were enrolled for the study. Group 1 included 19 young adults in the age range of 18 to 25 years (12 Females, Mean age = 20.95 years), and Group 2 included 19 older adults within the age range of 50 to 70 years (10 Females, Mean age = 56.35 years). Bisyllabic Kannada digits were used to assess binaural integration. The material consists of a total of 30 presentations with each presentation having two-digit pair. Single correct scores and double correct scores were noted down for the participants.

Results and Discussion:

Results showed that the right ear single correct scores were high for both the groups, and there was a significant difference in the right correct scores (p < .05), left correct scores (p < .001) as well as double correct scores (p < .01) between the two groups. It was also seen that the right ear advantage was more pronounced in older adults (21.40%) compared to the younger adults (5.61%) which could be due to the decline in the efficiency of interhemispheric transfer of information via the corpus callosum.

Conclusion:

To conclude, there is an age-related decline in dichotic digit scores, and thus, separate norms are required for older adults.
Revealing the inhomogeneous surface chemistry on the spherical layered oxide polycrystalline cathode particles*
Authors: Jiang Zhi-Sen , Li Shao-Feng , Xu Zheng-Rui , Nordlund Dennis , Ohldag Hendrik , Pianetta Piero , Lee Jun-Sik , Lin Feng , Liu Yi-Jin
Published: December 2019

The hierarchical structure of the composite cathodes brings in significant chemical complexity related to the interfaces, such as cathode electrolyte interphase. These interfaces account for only a small fraction of the volume and mass, they could, however, have profound impacts on the cell-level electrochemistry. As the investigation of these interfaces becomes a crucial topic in the battery research, there is a need to properly study the surface chemistry, particularly to eliminate the biased, incomplete characterization provided by techniques that assume the homogeneous surface chemistry. Herein, we utilize nano-resolution spatially-resolved x-ray spectroscopic tools to probe the heterogeneity of the surface chemistry on LiNi0.8Mn0.1Co0.1O2 layered cathode secondary particles. Informed by the nano-resolution mapping of the Ni valance state, which serves as a measurement of the local surface chemistry, we construct a conceptual model to elucidate the electrochemical consequence of the inhomogeneous local impedance over the particle surface. Going beyond the implication in battery science, our work highlights a balance between the high-resolution probing the local chemistry and the statistical representativeness, which is particularly vital in the study of the highly complex material systems.
Atomically flat surface preparation for surface-sensitive technologies*
Authors: Tang Cen-Yao , Rao Zhi-Cheng , Yuan Qian-Qian , Tian Shang-Jie , Li Hang , Huang Yao-Bo , Lei He-Chang , Li Shao-Chun , Qian Tian , Sun Yu-Jie , Ding Hong
Published: December 2019

Surface-sensitive measurements are crucial to many types of researches in condensed matter physics. However, it is difficult to obtain atomically flat surfaces of many single crystals by the commonly used mechanical cleavage. We demonstrate that the grind-polish-sputter-anneal method can be used to obtain atomically flat surfaces on topological materials. Three types of surface-sensitive measurements are performed on CoSi (001) surface with dramatically improved quality of data. This method extends the research area of surface-sensitive measurements to hard-to-cleave alloys, and can be applied to irregular single crystals with selective crystalline planes. It may become a routine process of preparing atomically flat surfaces for surface-sensitive technologies.
Effect of increasing dietary energy density during late gestation and lactation on sow performance, piglet vitality, and lifetime growth of offspring
Authors: Rooney Hazel B , O’driscoll Keelin , O’doherty John V , Lawlor Peadar G
Published: December 2019

Genetic selection for hyperprolificacy in sows has resulted in a significant increase in the number of piglets born alive per litter but subsequently, decreased piglet vitality and growth. As a consequence, increasing sows’ energy intake during lactation to help increase piglet vitality and growth is increasingly important. The objective of this study was to investigate the effect of increasing dietary energy density for lactating sows on weight and back-fat changes in sows, milk composition, and vitality and growth of progeny. Gestating sows (N = 100; Large White × Landrace) were randomly assigned to one of four energy dense diets at day 108 of gestation until subsequent service; 13.8 (LL), 14.5 (L), 15.2 (H), and 15.9 MJ DE/kg (HH). All diets contained 1.2% total lysine. Blood samples from sows were taken on day 108 of gestation and at weaning (day 26 of lactation) and colostrum (day 0) and milk samples (day 14) were collected during lactation. Sow lactation feed intakes were recorded daily. The number of piglets born per litter (total and live), piglet birth weight (total and live), intrauterine growth restriction (IUGR) traits and muscle tone were recorded in piglets at birth. Piglet tympanic ear temperature (TEMP) was recorded at birth and at 24 h. Pigs were weighed on days 1, 6, 14, 26, 33, 40, 54, 75, and 141 of life. Postweaning (PW) pigs were fed standard cereal-based diets. Pig carcass data were collected at slaughter (day 141). Lactation energy intake was higher for HH sows than for all other treatments (P < 0.01). Colostrum and milk composition and lactation feed intake were not affected by treatment. The number of piglets born per litter (total and live) and piglet birthweight (total and live) was similar between treatments. Piglets from LL sows had more IUGR traits (P < 0.01), while those from HH sows had better muscle tone (P < 0.01) than all other treatments. Piglets from LL sows (P < 0.01) and piglets from H sows (P < 0.01) had a higher 24 h TEMP than piglets from HH sows. H sows weaned a greater number of piglets than L sows (P < 0.05) and HH sows (P < 0.01), while L sows weaned lighter litters than H (P < 0.05) and LL sows (P < 0.05). Pig growth PW was unaffected by treatment. High energy dense diets increased energy intake in sows, without depressing appetite. Feeding an HH diet improved piglet muscle tone at birth, whereas feeding an H diet increased litter size at weaning. Inconsistent results were observed for other traits of piglet vitality and for preweaning litter growth performance.
Measuring behavioral and physiological responses to pain mitigation for ovariectomy in Bos taurus yearling beef heifers
Authors: Lauder Jean K , Marti Sonia , Schwartzkopf-Genswein Karen S , Jelinski Murray D , Janzen Eugene D
Published: December 2019

Ovariectomy (spaying) using the trans-vaginal dropped ovary technique (DOT) is performed to prevent pregnancy in cull female beef cattle that are not retained for breeding stock in areas practicing extensive grazing management. There are no reports describing analgesia for this surgical procedure. The objective of this study was to measure behavioral and physiological responses to determine whether an analgesic protocol of BXK [butorphanol (0.01 mg/kg), xylazine (0.02 mg/kg), and ketamine (0.04 mg/kg)] injected intramuscularly (i.m.) before spaying could mitigate procedural and immediate postsurgical pain, and whether oral meloxicam (1 mg/kg) administered at the time of spaying could mitigate postsurgical inflammatory pain. Forty-four red Angus and Angus crossbred yearling heifers (322 ± 27.0 kg BW) were randomly allocated to 1 of 3 groups: PALP (control; palpated but not spayed; n = 14), SPAY (spayed with no analgesia; n = 15), and BXKM (spayed with analgesia; n = 15). Behavioral measurements included visual analog scale (VAS) score, flight speed (FS), stride length (SL), and gait score (GS), as well as activity (lying, standing) and feeding behavior. Physiological measurements included salivary cortisol (SC), haptoglobin (Hp), serum amyloid A (SAA), substance P (SP), complete blood count (CBC), and rectal temperature (RT). Saliva and blood samples were collected, and RT, FS, SL, and GS were measured on day −1, day 0 (time of palpation/spaying), and hours 1, 2, 4, and days 1, 2, 4, and 7 after palpation/spaying. The BXKM heifers had lower SC concentrations than SPAY heifers at 1 h (P = 0.01) and 2 h (P = 0.004). Heifers treated with BXKM had Hp concentrations lower than SPAY heifers at 2 d (P = 0.01), 4 d (P < 0.001), and 7 d (P = 0.008), and lower Hp concentrations than PALP heifers at 4 d (P < 0.001). Concentrations of SAA were greater (P = 0.04) in BXKM heifers than in PALP heifers at 1 h and lower in PALP heifers than in BXKM heifers (P = 0.02) and SPAY heifers (P = 0.05) at 1 d. Heifers in the BXKM group had higher RT than PALP and SPAY heifers at 1 h (P < 0.001) and 2 h (P = 0.004). Results suggest that DOT ovariectomy is acutely stressful and painful and administration of BXK before spaying and meloxicam at the time of spaying mitigated the procedural and postsurgical stress, pain, and inflammation.
Poor maternal nutrition during gestation in sheep alters prenatal muscle growth and development in offspring
Authors: Gauvin Mary C , Pillai Sambhu M , Reed Sarah A , Stevens John R , Hoffman Maria L , Jones Amanda K , Zinn Steven A , Govoni Kristen E
Published: December 2019

Poor maternal nutrition during gestation can have immediate and life-long negative effects on offspring growth and health. In livestock, this leads to reduced product quality and increased costs of production. Based on previous evidence that both restricted- and overfeeding during gestation decrease offspring muscle growth and alter metabolism postnatally, we hypothesized that poor maternal nutrition during gestation would reduce the growth and development of offspring muscle prenatally, reduce the number of myogenic progenitor cells, and result in changes in the global expression of genes involved in prenatal muscle development and function. Ewes were fed a control (100% NRC)-, restricted (60% NRC)-, or overfed (140% NRC) diet beginning on day 30 of gestation until days 45, 90, and 135 of gestation or until parturition. At each time point fetuses and offspring (referred to as CON, RES, and OVER) were euthanized and longissimus dorsi (LM), semitendinosus (STN), and triceps brachii (TB) were collected at each time point for histological and RNA-Seq analysis. In fetuses and offspring, we did not observe an effect of diet on cross-sectional area (CSA), but CSA increased over time (P < 0.05). At day 90, RES and OVER had reduced secondary:primary muscle fiber ratios in LM (P < 0.05), but not in STN and TB. However, in STN and TB percent PAX7-positive cells were decreased compared with CON (P < 0.05). Maternal diet altered LM mRNA expression of 20 genes (7 genes downregulated in OVER and 2 downregulated in RES compared with CON; 5 downregulated in OVER compared with RES; false discovery rate (FDR)-adj. P < 0.05). A diet by time interaction was not observed for any genes in the RNA-Seq analysis; however, 2,205 genes were differentially expressed over time between days 90 and 135 and birth (FDR-adj. P < 0.05). Specifically, consistent with increased protein accretion, changes in muscle function, and increased metabolic activity during myogenesis, changes in genes involved in cell cycle, metabolic processes, and protein synthesis were observed during fetal myogenesis. In conclusion, poor maternal nutrition during gestation contributes to altered offspring muscle growth during early fetal development which persists throughout the fetal stage. Based on muscle-type-specific effects of maternal diet, it is important to evaluate more than one type of muscle to fully elucidate the effects of maternal diet on offspring muscle development.
Geospatial Mapping as a Guide for Resource Allocation Among Burn Centers in India
Authors: Ranganathan Kavitha , Mouch Charles A , Chung Michael , Mathews Ian B , Cederna Paul S , Raja Sabapathy S , Raghavendran Krishnan , Singhal Maneesh
Published: December 2019

Timely treatment is essential for optimal outcomes after burn injury, but the method of resource distribution to ensure access to proper care in developing countries remains unclear. We therefore sought to examine access to burn care and the presence/absence of resources for burn care in India. We surveyed all eligible burn centers (n = 67) in India to evaluate burn care resources at each facility. We then performed a cross-sectional geospatial analysis using geocoding software (ArcGIS 10.3) and publicly available hospital-level data (WorldStreetMap, WorldPop database) to predict the time required to access care at the nearest burn center. Our primary outcome was the time required to reach a burn facility within India. Descriptive statistics were used to present our results. Of the 67 burn centers that completed the survey, 45% were government funded. More than 1 billion (75.1%) Indian citizens live within 2 hours of a burn center, but only 221.9 million (15.9%) live within 2 hours of a burn center with both an intensive care unit (ICU) and a skin bank. Burn units are staffed primarily by plastic surgeons (n = 62, 93%) with an average of 5.8 physicians per unit. Most burn units (n = 53, 79%) have access to hemodialysis. While many Indian citizens live within 2 hours of a burn center, most centers do not offer ICU and skin bank services that are essential for modern burn care. Reallocation of resources to improve transportation and availability of ICU and skin bank services is necessary to improve burn care in India.
The Twin Instrument: Fertility and Human Capital Investment
Authors: Bhalotra Sonia , Clarke Damian
Published: December 2019

Twin births are often used as an instrument to address selection of women into fertility. However, recent work shows selection of women into twin birth such that, while OLS estimates tend to be downward biased, twin-IV estimates will tend to be upward biased. This is pertinent given the emerging consensus that fertility has limited impacts on women’s labour supply, or on investments in children. Using data for developing countries and the United States to estimate the trade-off between fertility and children’s human capital, we demonstrate the nature and size of the bias in the twin-IV estimator and estimate bounds on the true parameter.
Evaluation of Novel Trapping Lures for Monitoring Exotic and Native Container-Inhabiting Aedes spp. (Diptera: Culicidae) Mosquitoes
Authors: Eastwood Gillian , Donnellycolt Andrew K , Shepard John J , Misencik Michael J , Bedoukian Robert , Cole Lacey , Armstrong Philip M , Andreadis Theodore G
Published: December 2019

Surveillance for diurnal container-inhabiting mosquitoes such as Aedes albopictus (Skuse), Aedes japonicus japonicus (Theobald), and Aedes triseriatus (Say) have routinely relied on the deployment of multiple trap types, including CO2-baited light traps, gravid traps, oviposition traps, and BG-Sentinel. These trap configurations have met with varying degrees of effectiveness and in many instances likely under-sample these key mosquito vectors. Most recently, the BG-Sentinel trap used in conjunction with the human-scent lure has been largely accepted as the gold-standard for monitoring Ae. albopictus. However, its ability to attract other container-inhabiting Aedes species has not been fully evaluated. During 2018, we tested new scent lures, TrapTech Lure-A and Lure-H (Bedoukian Research, Inc.), using BG-Sentinel traps with CO2 in two regions of Connecticut, Stamford and Hamden, against the BG-Lure. Pooled mosquitoes were additionally screened for arbovirus infection. A total of 47,734 mosquitoes representing 8 genera and 32 species were captured during the study, with the Stamford site deriving on average three times as many mosquitoes per trap, adjusting for sampling effort. Lure-A and Lure-H outperformed the BG-Lure in terms of total numbers, diversity evenness, and the proportion of both Ae. j. japonicus and Ae. triseriatus. There were no significant differences among lures in capturing Ae. albopictus, and in terms of species richness. Fifty-seven isolates of virus (West Nile, Jamestown Canyon, and La Crosse viruses) were obtained during the study, with no significant difference between trap-lure. We highlight both novel lures as effective attractants for use in mosquito surveillance=, which either outperform, or equal, BG-Lure.
A stochastic microscopic approach to the $^{10}{\rm Be}$ and $^{11}{\rm Be}$ nuclei
Authors: Descouvemont Pierre , Itagaki Naoyuki
Published: December 2019

We use a microscopic multicluster model to investigate the structure of $^{10}{\rm Be}$ and of $^{11}{\rm Be}$. These nuclei are described by $\alpha +\alpha+n+n$ and $\alpha +\alpha+n+n+n$ configurations, respectively, within the Generator Coordinate Method (GCM). The 4- and 5-body models raise the problem of a large number of generator coordinates (6 for $^{10}{\rm Be}$ and 9 for $^{11}{\rm Be}$), which requires specific treatment. We address this issue by using the Stochastic Variational Method (SVM), which is based on an optimal choice of the basis functions, generated randomly. The model provides good energy spectra for low-lying states of both nuclei. We also compute rms radii and densities, as well as electromagnetic transition probabilities. We analyze the structure of $^{10}{\rm Be}$ and of $^{11}{\rm Be}$ by considering energy curves, where one of the generator coordinates is fixed during the minimization procedure.
Matrix geometry for ellipsoids
Authors: Matsuura Kaho , Tsuchiya Asato
Published: December 2019

We study description of ellipsoids by matrices to gain insights into emergence of space in matrix models. We apply the coherent state method to the fuzzy ellipsoids and perform the Berezin-Toeplitz quantization for ellipsoids. We see that the manifold described by the coherent state method is an ellipsoid. We find that the Toeplitz operators obtained in the Berezin-Toeplitz quantization agree with the matrices for the fuzzy ellipsoids used in the coherent state method and that the wave functions in the above two methods coincide.
Five-year nitrogen addition affects fine root exudation and its correlation with root respiration in a dominant species, Quercus crispula, of a cool temperate forest, Japan
Authors: Ataka Mioko , Sun Lijuan , Nakaji Tatsuro , Katayama Ayumi , Hiura Tsutom
Published: December 2019

In forest ecosystems, fine root respiration directly contributes to belowground carbon (C) cycling. Exudation from fine roots indirectly affects C cycling via enhanced microbial decomposition of soil organic matter. Although these root-derived C fluxes are essential components of belowground C cycling, how nitrogen (N) addition affects these fluxes and their correlations remains unclear. In this study, fine root exudation, respiration and chemical/morphological traits were measured in a dominant canopy species, Quercus crispula Blume, found in a cool temperate forest, the Tomakomai Experimental Forest, Hokkaido University, which has undergone 5-year N addition. Soil-dissolved organic carbon (DOC) was also measured in both bulk and rhizosphere soils to evaluate the impact of fine root exudation on soil C cycling. Compared with a control plot with no N treatment, fine roots in the N addition plot exhibited larger diameters and higher N concentrations, but lower specific root lengths and areas. On a root-weight basis, respiration was not different between plots, but exudation was slightly higher under N addition. On a root-area basis, exudation was significantly higher in the N addition plot. Additionally, differences in DOC between rhizosphere and bulk soils were two times higher in the N addition plot than the control plot. Although fine root respiration was positively correlated with exudation in both the control and N addition plots, the ratio of exudation C to respiration C decreased after 5-year N addition. Nitrogen addition also affected absolute C allocation to fine root exudation and changed the C allocation strategy between exudation and respiration fluxes. These findings will help enhance predictions of belowground C allocation and C cycling under N-rich conditions in the future.
HeiDI: A model for Pavlovian learning and performance with reciprocal associations
Authors: Honey Robert C. , Dwyer Dominic M. , Iliescu Adela F.
Published: December 2019

Associative treatments of how Pavlovian conditioning affects conditioned behavior are rudimentary: A simple ordinal mapping is held to exist between the strength of an association (V) between a conditioned stimulus (CS) and an unconditioned stimulus (US; i.e., VCS-US) and conditioned behavior in a given experimental preparation. The inadequacy of this simplification is highlighted by recent studies that have taken multiple measures of conditioned behavior: Different measures of conditioned behavior provide the basis for drawing opposite conclusions about VCS-US. Here, we develop a simple model involving reciprocal associations between the CS and US (VCS-USand VUS-CS) that simulates these qualitative individual differences in conditioned behavior. The new model, HeiDI (How excitation and inhibition Determine Ideo-motion), enables a broad range of phenomena to be accommodated, which are either beyond the scope of extant models or require them to appeal to additional (learning) processes. It also provides an impetus for new lines of inquiry and generates novel predictions.
Vglut2 expression in dopamine neurons contributes to post-lesional striatal reinnervation
Authors: Kouwenhoven Willemieke M. , Fortin Guillaume , Penttinen Anna-Maija , Florence Clélia , Delignat-Lavaud Benoît , Bourque Marie-Josée , Trimbuch Thorsten , Luppi Milagros Pereira , Poulin Jean-François , Rosenmund Christian , Awatramani Raj , Trudeau Louis-Éric
Published: December 2019

In Parkinson’s disease, the most vulnerable neurons are found in the ventral tier of the substantia nigra (SN), while the adjacent dopamine (DA) neurons of the ventral tegmental area (VTA) are mostly spared. Although a significant subset of adult VTA DA neurons expressesVglut2, a vesicular glutamate transporter, and release glutamate as a second neurotransmitter in the striatum, only very few adult SN DA neurons have this capacity. Previous work has demonstrated that lesions created by neurotoxins such as MPTP and 6-hydroxydopamine (6-OHDA) can upregulate the expression of Vglut2 in surviving DA neurons. Currently, the molecular mechanisms explaining the plasticity of Vglut2 expression in DA neurons are unknown, as are the physiological consequences for DA neuron function and survival. Here we aimed to characterize the developmental expression pattern of Vglut2 in DA neurons and the role of this transporter in post-lesional plasticity in these neurons. Using an intersectional genetic lineage-mapping approach, based on Vglut2-Cre and TH-Flpo drivers, we first found that more than 98% of DA neurons expressedVglut2at some point in their embryonic development. Expression of this transporter was detectable in most DA neurons until E11.5 and was found to be localized in developing axons. Moderate enhancement of VGLUT2 expression in primary DA neurons caused an increase in axonal arborization length. Compatible with a developmental role, constitutive deletion of Vglut2 caused a regional defect in TH-innervation of the dorsal striatum in E18.5 embryos. Moreover, using anin vitroneurotoxin model, we demonstrate thatVglut2expression can be upregulated in post-lesional DA neurons by 2.5-fold, arguing that the developmental expression ofVglut2in DA neurons can be reactivated at postnatal stages and contribute to post-lesional plasticity of dopaminergic axons. In support of this hypothesis, we find fewer mesostriatial dopaminergic projections in the striatum of conditional Vglut2 KO mice 7 weeks after a neurotoxic lesion, compared to control animals. Thus, we propose here that one of the functions of Vglut2 in adult DA neurons is to promote post-lesional recovery of meso-striatal axons.
Spatiotemporal dynamics of multi-vesicular release is determined by heterogeneity of release sites in central synapses
Authors: Maschi Dario , Klyachko Vitaly A.
Published: December 2019

Synapses can release multiple vesicles in response to a single action potential. This multi-vesicular release (MVR) occurs at most synapses but its spatiotemporal properties and relation to uni-vesicular release (UVR) are poorly understood. Nanoscale-resolution detection of individual release events in hippocampal boutons revealed a pattern of spatial organization of MVR, which preferentially overlapped with UVR at more central release sites. Pairs of fusion events comprising MVR were also not perfectly synchronized and the earlier event within the pair occurred closer to the active zone (AZ) center. Parallel to this organization, individual release sites had a gradient of release probability extending from the AZ center to periphery. This gradient, and spatial features of MVR, were similarly tightened by buffering intracellular calcium. These observations revealed a heterogeneous landscape of release site properties within individual AZs, which determines the spatiotemporal features of MVR and is controlled by non-uniform calcium elevation across the AZ.
Topographic functional interactions between caudate and cortex are organized by network and degrade with age
Authors: O’Rawe Jonathan F. , Leung Hoi-Chung
Published: December 2019

The striatum is postulated to play a role in gating cortical processing during goal-oriented behavior. However, the underlying circuit structure for striatal gating remains unclear. Deviating from previous approaches which typically treat the striatum as a homogenous structure or small compartments, we took a functional connectivity approach that utilizes the entire anatomical space of the caudate nucleus and examined its functional relationship with the cortex and how that relationship changes with age. We defined the topography of the caudate functional connectivity with the rest of the brain using three publicly available resting-state fMRI data samples. There were several key findings. First, our results revealed two stable gradients of connectivity patterns across the caudate: medial-lateral (M-L) and anterior-posterior (A-P) axes, which supports findings in previous anatomical studies of non-human primates that there is more than one organizational principle. Second, the differential connectivity patterns along the caudate’s M-L gradient were not limited to single structures but rather organized with respect to large-scale neural networks; in particular, networks associated with internal orienting behavior are closely linked to the medial extent of the caudate whereas networks associated with external orienting behavior are closely linked to the lateral extent of the caudate. Third, we found a decrease in the integrity of M-L organization with healthy aging which was associated with age-related changes in behavioral measures of flexible control. In sum, the caudate shows a topographic organization with respect to large-scale networks in the human brain and changes this organization seem to have implications for age-related decline in flexible control of behavior.
Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity
Authors: Smith Brandon C. , Sinyuk Maksim , Jenkins Julius E. , Psenicka Morgan W. , Williams Jessica L.
Published: December 2019

In early autoimmune neuroinflammation, interferon (IFN)γ and its upregulation of the immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNγ has protective properties and, the role of the iP remains to be fully elucidated. Here, we demonstrated that IFNγ signaling in regional astrocytes induces the iP and protects the CNS during autoimmunity. In MS tissue, iP expression was enhanced in spinal cord compared to brainstem lesions, which correlated with a decrease in oxidative stress.In vitro, IFNγ stimulation enhanced iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal model, experimental autoimmune encephalomyelitis (EAE), ONX 0914 treatment exacerbated disease and led to increased oxidative stress and poly-ubiquitinated protein build-up. Finally, mice with astrocyte-specific loss of the IFNγ receptor exhibited worsened chronic EAE associated with reduced iP expression, enhanced lesion size and oxidative stress and poly-ubiquitinated protein accumulation in astrocytes. Taken together, our data reveal a protective role for IFNγ in chronic neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity.
Widespread introgression of theMus musculus musculusY chromosome in Central Europe
Authors: Macholán Miloš , Baird Stuart J. E. , Fornůsková Alena , Martincová Iva , Rubík Pavel , Ďureje Ľudovít , Heitlinger Emanuel , Piálek Jaroslav
Published: December 2019

According to Haldane’s rule, sex chromosomes should harbour more incompatibilities than autosomes. As a consequence, transmission of sex-linked genes across a genetic barrier is expected to be hampered. A remarkable example of a contradiction of this assumption was reported from the hybrid zone between two house mouse subspecies in western Czechia and south-eastern Germany where unidirectional east→west Y chromosome introgression was observed. Since the phenomenon was coupled with differences in sex ratio, this was hypothesised to be caused by a genetic conflict between sex-specific genes on sex chromosomes or elsewhere in the genome. Here we capitalise on a large material consisting of almost 7500 mice collected across a vast area from the Baltic Sea to the Alps embracing a ~900 km long portion of the zone with the aim to (i) detect its exact course and (ii) reveal the extent and pattern of the Y chromosome introgression in Central Europe. We show that the path of the zone is quite tortuous even at the global scale and the introgression is rather a rule than an exception. We also show that although sex ratio perturbations described in our previous study appear also in other introgression areas, they may not be ubiquitous. Finally, we reveal that although not all Y chromosome types are associated with the introgression, it is not restricted to a single ‘winning’ haplotype.
Structure of the Glutamate-Like Receptor GLR3.2 ligand-binding domain
Authors: Gangwar Shanti Pal , Green Marriah , Sobolevsky Alexander I.
Published: December 2019

Glutamate-like receptors (GLRs) in plants play an important role in a number of physiological processes, including wound response, stomatal aperture control, seed germination, root development, innate immune responses, pollen tube growth and morphogenesis. GLRs share amino acid sequence similarity with ionotropic glutamate receptors (iGluRs) that mediate neurotransmission in the nervous system of vertebrates. In contrast to iGluRs, however, for which numerous full-length structures are available, the structural information about the plant GLRs has been missing. Here we determine crystal structures ofArabidopsis thalianaGLR3.2 ligand-binding domain (LBD) in complex with glycine and methionine to 1.57 and 1.86 Å resolution, respectively. Our structures show a fold similar to iGluRs, with several secondary structure elements either missing or different. The closed clamshell conformation of GLR3.2 LBD suggests that both glycine and methionine act as agonists. The structures reveal molecular determinants of ligand binding and explain the promiscuity of GLRs’ ligand activation compared to iGluRs. Structural similarities of LBDs confirm an evolutionary relationship between GLRs and iGluRs and predict common molecular principles of their gating mechanisms that are driven by the bilobed clamshell-like LBDs.
Plasma membrane damage removal by F-actin-mediated shedding from repurposed filopodia
Authors: Mageswaran Shrawan Kumar , Yang Wei Y. , Chakrabarty Yogaditya , Oikonomou Catherine M. , Jensen Grant J.
Published: December 2019

Repairing plasma membrane damage is vital to eukaryotic cell survival. Membrane shedding is thought to be key to this repair process, but a detailed view of how the process occurs is still missing. Here we used electron cryotomography to image the ultrastructural details of plasma membrane wound healing. We found that filopodia-like protrusions are built at damage sites, accompanied by retraction of neighboring filopodia, and that these repurposed protrusions act as scaffolds for membrane shedding. This suggests a new role for filopodia as reservoirs of membrane and actin for plasma membrane damage repair. Damage-induced shedding was dependent on F-actin dynamics and Myo1a, as well as Vps4B, an important component of the ESCRT machinery. Thus we find that damage shedding is more complex than current models of simple vesiculation from flat membrane domains. Rather, we observe structural similarities between damage-mediated shedding and constitutive shedding from enterocytes that argue for conservation of a general membrane shedding mechanism.
The interaction between non-fusogenic Sec22b-Stx complexes and Extended-Synaptotagmins promotes neurite growth and ramification
Authors: Gallo Alessandra , Danglot Lydia , Giordano Francesca , Binz Thomas , Vannier Christian , Galli Thierry
Published: December 2019

Axons and dendrites are long and often ramified neurites that need particularly intense plasma membrane (PM) expansion during the development of the nervous system. Neurite growth depends on non-fusogenic Sec22b–Stx1 SNARE complexes at endoplasmic reticulum (ER)-PM contacts. Here we show that Sec22b interacts with the endoplasmic reticulum lipid transfer proteins Extended-Synaptotagmins (E-Syts) and this interaction depends on the Longin domain of Sec22b. Overexpression of E-Syts stabilizes Sec22b-Stx1 association, whereas silencing of E-Syts has the opposite effect. Overexpression of wild-type E-Syt2, but not mutants unable to transfer lipids or attach to the ER, increase the formation of axonal filopodia and ramification of neurites in developing neurons. This effect is inhibited by a clostridial neurotoxin cleaving Stx1, expression of Sec22b Longin domain and a Sec22b mutant with extended linker between SNARE and transmembrane domains. We conclude that Sec22b-Stx1 ER-PM contact sites contribute to PM expansion by interacting with lipid transfer proteins such as E-Syts.
Unc-4 acts to promote neuronal identity and development of the take-off circuit in the Drosophila CNS
Authors: Lacin Haluk , Williamson W. Ryan , Card Gwyneth M. , Skeath James B. , Truman James W.
Published: December 2019

TheDrosophilaventral nerve cord (VNC), the fly equivalent of the spinal cord, is composed of thousands of neurons that are born from a set of individually identifiable stem cells. The VNC harbors neuronal circuits required for the execution of vital behaviors, such as flying and walking. Taking advantage of the lineage-based functional organization of the VNC and genetic tools we developed, we investigated the molecular and developmental basis of behavior by focusing on lineage-specific functions of the homeodomain transcription factor, Unc-4. We found that Unc-4 functions in lineage 11A to promote cholinergic neurotransmitter identity and suppress the GABA fate. In 7B lineage, Unc-4 promotes proper neuronal projections to the leg neuropil, the hub for leg-related neuronal circuits and a specific flight-related take-off behavior. We also uncovered that Unc-4 acts peripherally to promote the development of proprioceptive sense organs and the abilities of flies to execute specific leg-related behaviors such as walking, climbing, and grooming. Our findings, thus, initiates the work on revealing molecular and developmental events that shape the VNC related behaviors.
Donut-like organization of inhibition underlies categorical neural responses in the midbrain
Authors: Mahajan Nagaraj R. , Mysore Shreesh P.
Published: December 2019

Categorical neural responses underlie various forms of selection and decision-making. Such binary-like responses promote robust signaling of the winner in the presence of input ambiguity and neural noise. Here, we show that a ‘donut-like’ inhibitory mechanism in which each competing option suppresses all options except itself, is highly effective at generating categorical neural responses. It surpasses motifs of feedback inhibition, recurrent excitation, and divisive normalization invoked frequently in decision-making models. We demonstrate experimentally not only that this mechanism operates in the midbrain spatial selection network in barn owls, but also that it is necessary for categorical signaling by it. The functional pattern of neural inhibition in the midbrain forms an exquisitely structured ‘multi-holed’ donut consistent with this network’s combinatorial inhibitory function for stimulus selection. Additionally, modeling reveals a generalizable neural implementation of the donut-like motif for categorical selection. Self-sparing inhibition may, therefore, be a powerful circuit module central to categorization.
Earliest experience of a relatively rare sound but not a frequent sound causes long term changes in the adult auditory cortex
Authors: Mehra Muneshwar , Mukesh Adarsh , Bandyopadhyay Sharba
Published: December 2019

Sensory experience during a critical period alters sensory cortical responses and organization. We find that the earliest sound driven activity in the mouse auditory cortex (ACX) starts before ear-canal opening (ECO). Effects of auditory experience before ECO on ACX development are unknown. We find that mouse ACX subplate neurons (SPNs), crucial in thalamocortical maturation, respond to sounds before ECO showing oddball selectivity. Before ECO, SPNs are more selective to oddball sounds in auditory streams than thalamo-recipient layer 4 (L4) neurons and not after ECO. We hypothesize that SPNs’ oddball selectivity can direct development of L4 responses before ECO. Exposing mice before ECO with a rarely occurring tone in a stream of another tone occurring frequently leads to the strengthening of the adult cortical representation of the rare tone, but not that of the frequent tone. Results of control exposure experiments at multiple developmental windows and also with only a single tone corroborate the observations. A computational network model of known thalamic inputs to SPNs and L4 explains the observed developmental plasticity. Information-theoretic analysis with sparse coding assumptions also predicts the observations. Thus, salient low probability sounds in the earliest auditory environment cause long term changes in the ACX.
Cell wallO-acetyl and methyl esterification patterns of leaves reflected in atmospheric emission signatures of acetic acid and methanol
Authors: Dewhirst Rebecca A. , Afseth Cassandra A. , Castanha Cristina , Mortimer Jenny C. , Jardine Kolby J.
Published: December 2019

Plants emit high rates of methanol (meOH), generally assumed to derive from pectin demethylation, and this increases during abiotic stress. In contrast, less is known about the emission and source of acetic acid (AA). In this study,Populus trichocarpa(California poplar) leaves in different developmental stages were desiccated and quantified for total meOH and AA emissions together with bulk cell wall acetylation and methylation content. While young leaves showed high emissions of meOH (140 μmol m−2) and AA (42 μmol m−2), emissions were reduced in mature (meOH: 69%, AA: 60%) and old (meOH: 83%, AA: 76%) leaves. In contrast, the ratio of AA/meOH emissions increased with leaf development (young: 35%, mature: 43%, old: 82%), mimicking the pattern ofO-acetyl/methyl ester ratios of leaf bulk cell walls (young: 35%, mature: 38%, old: 51%), which is driven by an increase inO-acetyl and decrease in methyl ester content with age. The results are consistent with meOH and AA emission sources from cell wall de-esterification, with young expanding tissues producing highly methylated pectin that is progressively demethyl-esterified. We highlight the quantification of AA/meOH emission ratios as a potential tool for rapid phenotype screening of structural carbohydrate esterification patterns.
A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition
Authors: Gisler Santiago , Maia Ana Rita R. , Chandrasekaran Gayathri , van Lohuizen Maarten
Published: December 2019

BMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with the BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation. Our screen identified NUMA1-mutations as the most significant inducer of PTC-318 cell death resistance. Independent validations on NUMA1-proficient HAP1 and non-small cell lung cancer cell lines exposed to BMI1 inhibition by PTC-318 orBMI1knockdown resulted in cell death following mitotic arrest. Interestingly, cells with CRISPR-Cas9 derivedNUMA1knockout also showed a mitotic arrest phenotype following BMI1 inhibition but, contrary to cells with wildtype NUMA1, these cells were resistant to BMI1-dependent cell death. The current study brings new insights to BMI1 inhibition-induced mitotic lethality in cancer cells and presents a previously unknown role for NUMA1 in this process.