bluuebunny/crossref_metadata_2025 huggingface dataset:
Antimicrobial Susceptibility of Streptococcus pneumoniae from North America, Europe, Latin America, and the Asia-Pacific Region: Results From 20 Years of the SENTRY Antimicrobial Surveillance Program (1997–2016)
Authors: Sader Helio S , Mendes Rodrigo E , Le Jennifer , Denys Gerald , Flamm Robert K , Jones Ronald N
Published: March 2019

Background

The SENTRY Antimicrobial Surveillance Program monitors the frequency of occurrence and antimicrobial susceptibility of organisms from various infection types worldwide. In this investigation, we evaluated the antimicrobial susceptibility of Streptococcus pneumoniae isolates collected worldwide over 20 years (1997–2016).

Methods

A total of 65 993 isolates were consecutively collected (1 per infection episode) from North America (NA; n = 34 626; 2 nations), Europe (EUR; n = 19 123; 23 nations), the Asia-Pacific region (APAC; n = 7111; 10 nations), and Latin America (LATAM; n = 5133; 7 nations) and tested for susceptibility using reference broth microdilution methods. Resistant subgroups included multidrug-resistant (MDR; nonsusceptible to ≥3 classes of agents) and extensively drug-resistant (XDR; nonsusceptible to ≥5 classes).

Results

The isolates were collected primarily from respiratory tract infections (77.3%), and 25.4% were from pediatric patients. Penicillin susceptibility (≤0.06 mg/L) rates varied from 70.7% in EUR to 52.4% in APAC for all years combined. In NA, there was a slight improvement in susceptibility for the first few years of the program, from 66.5% in 1997–1998 to 69.4% in 1999–2000, followed by a decline until 2011–2012 (57.0%). Similar declines in penicillin susceptibility rates were observed in all regions, with the lowest rates of 67.3% in EUR (2011–2012), 41.6% in the APAC region (2007–2008), and 48.2% in LATAM (2013–2014). These declines were followed by improved susceptibility rates in all regions in later program years, with susceptibility rates of 55.6% to 71.8% in 2015–2016 (65.8% overall). Susceptibility rates to ceftriaxone, erythromycin, clindamycin, tetracycline, and trimethoprim-sulfamethoxazole followed a similar pattern, with a decrease in the first 12–14 years and a continued increase in the last 6–8 years of the program. MDR and XDR frequencies were highest in APAC (49.8% and 17.3% overall, respectively) and lowest in LATAM (10.8% and 1.9% overall, respectively). The most active agents for MDR/XDR isolates were ceftaroline (99.7%/99.1% susceptible), tigecycline (96.8%/95.9% susceptible), linezolid (100.0%/100.0% susceptible), and vancomycin (100.0%/100.0% susceptible).

Conclusions

S. pneumoniae susceptibility to many antibiotics increased in all regions in the last few years, and these increases may be related to PCV13 immunization, which was introduced in 2010.
A case of large-cell neuroendocrine carcinoma harboring rare ALK fusion with initial response to the ALK inhibitor crizotinib and acquired F1174L mutation after resistance
Authors: Wang Ye , Tian Panwen , Wang Weiya , Li Yalun , Wang Yu , Li Weimin
Published: March 2019

A 51-year-old, male, non-smoker with a 3.4 cm mass in the right middle lobe was diagnosed with large cell neuroendocrine carcinoma (LCNEC). Fluorescence in situ hybridization revealed anaplastic lymphoma kinase (ALK) gene translocation, in agreement with the immunohistochemistry result obtained with use of ALK-Ventana. Radiographic examinations showed both bone and brain metastasis. After two cycles of chemotherapy consisting of etoposide and cisplatin, the patient achieved stable disease, and was subsequently switched to crizotinib. Both computed tomography and magnetic resonance imaging revealed partial response after 4 months of crizotinib, but progressed after treatment for 10 months, when several hard lymph nodes were palpable in the left supraclavicular fossa. Lymph node biopsy showed similar histology of tumor cells and targeted next-generation sequencing revealed ALK F1174L on exon 23 with two rare forms of ALK rearrangements. This case provides evidence of responsiveness of ALK inhibitors for a rare pattern of ALK-rearranged LCNEC, and suggests that F1174L, a common resistant mutation found in non-small-cell lung cancer, also causes crizotinib resistance in LCNEC.
Estimation with Aggregate Shocks
Authors: Hahn Jinyong , Kuersteiner Guido , Mazzocco Maurizio
Published: March 2019

Aggregate shocks affect most households’ and firms’ decisions. Using three stylized models, we show that inference based on cross-sectional data alone generally fails to correctly account for decision making of rational agents facing aggregate uncertainty. We propose an econometric framework that overcomes these problems by explicitly parameterizing the agents’ decision problem relative to aggregate shocks. Our framework and examples illustrate that the cross-sectional and time-series aspects of the model are often interdependent. Therefore, estimation of model parameters in the presence of aggregate shocks requires the combined use of cross-sectional and time-series data. We provide easy-to-use formulas for test statistics and confidence intervals that account for the interaction between the cross-sectional and time-series variation. Lastly, we perform Monte Carlo simulations that highlight the properties of the proposed method and the risks of not properly accounting for the presence of aggregate shocks.
Effects of distillers dried grains with solubles on amino acid digestibility, growth performance, and carcass characteristics of growing pigs1
Authors: Curry Shelby M , Blavi Laia , Wiseman Julian , Stein Hans H
Published: March 2019

Two experiments were conducted to compare the standardized ileal digestibility (SID) of AA by growing pigs in European distillers dried grains with solubles (DDGS) produced from wheat, maize, or wheat–maize mixtures and to test the effect of increasing the inclusion levels of wheat DDGS on growth performance of growing-finishing pigs fed diets balanced for NE and SID Lys. In Exp. 1, 12 barrows (initial BW: 23.0 ± 2.2 kg) were surgically equipped with a T-cannula in the distal ileum and randomly allotted to a replicated 6 × 6 Latin square design with six diets and six periods. Five sources of European DDGS were used: wheat DDGS from 2011, wheat DDGS from 2012, wheat-80 DDGS (80% wheat and 20% maize), wheat-70 DDGS (70% wheat and 30% maize), and maize DDGS. Each diet contained one source of DDGS as the sole source of AA and an N-free diet was used to determine basal endogenous losses of AA. Results indicated that the SID of CP was greater (P < 0.05) in maize DDGS compared with wheat DDGS from 2011, wheat DDGS from 2012, and wheat-70 DDGS. The SID of all indispensable AA except Trp was also greater (P < 0.05) in maize DDGS compared with all other DDGS sources used in this experiment. For Trp, the SID in wheat-80 DDGS, wheat DDGS from 2011, and wheat DDGS from 2012 were not different from maize DDGS, but were greater (P < 0.05) than in wheat-70 DDGS. The SID for all indispensable AA except Ile and Trp in wheat-70 DDGS were not different from the values calculated for wheat DDGS from 2011 and wheat DDGS from 2012, and no differences between SID values for AA in wheat DDGS from 2011 and wheat DDGS from 2012 were observed. In Exp. 2, 36 growing pigs (initial BW: 38.3 ± 1.97 kg) were randomly allotted to one of four dietary treatments (one pig/pen and nine replicate pigs/treatment) in a 2-phase feeding program (35 to 65, and 35 to 105 kg BW). The four dietary treatments included diets containing 0%, 10%, 20%, or 30% wheat DDGS. Results indicated that there was no effect of wheat DDGS on pig growth performance or carcass quality. However, addition of wheat DDGS increased linearly (P < 0.015) the indole concentration in the carcasses of the pigs. In conclusion, the SID of AA in maize DDGS produced in Europe is greater than in European wheat DDGS and DDGS produced from mixtures of wheat and maize, but inclusion of 30% wheat DDGS in diets fed to growing-finishing pigs did not affect growth performance or carcass quality.
The effects of maternal dietary supplementation of cholecalciferol (vitamin D3) and 25(OH)D3 on sow and progeny performance1
Authors: Thayer Morgan T , Nelssen Jim L , Langemeier Austin J , Morton Jodi M , Gonzalez John M , Kruger Stephanie R , Ou Zhining , Makowski Andrew J , Bergstrom Jon R
Published: March 2019

A total of 69 sows (DNA Line 200 × 400) and their progeny were used to determine if feeding a combination of vitamin D3 and 25(OH)D3 influences neonatal and sow vitamin D status, muscle fiber morphometrics at birth and weaning, and subsequent growth performance. Within 3 d of breeding, sows were allotted to one of three dietary treatments fortified with 1,500 IU/kg vitamin D3 (CON), 500 IU/kg vitamin D3 + 25 μg/kg 25(OH)D3 (DL), or 1,500 IU/kg vitamin D3 + 50 μg/kg 25(OH)D3 (DH). When pigs were sacrificed at birth, there were no treatment effects for all fiber morphometric measures (P > 0.170), except primary fiber number and the ratio of secondary to primary muscle fibers (P < 0.016). Pigs from CON fed sows had fewer primary fibers than pigs from sows fed the DH treatment (P = 0.014), with pigs from sows fed DL treatment not differing from either (P > 0.104). Pigs from CON and DL fed sows had a greater secondary to primary muscle fiber ratio compared to pigs from DH sows (P < 0.022) but did not differ from each other (P = 0.994). There were treatment × time interactions for all sow and pig serum metabolites (P < 0.001). Therefore, treatment means were compared within the time period. At all time periods, sow serum 25(OH)D3 concentrations differed for all treatments with the magnitude of difference largest at weaning (P < 0.011), where serum 25(OH)D3 concentration was always the greatest when sows were fed the DH diet. At birth, piglets from DH fed sows had greater serum 25(OH)D3 concentrations than piglets from sows fed the DL treatment (P = 0.003), with piglets from sows fed CON treatment not differing from either (P > 0.061). At weaning, serum concentrations of 25(OH)D3 in piglets from all sow treatments were different (P < 0.001), with the greatest concentration in piglets from DH sows, followed by CON, and followed by DL. There were no treatment × time interactions for any of the metabolites measured in milk and no treatment or time main effects for 24,25(OH)2D3 concentration (P > 0.068). Colostrum collected within 12 h of parturition contained less (P = 0.001) 25(OH)D3 than milk collected on day 21 of lactation. Regardless of time, concentrations of 25(OH)D3 in milk were different (P < 0.030), with the largest 25(OH)D3 concentration from DH fed sows, followed by DL, and then CON. In conclusion, combining vitamin D3 and 25(OH)D3 in the maternal diet improves the vitamin D status of the dam and progeny and it increases primary muscle fiber number at birth.
Magnetic resonance imaging suggests functional role of previous year vessels and fibres in ring-porous sap flow resumption
Authors: Copini Paul , Vergeldt Frank J , Fonti Patrick , Sass-Klaassen Ute , den Ouden Jan , Sterck Frank , Decuyper Mathieu , Gerkema Edo , Windt Carel W , Van As Henk
Published: March 2019

Reactivation of axial water flow in ring-porous species is a complex process related to stem water content and developmental stage of both earlywood-vessel and leaf formation. Yet empirical evidence with non-destructive methods on the dynamics of water flow resumption in relation to these mechanisms is lacking. Here we combined in vivo magnetic resonance imaging and wood-anatomical observations to monitor the dynamic changes in stem water content and flow during spring reactivation in 4-year-old pedunculate oaks (Quercus robur L.) saplings. We found that previous year latewood vessels and current year developing earlywood vessels form a functional unit for water flow during growth resumption. During spring reactivation, water flow shifted from latewood towards the new earlywood, paralleling the formation of earlywood vessels and leaves. At leaves' full expansion, volumetric water content of previous rings drastically decreased due to the near-absence of water in fibre tissue. We conclude (i) that in ring-porous oak, latewood vessels play an important hydraulic role for bridging the transition between old and new water-conducting vessels and (ii) that fibre and parenchyma provides a place for water storage.
Resolving multisensory and attentional influences across cortical depth in sensory cortices
Authors: Gau Remi , Bazin Pierre-Louis , Trampel Robert , Turner Robert , Noppeney Uta
Published: March 2019

In our environment our senses are bombarded with a myriad of signals, only a subset of which is relevant for our goals. Using sub-millimeter-resolution fMRI at 7T we resolved BOLD-response and activation patterns across cortical depth in early sensory cortices to auditory, visual and audiovisual stimuli under auditory or visual attention. In visual cortices, auditory stimulation induced widespread inhibition irrespective of attention, whereas auditory relative to visual attention suppressed mainly central visual field representations. In auditory cortices, visual stimulation suppressed activations, but amplified responses to concurrent auditory stimuli, in a patchy topography. Critically, multisensory interactions in auditory cortices were stronger in deeper laminae, while attentional influences were greatest at the surface. These distinct depth-dependent profiles suggest that multisensory and attentional mechanisms regulate sensory processing via partly distinct circuitries. Our findings are crucial for understanding how the brain regulates information flow across senses to interact with our complex multisensory world.
RBPSponge: genome-wide identification of lncRNAs that sponge RBPs
Authors: HafezQorani Saber , Houdjedj Aissa , Arici Mehmet , Said Abdesselam , Kazan Hilal
Published: March 2019

Long noncoding RNAs (lncRNAs) can act as molecular sponges or decoys for an RNA-binding protein (RBP) through their RBP binding sites, thereby modulating the expression of all target genes of the corresponding RBP of interest. Here, we present a web tool named RBPSponge to explore lncRNAs based on their potential to act as a sponge for an RBP of interest. RBPSponge identifies the occurrences of RBP binding sites and CLIP peaks on lncRNAs, and enables users to run statistical analyses to investigate the regulatory network between lncRNAs, RBPs and targets of RBPs.

Availability

The web server is available athttps://www.RBPSponge.com

Contact

hilal.kazan@antalya.edu.tr
Cell-type specific innervation of cortical pyramidal cells at their apical tufts
Authors: Karimi Ali , Odenthal Jan , Drawitsch Florian , Boergens Kevin M. , Helmstaedter Moritz
Published: March 2019

We investigated the synaptic innervation of apical tufts of cortical pyramidal cells in a region between layers 1 and 2 using 3-D electron microscopy (3D-EM) applied to four cortical regions in mouse. Across all cortices, we found the relative inhibitory input at the apical dendrite’s main bifurcation to be more than 3-fold stronger for layer 2 pyramidal cells than for all other pyramidal cells. Towards the distal tuft dendrites in upper layer 1, however, the relative inhibitory input was about 2-fold stronger for L5 pyramidal cells than for all others. Only L3 pyramidal cells showed homogeneous inhibitory input density. The inhibitory to excitatory synaptic balance is thus specific for the types of pyramidal cells. Inhibitory axons preferentially innervated either layer 2 or L3/5 apical dendrites, but not both. These findings describe connectomic principles for the control of pyramidal cells at their apical dendrites in the upper layers of the cerebral cortex and point to differential computational properties of layer 2, layer 3 and layer 5 pyramidal cells in cortex.
Zn2+ intoxication of Mycobacterium marinum during Dictyostelium discoideum infection is counteracted by induction of the pathogen Zn2+ exporter CtpC
Authors: Lefrançois Louise H. , Kalinina Vera , Cardenal-Muñoz Elena , Hanna Nabil , Koliwer-Brandl Hendrik , Appiah Joddy , Leuba Florence , Hilbi Hubert , Soldati Thierry , Barisch Caroline
Published: March 2019

Macrophages use diverse strategies to kill or restrict intracellular pathogens. Some of these strategies involve the deprivation of bacteria from (micro)nutrients such as transition metals, and the bacteria intoxication through metal accumulation. Little is known about the chemical warfare between Mycobacterium marinum, a close relative of the human pathogen M. tuberculosis, and its hosts. Here we use the professional phagocyte Dictyostelium discoideum to investigate the role of Zn2+ during M. marinum infection. We show that M. marinum infection induces the accumulation of Zn2+ inside the Mycobacterium-containing vacuole (MCV), achieved by the induction and recruitment of the D. discoideum Zn2+ efflux pumps ZntA and ZntB. In cells lacking the ZntA detoxifying transporter there is further attenuation of M. marinum growth, possibly due to a compensatory efflux of Zn2+ into the MCV. This efflux is presumably carried out by ZntB, the main Zn2+ transporter in endosomes and phagosomes. Counterintuitively, M. marinum growth is also impaired in zntB KO cells, where MCVs accumulate less Zn2+. We also demonstrate that M. marinum senses toxic levels of Zn2+ and responds by upregulating its Zn2+ exporter CtpC, which supports bacteria survival under these restrictive conditions. Attenuation of M. marinum intracellular proliferation in zntA and zntB KO cells is accentuated in the absence of CtpC, confirming that mycobacteria face noxious levels of Zn2+. Altogether, we show for the first time that M. marinum infection induces a deleterious Zn2+ elevation in D. discoideum, which is counteracted by the bacteria with the induction of its Zn2+ exporter CtpC.
High-Affinity Binding of Chemokine Analogs that Display Ligand Bias at the HIV-1 Co-receptor CCR5
Authors: Rico Carlos A. , Berchiche Yamina A. , Horioka Mizuho , Peeler Jennifer C. , Lorenzen Emily , Tian He , Kazmi Manija A. , Fürstenberg Alexandre , Gaertner Hubert , Hartley Oliver , Sakmar Thomas P. , Huber Thomas
Published: March 2019

The chemokine receptor CCR5 is a drug target to prevent transmission of HIV/AIDS. We studied four analogs of the native chemokine RANTES (CCL5) that have anti-HIV potencies of around 25 pM, which is more than four orders-of-magnitude higher than that of RANTES itself. It has been hypothesized that the ultra-high potency of the analogs is due to their ability to bind populations of receptors not accessible to native chemokines. To test this hypothesis, we developed a homogeneous dual-color fluorescence cross-correlation spectroscopy (FCCS) assay for saturation and competition binding experiments. The FCCS assay has the advantage that it does not rely on competition with radioactively labeled native chemokines used in conventional assays. We prepared site-specifically labeled fluorescent analogs using native chemical ligation of synthetic peptides, followed by bioorthogonal fluorescent labeling. We engineered a mammalian cell expression construct to provide fluorescently labeled CCR5, which was purified using a tandem immunoaffinity and size-exclusion chromatography approach to obtain monomeric fluorescent CCR5 in detergent solution. We found subnanomolar binding affinities for the two analogs 5P12-RANTES and 5P14-RANTES, and about twenty-fold reduced affinities for PSC-RANTES and 6P4-RANTES. Using homologous and heterologous competition experiments with unlabeled chemokine analogs, we conclude that the analogs all bind at the same binding site; whereas, the native chemokines (RANTES and MIP1α) fail to displace bound fluorescent analogs even at tens of micromolar concentrations. Our results can be rationalized withde novostructural models of the N-terminal tails of the synthetic chemokines that adopt a different binding mode as compared to the parent compound.
Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease
Authors: Karjalainen Minna K. , Holmes Michael V. , Wang Qin , Anufrieva Olga , Kähönen Mika , Lehtimäki Terho , Havulinna Aki S. , Kristiansson Kati , Salomaa Veikko , Perola Markus , Viikari Jorma S. , Raitakari Olli T. , Järvelin Marjo-Riitta , Ala-Korpela Mika , Kettunen Johannes
Published: March 2019

Rationale

Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD) with phase III cardiovascular outcome trials currently underway. Although circulating apoA-I levels inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking.

Objective

To assess the causal role of apoA-I in CAD using human genetics.

Methods and Results

We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations at GWAS significance (P<5×10−8) in 20,370 Finnish participants and meta-analyzed our data with a previous genome-wide association study of apoA-I. We obtained genetic estimates of CAD from UK Biobank and CARDIoGRAMplusC4D (totaling 122,733 CAD cases) and conducted a two-sample Mendelian randomization analysis. We compared our genetic findings to observational associations of apoA-I with risk of CAD in 918 incident CAD cases among 11,535 individuals from population-based prospective cohorts. We also summarized the available evidence from randomized controlled trials (RCTs) of apoA-I infusion therapies reporting CAD events. ApoA-I was associated with a lower risk of CAD in observational analyses (HR 0.81; 95%CI: 0.75, 0.88; per 1-SD higher apoA-I), with the association showing a dose-response relationship. Rs12225230 associated with apoA-I concentrations (per-C allele beta 0.076 SD; SE: 0.013; P=1.5×10−9) but not with potential confounders. In Mendelian randomization analyses, apoA-I was not related to risk of CAD (OR 1.13; 95%CI: 0.98, 1.30 per 1-SD higher apoA-I), which was different to the observational association (P-het<0.001). RCTs of apoA-I infusions did not show an effect on the risk of CAD.

Conclusions

Genetic evidence fails to support a cardioprotective role for apoA-I. This casts doubt on the likely benefit of apoA-I infusion therapy in the ongoing phase III cardiovascular outcome trial.
HiLDA: a statistical approach to investigate differences in mutational signatures
Authors: Yang Zhi , Pandey Priyatama , Shibata Darryl , Conti David V. , Marjoram Paul , Siegmund Kimberly D.
Published: March 2019

We propose a hierarchical latent Dirichlet allocation model (HiLDA) for characterizing somatic mutation data in cancer. The method allows us to infer mutational patterns and their relative frequencies in a set of tumor mutational catalogs and to compare the estimated frequencies between tumor sets. We apply our method to somatic mutations in colon cancer with mutations classified by the time of occurrence, before or after tumor initiation. Applying the methods to 16 colon cancers, we found significant associations between the relative frequencies of mutational patterns and the time of occurrence of mutations. Our novel method provides higher statistical power for detecting differences in mutational signatures.
Variation of human neural stem cells generating organizer statesin vitrobefore committing to cortical excitatory or inhibitory neuronal fates
Authors: Micali Nicola , Kim Suel-Kee , Diaz-Bustamante Marcelo , Stein-O’Brien Genevieve , Seo Seungmae , Shin Joo-Heon , Rash Brian G. , Ma Shaojie , Wang Yanhong , Olivares Nicolas A. , Arellano Jon , Maynard Kristen R. , Fertig Elana J. , Cross Alan J. , Burli Roland , Brandon Nicholas J. , Weinberger Daniel R. , Chenoweth Joshua G. , Hoeppner Daniel J. , Sestan Nenad , Rakic Pasko , Colantuoni Carlo , McKay Ronald D.
Published: March 2019

Better understanding the progression of neural stem cells (NSCs) in the developing cerebral cortex is important for modeling neurogenesis and defining the pathogenesis of neuropsychiatric disorders. Here we used RNA-sequencing, cell imaging and lineage tracing of mouse and humanin vitroNSCs to model the generation of cortical neuronal fates. We show that conserved signaling mechanisms regulate the acute transition from proliferative NSCs to committed glutamatergic excitatory neurons. As human telencephalic NSCs developed from pluripotencyin vitro, they first transitioned through organizer states that spatially pattern the cortex before generating glutamatergic precursor fates. NSCs derived from multiple human pluripotent lines varied in these early patterning states leading differentially to dorsal or ventral telencephalic fates. This work furthers systematic analysis of the earliest patterning events that generate the major neuronal trajectories of the human telencephalon.
Hypothalamic-extended amygdala circuit regulates temporal discounting
Authors: Rossi Mark A. , Li Haofang E. , Watson Glenn W. , Moore H. Gregory , Cai Min Tong , Kim Namsoo , Vokt Katrina A. , Lu Dongye , Bartholomew Ryan A. , Yin Henry H.
Published: March 2019

Choice behavior is characterized by temporal discounting, i.e., preference for immediate rewards over delayed rewards. Temporal discounting is often dysfunctional in psychiatric disorders, addiction, and eating disorders. However, the underlying neural mechanisms governing temporal discounting are still poorly understood. We found that food deprivation resulted in steep temporal discounting of food rewards, whereas satiation abolished discounting. In addition, optogenetic activation of AgRP-expressing neurons in the arcuate nucleus or their axon terminals in the posterior bed nucleus of stria terminalis (BNST) restored temporal discounting in sated mice. Activation of postsynaptic neuropeptide Y receptors (Y1Rs) within the BNST, which is influenced by neuropeptide released by AgRP neurons, was sufficient to restore temporal discounting. These results demonstrate for the first time a profound effect of motivational signals from hypothalamic feeding circuits on temporal discounting and reveal a novel neural circuit that regulates choice behavior.
Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent vs adult mice
Authors: Guilhaume-Correa Fernanda , Cansler Shelby M. , Shalosky Emily M. , Goodman Michael D. , Evanson Nathan K.
Published: March 2019

Introduction

Traumatic brain injury (TBI) is a major public health concern affecting 2.8 million people per year, of which about 1 million are children under 19 years old. Animal models of TBI have been developed and used in multiple ages of animals, but direct comparisons of adult and adolescent populations are rare. The current studies were undertaken to directly compare outcomes between adult and adolescent mice, using a closed head, single impact model of TBI.

Methods

Six-week-old adolescent and 9-week-old adult male mice were subjected to TBI using a closed head weight drop model. Histological measures for neurodegeneration, gliosis, and microglial neuroinflammation, and behavioral tests of locomotion and memory were performed.

Results

Adolescent TBI mice have increased mortality (X2= 20.72, p < 0.001) compared to adults. There is also evidence of hippocampal neurodegeneration in adolescents, but not adults. Presence of hippocampal neurodegeneration correlates with histologic activation of microglia, but not with increased markers of astrogliosis. Adults and adolescents have similar locomotion deficits after TBI that recover by 16 days post-injury. Adolescents have memory deficits as evidenced by impaired novel object recognition performance 3 and 16 days post injury (F1,26 = 5.23, p = 0.031) while adults do not.

Conclusions

Adults and adolescents within a close age range (6-9 weeks) respond to TBI differently. Adolescents are more severely affected by mortality, neurodegeneration, and inflammation in the hippocampus compared to adults. Adolescents, but not adults, have worse memory performance after TBI that lasts up to 16 days post injury.
Is evolution predictable? Quantitative genetics under complex genotype-phenotype maps
Authors: Milocco Lisandro , Salazar-Ciudad Isaac
Published: March 2019

A fundamental aim of post-genomic 21st century biology is to understand the genotype-phenotype map (GPM) or how specific genetic variation relates to specific phenotypic variation (1). Quantitative genetics approximates such maps using linear models, and has developed methods to predict the response to selection in a population (2, 3). The other major field of research concerned with the GPM, developmental evolutionary biology or evo-devo (1, 4–6), has found the GPM to be highly nonlinear and complex (4, 7). Here we quantify how the predictions of quantitative genetics are affected by the complex, nonlinear maps found in developmental biology. We combine a realistic development-based GPM model and a population genetics model of recombination, mutation and natural selection. Each individual in the population consists of a genotype and a multi-trait phenotype that arises through the development model. We simulate evolution by applying natural selection on multiple traits per individual. In addition, we estimate the quantitative genetics parameters required to predict the response to selection. We found that the disagreements between predicted and observed responses to selection are common, roughly in a third of generations, and are highly dependent on the traits being selected. These disagreements are systematic and related to the nonlinear nature of the genotype-phenotype map. Our results are a step towards integrating the fields studying the GPM.
Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors
Authors: Felix Jan , Weinhäupl Katharina , Chipot Christophe , Dehez François , Hessel Audrey , Gauto Diego F. , Morlot Cecile , Abian Olga , Gutsche Irina , Velazquez-Campoy Adrian , Schanda Paul , Fraga Hugo
Published: March 2019

Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. ClpP protease is a tetradecameric complex that has emerged as a drug target against multiple pathogenic bacteria. During drug development efforts, the activation of different ClpPs by inhibitors was independently reported, but so far, no rationale for inhibitor-induced activation has been proposed. Using an integrated approach that included X-ray crystallography, solid-and solution-state NMR, MD simulations and ITC we show that the proteasome-inhibitor bortezomib binds to the ClpP active site serine mimicking a peptide substrate and induces the concerted allosteric activation of the complex. The bortezomib activated conformation also displays a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association as well as protein processive degradation.
Reward boosts neural coding of task rules to optimise cognitive flexibility
Authors: Hall-McMaster S. , Muhle-Karbe P.S. , Myers N.E. , Stokes M.G.
Published: March 2019

Cognitive flexibility is critical for intelligent behaviour. However, its execution is effortful and often suboptimal. Recent work indicates that flexible behaviour can be improved by the prospect of reward, which suggests that rewards optimise flexible control processes. Here we investigated how different reward prospects influence neural encoding of task rule information to optimise cognitive flexibility. We applied representational similarity analysis (RSA) to human electroencephalograms, recorded while female and male participants performed a rule-guided decision-making task. During the task, the prospect of reward varied from trial to trial. Participants made faster, more accurate judgements on high reward trials. Critically, high reward boosted neural coding of the active task rule and the extent of this increase was associated with improvements in task performance. Additionally, the effect of high reward on task rule coding was most pronounced on switch trials, where rules were updated relative to the previous trial. These results suggest that reward prospect can promote cognitive performance by strengthening neural coding of task rule information, helping to improve cognitive flexibility during complex behaviour.

Significance Statement

The importance of motivation is evident in the ubiquity with which reward prospect guides adaptive behaviour and the striking number of neurological conditions associated with motivational impairments. In this study, we investigated how dynamic changes in motivation, as manipulated through reward, shape neural coding for task rules during a flexible decision-making task. The results of this work suggest that motivation to obtain reward modulates encoding of task rules needed for flexible behaviour. The extent to which reward increased task rule coding also tracked improvements in behavioural performance under high reward conditions. These findings help inform how motivation shapes neural processing in the healthy human brain.
Rere-dependent Retinoic Acid signaling controls brain asymmetry and handedness
Authors: Rebagliati Michael , Vilhais-Neto Gonçalo C. , Petiet Alexandra , Lange Merlin , Michaut Arthur , Plassat Jean-Luc , Vermot Julien , Riet Fabrice , Noblet Vincent , Brasse David , Laquerrière Patrice , Cussigh Delphine , Bedu Sébastien , Dray Nicolas , Gomaa Mohamed Sayed , Simons Claire , Meziane Hamid , Lehéricy Stéphane , Bally-Cuif Laure , Pourquié Olivier
Published: March 2019

While the vertebrate brain appears largely bilaterally symmetrical in humans, it presents local morphological Left-Right (LR) asymmetries as, for instance, in thepetalia. Moreover, higher functions such as speech or handedness are asymmetrically localized in the cortex. How these brain asymmetries are generated remains unknown. Here, we reveal a striking parallel between the control of bilateral symmetry in the brain and in the precursors of vertebrae called somites, where a “default” asymmetry is buffered by Retinoic Acid (RA) signaling. This mechanism is evident in zebrafish and mouse and, when perturbed in both species, it translates in the brain into lateralized alterations of patterning, neuronal differentiation and behavior. We demonstrate that altering levels of the mouse RA coactivator Rere results in subtle cortex asymmetry and profoundly altered handedness, linking patterning and function in the motor cortex. Together our data uncover a novel mechanism that could underlie the establishment of brain asymmetries and handedness in vertebrates.
Kindlin-3 Mutation in Mesenchymal Stem Cells Results in Enhanced Chondrogenesis
Authors: Kerr Bethany A. , Shi Lihong , Jinnah Alexander H. , Willey Jeffrey S. , Lennon Donald P. , Caplan Arnold I. , Byzova Tatiana V.
Published: March 2019

Identifying patient mutations driving skeletal development disorders has driven our understanding of bone development. Integrin adhesion deficiency disease is caused by a Kindlin-3 (fermitin family member 3) mutation and its inactivation results in bleeding disorders and osteopenia. In this study, we uncover a role for Kindlin-3 in the differentiation of bone marrow mesenchymal stem cells (BMSCs) down the chondrogenic lineage. Kindlin-3 expression increased with chondrogenic differentiation similar to RUNX2. BMSCs isolated from a Kindlin-3 deficient patient expressed chondrocyte markers including SOX9 under basal conditions, which were further enhanced with chondrogenic differentiation. Rescue of integrin activation by a constitutively activated β3 integrin construct increased adhesion to multiple extracellular matrices and reduced SOX9 expression to basal levels. Growth plates from mice expressing a mutated Kindlin-3 with the integrin binding site ablated demonstrated alterations in chondrocyte maturation similar to that seen with the human Kindlin-3 deficient BMSCs. These findings suggest that Kindlin-3 expression mirrors RUNX2 during chondrogenesis.

This study by Kerr et al. describes a new role for Kindlin-3 in controlling early chondrocyte differentiation from mesenchymal stem cells and later hypertrophic differentiation of chondrocytes.
Imaging the Electrical Activity Of Organelles in living cells
Authors: Matamala Ella , Castillo Cristian , Vivar Juan Pablo , Brauchi Sebastian
Published: March 2019

Eukaryotic cells are complex systems compartmentalized in membrane-bound organelles. Visualization of organellar electrical activity in living cells requires both a suitable reporter and non-invasive imaging at high spatiotemporal resolution. Here we present hVoSorg, an optical method to monitor changes in the membrane potential of subcellular membranes. This method takes advantage of a FRET pair consisting of a membrane-bound voltage-insensitive fluorescent donor and a colorless voltage-dependent acceptor that rapidly moves across the membrane in response to changes in polarity. Compared to the currently available techniques, hVoSorg has advantages including simple and precise subcellular targeting, the ability to record from individual organelles, and the potential for optical multiplexing.

By adapting a hybrid-FRET voltage sensor we report here the resting membrane potential of different organelles in living cells.
Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides
Authors: Tanti Arnaud , Lutz Pierre-Eric , Kim John , O’Leary Liam , Turecki Gustavo , Mechawar Naguib
Published: March 2019

Glial dysfunction is a major feature in the pathophysiology of mood disorders. While altered astrocyte (AS) and oligodendrocyte-lineage (OL) cell functions have been associated with depression, the crosstalk between these two major glial cell types has never been assessed in that context. AS are potent regulators of OL cells and myelination, in part through gap junction-mediated intercellular communication made possible by the heterotypic coupling of AS-specific (Cx30 and Cx43) and OL-specific (Cx32 and Cx47) connexins, allowing cytosolic transport and metabolic support to OL cells. Because changes in the expression of AS-specific connexins have been previously reported in the brain of depressed individuals, this study aimed at addressing the integrity of AS-OL coupling in the anterior cingulate cortex (ACC) of depressed suicides. Using immunofluorescence and confocal imaging, we characterized the distribution of the AS-specific Cx30 in the ACC, and mapped its expression onto oligodendrocyte somas and myelinated axons as well as brain vasculature in post-mortem brain samples from depressed suicides (N=48) and matched controls (N=23). The differential gene expression of key components of the gap junction nexus was also screened through RNA-sequencing dataset previously generated by our group, and validated by quantitative real-time PCR. Our results indicate that Cx30 expression mapping to OL cells is selectively decreased in depressed suicides, an effect that was associated with decreased expression of OL-specific connexins Cx32 and Cx47, as well as the downregulation of major connexin-interacting proteins essential for the scaffolding, trafficking and function of gap junction channels. These results provide a first evidence of impaired gap junction mediated communication between astrocytes and oligodendrocytes in the ACC of individuals with mood disorders. These changes in glial coupling are likely to have significant impact on brain function, and may contribute to the altered OL function previously reported in this brain region.
Blood cells of adultDrosophilado not expand, but control survival after bacterial infection by induction ofDrosocinaround their reservoir at the respiratory epithelia
Authors: Bosch Pablo Sanchez , Makhijani Kalpana , Herboso Leire , Gold Katrina S , Baginsky Rowan , Woodcock Katie J , Alexander Brandy , Kukar Katelyn , Corcoran Sean , Ouyang Debra , Wong Corinna , Ramond Elodie JV , Rhiner Christa , Moreno Eduardo , Lemaitre Bruno , Geissmann Frederic , Brückner Katja
Published: March 2019

Drosophila melanogasterhas been an excellent model for innate immunity, but the role and regulation of adult blood cells and organismal immunity have remained incompletely understood. Here we address these questions in a comprehensive investigation of the blood cell system in adultDrosophila. As a central finding, we reveal the largest reservoir of blood cells (hemocytes) at the respiratory epithelia (tracheal air sacs) and fat body of the thorax and head. We show that most hemocytes of adultDrosophilaare phagocytic macrophages (plasmatocytes), derived by more than 60% from the embryonic lineage that parallels vertebrate tissue macrophages. Surprisingly, in contrast to hemocytes at the larval stage, we find no capacity of the adult blood cell system to expand. Instead, we demonstrate its central role in relaying an innate immune response to tissues surrounding the blood cell reservoir: Hemocytes, through Imd signaling and the Jak/Stat pathway ligand Upd3, act as sentinels of bacterial infection that induce expression of the antimicrobial peptide geneDrosocin in the respiratory epithelia and colocalizing domains of the fat body. We demonstrate that endogenousDrosocinexpression in these tissues promotes animal survival after bacterial infection. Our work identifies the first molecular step in a new relay of organismal immunity, establishing adultDrosophilaas model to dissect mechanisms of inter-organ immunity.
Robustness and timing of cellular differentiation through population-based symmetry breaking
Authors: Stanoev Angel , Schröter Christian , Koseska Aneta
Published: March 2019

During mammalian development, cell types expressing mutually exclusive genetic markers are differentiated from a multilineage primed state. These observations have invoked single-cell multistability view as the dynamical basis of differentiation. However, the robust regulative nature of mammalian development is not captured therein. Considering the well-established role of cell-cell communication in this process, we propose a fundamentally different dynamical treatment in which cellular identities emerge and are maintained on population level, as a novel unique solution of the coupled system. Subcritical system’s organization here enables symmetry-breaking to be triggered by cell number increase in a timed, self-organized manner. Robust cell type proportions are thereby an inherent feature of the resulting inhomogeneous solution. This framework is generic, as exemplified for early embryogenesis and neurogenesis cases. Distinct from mechanisms that rely on pre-existing asymmetries, we thus demonstrate that robustness and accuracy necessarily emerge from the cooperative behaviour of growing cell populations during development.
Gene Expression Mediated Antiproliferative Potential and Safety of Selected Medicinal Plants Against Cancerous and Normal Cells
Authors: Mbugua Regina Wachuka , Njagi Eliud Mwaniki , Ngule Chrispus Mutuku , Mwitari Peter
Published: March 2019

Globally, approximately 13% of all deaths annually are attributed to cancer. Surgery, radiation and chemotherapy are the current treatment techniques for cancer, however these methods are expensive, have high failure rates and have been associated with detrimental side effects. Plant derived products could be good candidates in alleviating challenges being experienced with these current methods. This study aimed at evaluating the phytochemistry, antiproliferation potential, and probable mechanism of action ofAlbizia gummifera,Rhamnus staddoandSenna didymobotryaplant extracts. Phytochemical screening was done as per standard procedures. The common 3– (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium (MTT) dye was used in the determination of the antiproliferative activity of the extracts. Extracts induction ofVEGF(angiogenesis) and p53 (apoptosis) genes’ expression was evaluated using Real Time Polymerase Chain Reaction. Phytochemical screening revealed presence of alkaloids, tannins, glycosides, flavonoids, terpenes, phenolics and saponins in the plants extracts.A. gummifera’sstem bark methanol: dichloromethane extract had the highest activity against the cancerous cell lines tested: HCC1395 (IC506.07±0.04μg/ml), DU145 (IC503.34±0.05μg/ml), CT26 (IC505.78±0.08μg/ml) and Hep2 (IC507.02±0.01μg/ml).R. staddoroot bark methanol: dichloromethane extract had an IC50value of 15.71±0.04μg/ml on HCC, 9.81±0.09μg/ml on Hep2 and 11.14±0.39μg/ml on CT26.S. didymobotryaroot bark methanol: dichloromethane extract inhibited HCC with an IC50of 65.06±0.07μg/ml, CT26 with an IC50of 15.71±0.04μg/ml and Hep2 with an IC50of 62.10±0.11μg/ml. From the results obtained, the plants exhibited selective toxicity to cancer cells while sparing the normal cells (SI ≥ 3).A. gummiferaandS. didymobotryaandR. staddoplant extracts upregulated p53 and down-regulatedVEGFgenes. In conclusion, this study confirms that these plant extracts could be potential candidates for development of drugs for the management of breast, prostrate, colorectal and throat cancer.
The Beacon Calculus: A formal method for the flexible and concise modelling of biological systems
Authors: Boemo Michael A. , Cardelli Luca , Nieduszynski Conrad A.
Published: March 2019

Biological systems are made up of components that change their actions (and interactions) over time and coordinate with other components nearby. Together with a large state space, the complexity of this behaviour can make it difficult to create concise mathematical models that can be easily extended or modified. This paper introduces the Beacon Calculus, a process algebra designed to simplify the task of modelling interacting biological components. Its breadth is demonstrated by creating models of DNA replication dynamics, the gene expression dynamics in response to DNA methylation damage, and a multisite phosphorylation switch. The flexibility of these models is shown by adapting the DNA replication model to further include two topics of interest from the literature: cooperative origin firing and replication fork barriers. The Beacon Calculus is supported with the open-source simulator bcs (https://github.com/MBoemo/bcs.git) to allow users to develop and simulate their own models.

Author summary

Simulating a model of a biological system can suggest ideas for future experiments and help ensure that conclusions about a mechanism are consistent with data. The Beacon Calculus is a new language that makes modelling simple by allowing users to simulate a biological system in only a few lines of code. This simplicity is critical as it allows users the freedom to come up with new ideas and rapidly test them. Models written in the Beacon Calculus are also easy to modify and extend, allowing users to add new features to the model or incorporate it into a larger biological system. We demonstrate the breadth of applications in this paper by applying the Beacon Calculus to DNA replication and DNA damage repair, both of which have implications for genome stability and cancer. We also apply it to multisite phosphorylation, which is important for cellular signalling. To enable users to create their own models, we created the open-source Beacon Calculus simulator bcs (https://github.com/MBoemo/bcs.git) which is easy to install and is well-supported by documentation and examples.