bluuebunny/crossref_metadata_2025 huggingface dataset:
Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Humans and Mice
Authors: Ehrhardt Nicole , Cui Jinrui , Dagdeviren Sezin , Saengnipanthkul Suchaorn , Goodridge Helen S. , Kim Jason K. , Lantier Louise , Guo Xiuqing , Chen Yii-Der I. , Raffel Leslie J. , Buchanan Thomas A. , Hsueh Willa A. , Rotter Jerome I. , Goodarzi Mark O. , Péterfy Miklós
Published: May 2018

Aims/hypothesis

Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-related insulin resistance is due to age per se, or increased adiposity associated with advanced age. In the present study, we investigate the impact of aging on insulin sensitivity independent of changes in body composition.

Methods

Cohorts of C57BL/6J male mice at 4-8 months of age (‘young’) and 18-27 mo (‘aged’) exhibiting similar body composition were characterized with static (plasma glucose and insulin levels) and dynamic (glucose and insulin tolerance tests) measures of glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis. The relationship between aging and insulin resistance in humans was investigated in 1,250 non-diabetic Mexican-American individuals who underwent hyperinsulinemic-euglycemic clamps.

Results

In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. However, aged mice demonstrated mildly, but reproducibly, improved glucose tolerance on both chow and high-fat diets due to increased glucose-stimulated insulin secretion. Moreover, hyperinsulinemic-euglycemic clamps revealed impaired insulin sensitivity and reduced insulin clearance in aged mice on both diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican-Americn males. Advanced age was also associated with diminished insulin clearance, but this effect was dependent on increased BMI.

Conclusions/interpretation

This study demonstrates for the first time that aging per se impairs insulin sensitivity independent of adiposity in mice and humans. These results raise the possibility that the pathogenetic mechanisms of age-related and obesity-associated insulin resistance are distinct.

Abbreviations

BAI

body adiposity index

GEE

generalized estimating equations HF high-fat

IQR

interquartile range

MCRI

metabolic clearance rate of insulin

T2D

type 2 diabetes
Forebrain dopamine value signals arise independently from midbrain dopamine cell firing
Authors: Mohebi Ali , Pettibone Jeffrey , Hamid Arif , Wong Jenny-Marie , Kennedy Robert , Berke Joshua
Published: May 2018

The mesolimbic dopamine projection from the ventral tegmental area (VTA) to nucleus accumbens (NAc) is a key pathway for reward-driven learning, and for the motivation to work for more rewards. VTA dopamine cell firing can encode reward prediction errors (RPEs1,2), vital learning signals in computational theories of adaptive behavior. However, NAc dopamine release more closely resembles reward expectation (value), a motivational signal that invigorates approach behaviors3-7. This discrepancy might be due to distinct behavioral contexts: VTA dopamine cells have been recorded under head-fixed conditions, while NAc dopamine release has been measured in actively-moving subjects. Alternatively the mismatch may reflect changes in the tonic firing of dopamine cells8, or a fundamental dissociation between firing and release. Here we directly compare dopamine cell firing and release in the same adaptive decision-making task. We show that dopamine release covaries with reward expectation in two specific forebrain hotspots, NAc core and ventral prelimbic cortex. Yet the firing rates of optogenetically-identified VTA dopamine cells did not correlate with reward expectation, but instead showed transient, error-like responses to unexpected cues. We conclude that critical motivation-related dopamine dynamics do not arise from VTA dopamine cell firing, and may instead reflect local influences over forebrain dopamine varicosities.
Reconstructing Neuronal Circuitry from Parallel Spike Trains
Authors: Kobayashi Ryota , Kurita Shuhei , Kitano Katsunori , Mizuseki Kenji , Richmond Barry J. , Shinomoto Shigeru
Published: May 2018

State-of-the-art techniques allow researchers to record large numbers of spike trains parallel for many hours. With enough such data, we should be able to infer the connectivity among neurons. Here we develop a computationally realizable method for reconstructing neuronal circuitry by applying a generalized linear model (GLM) to spike crosscorrelations. Our method estimates interneuronal connections in units of postsynaptic potentials and the amount of spike recording needed for verifying connections. The performance of inference is optimized by counting the estimation errors using synthetic data from a network of Hodgkin-Huxley type neurons. By applying our method to rat hippocampal data, we show that the numbers and types of connections estimated from our calculations match the results inferred from other physiological cues. Our method provides the means to build a circuit diagram from recorded spike trains, thereby providing a basis for elucidating the differences in information processing in different brain regions.
Depolymerized lamins link nuclear envelope breakdown to mitotic transcriptional quiescence
Authors: Ikegami Kohta , Secchia Stefano , Lieb Jason D. , Moskowitz Ivan P.
Published: May 2018

The nuclear envelope, a defining feature of eukaryotic cells, restricts DNA-dependent processes including gene transcription to the nucleus. The nuclear lamina is an integral component of the animal nuclear envelope, composed of polymers of nuclear lamin proteins1,2. Upon mitosis, the nuclear lamina disassembles, the nuclear envelope breaks down, and transcription becomes quiescent3,4. We report here a direct molecular link between nuclear lamina disassembly and mitotic transcriptional quiescence. We found that, at the G2 cell-cycle phase immediately preceding mitosis, nuclear lamin A/C (LMNA) became phosphorylated at Ser22 and depolymerized from the nuclear lamina. Depolymerized LMNA accumulated in the nuclear interior and physically associated with active cis-regulatory elements genome-wide. Depolymerized LMNA-associated sites were overrepresented near genes repressed by LMNA, suggesting that depolymerized LMNA participates in transcriptional repression at G2. Consistently, depolymerized LMNA-target genes underwent a steep expression decline from S to G2/M. Furthermore, LMNA deletion caused inappropriate RNA Polymerase II (Pol II) accumulation downstream of Pol II pause sites at promoters and enhancers genome-wide, leading to inappropriate and excessive transcriptional elongation. A subset of depolymerized LMNA-target genes were upregulated in fibroblasts of patients with Hutchinson-Gilford progeria, a premature aging disorder caused by LMNA mutations5, raising the possibility that defects in depolymerized LMNA-mediated mitotic transcriptional quiescence contribute to progeria pathogenesis. These observations support a model in which depolymerized LMNA targets active regulatory elements to promote RNA Pol II pausing preceding mitosis, coupling nuclear envelope breakdown to mitotic transcriptional quiescence.
Microbial Community Structure and Diversity of Shrimp Paste at Different Fermentation Stages
Authors: Dai Lingying , Wang Limei , Sun Jiang , Zheng Lixue , Qi Bin
Published: May 2018

High-throughput sequencing was used to reveal the highly diverse bacterial populations in shrimp paste at different fermentation stages. We studied three stages of fermentation and obtained 448,916 reads. Using this approach, we revealed the presence of 30 phyla, 55 classes, 86 orders, 206 families and 695 genera of bacteria in the shrimp paste. Shrimp paste in fermentation metaphase had a more diverse microbiota than that in fermentation prophase and fermentation anaphase. Diversity appeared greatest in fermentation anaphase. The four dominant phyla were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. The most common genera were Psychrobacter, Halomonas, Bacillus, Alteribacillus, and Lactococcus. Their content varied at different stages of fermentation. All the microbiome presented a variety of changes in the microbial diversity of shrimp paste.

Importance

Most research on the microbial diversity of shrimp paste has focused on the shrimp culture environment, or the chemical composition and sensory attributes of the paste. Little research has been conducted on the microbial diversity and composition of shrimp paste. The relationship between microbes and the flavor and quality of shrimp paste has thus been unknown. We therefore analyzed the microbial composition and variation of shrimp paste at different stages of fermentation. The dominant bacteria in fermentation prophase, metaphase, and anaphase were identified. Our preliminary findings give some insight into which microbes contribute to the flavor of shrimp paste and suggest how to improve its flavor. In addition, our findings are relevant to optimizing the production of shrimp paste and guaranteeing its quality and safety.
The Metabolic Capability and Phylogenetic Diversity of Mono Lake During a Bloom of the Eukaryotic Phototroph Picocystis strain ML
Authors: Stamps Blake W. , Nunn Heather S. , Petryshyn Victoria A. , Oremland Ronald S. , Miller Laurence G. , Rosen Michael R. , Bauer Kohen W. , Thompson Katharine J. , Tookmanian Elise M. , Waldeck Anna R. , Lloyd Sean J. , Johnson Hope A. , Stevenson Bradley S. , Berelson William M. , Corsetti Frank A. , Spear John R.
Published: May 2018

Algal blooms in lakes are often associated with anthropogenic eutrophication; however, they can occur naturally. In Spring of 2016 Mono Lake, a hyperalkaline lake in California, was near the height of a rare bloom of the algae Picocystis strain ML and at the apex of a multi-year long drought. These conditions presented a unique sampling opportunity to investigate microbiological dynamics during an intense natural bloom. We conducted a comprehensive molecular analysis along a depth transect near the center of the lake from surface to 25 m depth during June 2016. Across sampled depths, rRNA gene sequencing revealed that Picocystis associated chloroplast were found at 40-50 % relative abundance, greater than values recorded previously. Despite the presence of the photosynthetic oxygenic algal genus Picocystis, oxygen declined below detectible limits below 15 m depth, corresponding with an increase in microorganisms known to be anaerobic. In contrast to previously sampled years, metagenomic and metatranscriptomic data suggested a loss of sulfate reducing microorganisms throughout the lake’s water column. Gene transcripts associated with Photosystem I and II were expressed at both 2 m and 25 m, suggesting that limited oxygen production may occur at extremely low light levels at depth within the lake. Oxygenic photosynthesis under low light conditions, in the absence of potential grazing by the brine shrimp Artemia, may allow for a cryptic redox cycle to occur in an otherwise anoxic setting at depth in the lake with the following effects: enhanced productivity, reduced grazing pressure on Picocystis, and an exacerbation of bloom.

IMPORTANCE

Mono Lake, California provides habitat to a unique ecological community that is heavily stressed due to recent human water diversions and a period of extended drought. To date, no baseline information exists about Mono Lake to understand how the microbial community responds to drought, bloom, and what genetic functions are lost in the water column. While previously identified anaerobic members of the microbial community disappear from the water column during drought and bloom, sediment samples suggest these microorganisms seek refuge at lake bottom or in the subsurface. Thus, the sediments may represent a type of seed bank which could restore the microbial community as a bloom subsides. Our work also sheds light on the activity of the halotolerant algae Picocystis strain ML during a bloom at Mono Lake, its ability to potentially produce oxygen via photosynthesis even under extreme low-light conditions, and how the remainder of the microbial community responds.
In vitro characterization of multidrug-resistant influenza A(H1N1)pdm09 viruses carrying a dual amino acid substitution associated with reduced susceptibility to neuraminidase inhibitors
Authors: Takashita Emi , Fujisaki Seiichiro , Yokoyama Masaru , Shirakura Masayuki , Nakamura Kazuya , Kuwahara Tomoko , Kishida Noriko , Sato Hironori , Doi Ikuko , Sato Yuji , Takao Shinichi , Shimazu Yukie , Shimomura Takeshi , Ito Takuo , Watanabe Shinji , Odagiri Takato ,   The Influenza Virus Surveillance Group of Japan
Published: May 2018

We detected influenza A(H1N1)pdm09 viruses carrying dual H275Y/I223R, H275Y/I223K, or H275Y/G147R substitutions in their neuraminidase protein, respectively. These viruses showed cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir. The H275Y/G147R virus retained its replication capability at least in vitro, but the H275Y/I223R and H275Y/I223K viruses did not.
Characterization of influenza B virus variants with reduced neuraminidase inhibitor susceptibility
Authors: Farrukee R , Zarebski AE , McCaw JM , Bloom JD , Reading PC , Hurt AC
Published: May 2018

Treatment options for influenza B virus infections are limited to neuraminidase inhibitors (NAIs) which block the neuraminidase (NA) glycoprotein on the virion surface. The development of NAI resistance would therefore result in a loss of antiviral treatment options for influenza B infections. This study characterized two contemporary influenza B viruses with known resistance-conferring NA amino acid substitutions, D197N and H273Y, detected during routine surveillance. The D197N and H273Y variants were characterizedin vitroby assessing NA enzyme activity and affinity, as well as replication in cell culture compared to NAI-sensitive wild-type viruses.In vivostudies were also performed in ferrets to assess the replication and transmissibility of each variant. Mathematical models were used to analyse within-host and between-host fitness of variants relative to wild-type viruses. The data revealed that the H273Y variant had similar NA enzyme function relative to its wild-type but had slightly reduced replication and transmission efficiencyin vivo. The D197N variant had impaired NA enzyme function but there was no evidence of reduction in replication or transmission efficiency in ferrets. Our data suggest that the influenza B variant with H273Y NA substitution had a more notable reduction in fitness compared to wild-type viruses than the influenza B variant with the D197N NA substitution. Although a D197N variant is yet to become widespread, it is the most commonly detected NAI-resistant influenza B virus in surveillance studies. Our results highlight the need to carefully monitor circulating viruses for the spread of influenza B viruses with the D197N NA substitution.
Transdermal, but not oral mucosa exposure, causes sublethal leptospirosis in mice
Authors: Nair Nisha , Gomes-Solecki Maria
Published: May 2018

The goal of this study was to determine the timing ofLeptospiradissemination after infection using natural physiologic routes and its correlation with signs and symptoms of leptospirosis. Groups of C3H-HeJ mice were sub-lethally infected through exposure of a dermis wound and the oral mucosa toL. interrogansserovar Copenhageni, and compared to mice infected via standard laboratory practice of intraperitoneal inoculation. We found that transdermal infection leads to delayed bacterial dissemination in blood and urine when compared to intraperitoneal infection using the same infectious dose, and that the overlapping presence ofL. interrogansin both fluids was twice as long as the standard intraperitoneal infection. Furthermore, dissemination ofL. interrogansand disease did not occur in mice infected with the same dose ofL. interrogansvia the oral mucosa. Over the course of these studies we also observed that the timing of exit ofLeptospirafrom blood and establishment of colonization of the kidney in the second week of infection correlated well with weight loss, but not with hypothermia. Thus, a non-invasive sign of leptospirosis such as weigh loss can be used to monitor bacterial dissemination and disease stage in mice. Our findings underline the importance of precise determination of windows of pathogen dissemination in biological fluids and how the route of infection affects the progression of disease. These studies could help focus the development of better treatment strategies and new technologies for diagnostic use.
New guidelines for DNA methylome studies regarding 5-hydroxymethylcytosine for understanding transcriptional regulation
Authors: Li Le , Gao Yuwei , Wu Qiong , Cheng Alfred S. L. , Yip Kevin Y.
Published: May 2018

Many DNA methylome profiling methods cannot distinguish between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Since 5mC typically acts as a repressive mark whereas 5hmC is an intermediate form during active demethylation, the inability to separate their signals could lead to incorrect interpretation of the data. Meanwhile, many analysis pipelines quantify methylation level by the count or ratio of methylated reads, but the proportion of discordant reads (PDR) has recently been proposed to be a better indicator of gene expression level. Is the amount of extra information contained in 5hmC signals and PDR worth the additional experimental and computational costs? Here we combine whole-genome bisulfite sequencing (WGBS) and oxidative WGBS (oxWGBS) data in normal human lung and liver tissues and their paired tumors to investigate the quantitative relationships between gene expression and signals of the two forms of DNA methylation at promoters, transcript bodies, and immediate downstream regions. We find that 5mC and 5hmC signals correlate with gene expression in the same direction in most samples, but considering both types of signals increases the accuracy of expression levels inferred from methylation data by a median of 18.2% as compared to having only standard WGBS data, showing that the two forms of methylation provide complementary information about gene expression. In addition, differential analysis between matched tumor and normal pairs is particularly affected by the superposition of 5mC and 5hmC signals in WGBS data, with at least 25-40% of the differentially methylated regions (DMRs) identified from 5mC signals not detected from WGBS data. We do not find PDR to be more informative about expression levels than ratio of methylated reads, and integrating the two types of methylation features only improves the accuracy of inferred expression levels by at most 9.8%. Our results also confirm previous finding that methylation signals at transcript bodies are more indicative of gene expression levels than promoter methylation signals, and further show that in addition to the first exon, methylation signals at the last exon and internal introns also contain non-redundant information about gene expression. Overall, our study provides concrete data for evaluating the cost effectiveness of some experimental and analysis options in the study of DNA methylation in normal and cancer samples.
Commensal bacteria act as a broad genetic buffer in Drosophila during chronic under-nutrition
Authors: Ma Dali , Bou-Sleiman Maroun , Joncour Pauline , Indelicato Claire-Emmanuelle , Frochaux Michael , Braman Virginie , Litovchenko Maria , Storelli Gilles , Deplancke Bart , Leulier François
Published: May 2018

Eukaryotic genomes encode several well-studied buffering mechanisms that robustly maintain invariant phenotypic outcome despite fluctuating environmental conditions. Here we show that the gut microbiota, represented by a single Drosophila facultative symbiont, Lactobacillus plantarum (LpWJL), acts also as a broad genetic buffer that masks the contribution of the cryptic genetic variations in the host under nutritional stress. During chronic under-nutrition, LpWJL consistently reduces variation in different host phenotypic traits and ensures robust organ patterning; LpWJL also decreases genotype-dependent expression variation, particularly for development-associated genes. We further demonstrate that LpWJL buffers via reactive oxygen species (ROS) signaling whose inhibition severely impairs microbiota-mediated phenotypic robustness. We thus identified an unexpected contribution of facultative symbionts to Drosophila fitness by assuring developmental robustness and phenotypic homogeneity in times of nutritional stress.
Pellino 1 Communicates Intercellular Signaling in Chronic Skin Inflammatory Microenvironment
Authors: Kim Suhyeon , Bae Seoyoon , Park Jihyun , Ha Geun-Hyoung , Hwang Kyungrim , Kim Hyun-Soo , Ji Jae-Hoon , Go Heounjeong , Lee Chang-Woo
Published: May 2018

Chronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signal-responsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination. Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses. Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.
Physiologically driven, altitude-adaptive model for the interpretation of pediatric oxygen saturation at altitudes above 2000 m a.s.l
Authors: Tüshaus Laura , Moreo Monica , Zhang Jia , Hartinger Stella Maria , Mäusezahl Daniel , Karlen Walter
Published: May 2018

Measuring peripheral oxygen saturation (SpO2) with pulse oximeters at the point of care is widely established. However, since SpO2 is dependent on ambient atmospheric pressure, the distribution of SpO2 values in populations living above 2000 m a.s.l. is largely unknown. Here, we propose and evaluate a computer model to predict SpO2 values for pediatric permanent residents living between 0 and 4000 m a.s.l. Based on a sensitivity analysis of oxygen transport parameters, we created an altitude-adaptive SpO2 model that takes physiological adaptation of permanent residents into account. From this model, we derived an altitude-adaptive abnormal SpO2 threshold using patient parameters from literature. We compared the obtained model and threshold against a previously proposed threshold derived statistically from data and two empirical datasets independently recorded from Peruvian children living at altitudes up to 4100 m a.s.l. Our model followed the trends of empirical data, with the empirical data having a narrower healthy SpO2 range below 2000 m a.s.l., but the medians did never differ more than 2.29% across all altitudes. Our threshold estimated abnormal SpO2 in only 17 out of 5981 (0.3%) healthy recordings, whereas the statistical threshold returned 95 (1.6%) recordings outside the healthy range. The strength of our parametrised model is that it is rooted in physiology-derived equations and enables customisation. Furthermore, as it provides a reference SpO2, it could assist practitioners in interpreting SpO2 values for diagnosis, prognosis, and oxygen administration at higher altitudes.

New & Noteworthy

Our model describes the altitude-dependent decrease of SpO2 in healthy pediatric residents based on physiological equations and can be adapted based on measureable clinical parameters. The proposed altitude-specific abnormal SpO2 threshold might be more appropriate than rigid guidelines for administering oxygen that currently are only available for sea level patients. We see this as a starting point to discuss and adapt oxygen administration guidelines.
Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells
Authors: Phuong Tran Thi Thu , Eichholz Karsten , Amelio Patrizia , Moyer Crystal , Nemerow Glen R , Perreau Matthieu , Mennechet Franck JD , Kremer Eric J
Published: May 2018

Following repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised, reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus-specific T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (Tregs). As peripherally induced Tregsare generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen-loaded tolerogenic DCs can drive naïve T cells to mature into adenovirus-specific Tregs. Our results may provide ways to improve antiviral therapy and/or pre-screening high-risk individuals undergoing immunosuppression.

Author summary

While numerous studies have addressed the cellular and humoral response to primary virus encounters, relatively little is known about the interplay between persistent infections, neutralizing antibodies, antigen-presenting cells, and the T-cell response. Our studies suggests that if adenovirus–antibody complexes are taken up by professional antigen-presenting cells (dendritic cells), the DCs generate an environment that causes bystander dendritic cells to become tolerogenic. These tolerogenic dendritic cells favors the creation of adenovirus-specific regulatory T cells. While this pathway likely favors pathogen survival, there may be advantages for the host also.
Bidirectional alterations in antibiotics susceptibility in Staphylococcus aureus - Pseudomonas aeruginosa dual-species biofilm
Authors: Trizna Elena Y. , Yarullina Maria N. , Baidamshina Diana R. , Akhatova Farida S. , Rozhina Elvira V. , Fakhrullin Rawil F. , Khabibrakhmanova Alsu M. , Kurbangalieva Almira R. , Bogachev Mikhail I. , Kayumov Airat R.
Published: May 2018

While in biofilms bacteria are embedded into an extracellular matrix which forms inaccessible barrier for antimicrobials thereby drastically increasing the concentrations of antibiotics required for treatment. Here we show that the susceptibility of S. aureus and P. aeruginosa to antibiotics in mixed biofilms significantly differs from monoculture biofilms depending on both conditions and chosen antimicrobial agents. While S. aureus could completely avoid vancomycin, ampicillin and ceftriaxone by embedding into the biofilm of P. aeruginosa, the very same consortium was characterized by 10–fold increase in susceptibility to broad-spectrum antimicrobials like ciprofloxacin and aminoglycosides compared to monocultures. These data clearly indicate that efficient treatment of biofilm-associated mixed infections requires antimicrobials active against both pathogens, since the interbacterial antagonism would enhance the efficacy of treatment. Moreover, similar increase in antibiotics efficacy was observed when P. aeruginosa suspension was added to the mature S. aureus biofilm, compared to S. aureus monoculture, and vice versa. These findings open promising perspectives to increase the antimicrobial treatment efficacy of the wounds infected with nosocomial pathogens by the transplantation of the skin residential microflora.
A mosaic of independent innovations involvingeyes shutare critical for the evolutionary transition from closed to open rhabdoms
Authors: Mahato Simpla , Nie Jing , Plachetzki David C. , Zelhof Andrew C.
Published: May 2018

A fundamental question in evolutionary biology is how developmental processes are modified to produce morphological innovations while abiding by functional constraints. Here we address this question by investigating the cellular mechanism responsible for the transition between fused and open rhabdoms in ommatidia of apposition compound eyes; a critical step required for the development of visual systems based on neural superposition. UtilizingDrosophilaandTriboliumas representatives of fused and open rhabdom morphology respectively, we identified three changes required for this innovation to occur. First, the expression pattern of the extracellular matrix protein Eyes Shut (EYS) was co-opted and expanded from mechanosensory neurons to the photoreceptor cells in taxa with open rhabdoms. Second, EYS homologs in these taxa obtained a novel extension of the amino terminus leading to the internalization of a cleaved signal sequence. This amino terminus extension does not interfere with cleavage or function in mechanosensory neurons, but it does permit specific targeting of the EYS protein to the apical photoreceptor membrane. Finally, a specific interaction evolved between EYS and a subset of Prominin homologs that is required for the development of open, but not fused, rhabdoms. Together, our findings portray a case study wherein the evolution of a set of molecular novelties has precipitated the origin of an adaptive photoreceptor cell arrangement.

Author Summary

Understanding how adaptive morphologies originate is a central question in evolutionary developmental biology. Once confined largely to arguments about the relative frequencies of protein coding vs. regulatory mutations, numerous studies have since revealed more complex interactions involving alterations in gene expression and novel protein-protein interactions as drivers of novel trait evolution. Our study exploits the genetic amenability ofDrosophilaand utilizes direct comparisons withTriboliumto define a set of cellular mechanisms necessary for the evolutionary transition from a fused (Tribolium) to an open (Drosophila) rhabdom. Our results depict an evolutionary transition involving both non-coding and coding changes that resulted in a novel visual architecture, permitting a subset of diurnal insects to diversify into niches characterized by low light.
Cellular heterogeneity in pressure and growth emerges from tissue topology and geometry
Authors: Long Yuchen , Cheddadi Ibrahim , Mirabet Vincent , Mosca Gabriella , Dumond Mathilde , Traas Jan , Godin Christophe , Boudaoud Arezki
Published: May 2018

Cell-to-cell heterogeneity prevails in many biological systems, although its origin and function are often unclear. Cell hydrostatic pressure, alias turgor pressure, is essential in physiology and morphogenesis, and its spatial variations are often overlooked. Here, based on a mathematical model describing cell mechanics and water movement in a plant tissue, we predict that cell pressure anticorrelates with cell neighbour number. Using atomic force microscopy, we confirm this prediction in the Arabidopsis shoot apical meristem, a population of stem cells that generate all plant aerial organs. Pressure is predicted to correlate either positively or negatively with cellular growth rate depending on osmotic drive, cell wall extensibility, and hydraulic conductivity. The meristem exhibits one of these two regimes depending on conditions, suggesting that, in this tissue, water conductivity is non-negligible in growth control. Our results illustrate links between local topology, cell mechanical state and cell growth, with potential roles in tissue homeostasis.
Domain Insertion Permissibility is a Measure of Engineerable Allostery in Ion Channels
Authors: Coyote-Maestas Willow , He Yungui , Myers Chad L. , Schmidt Daniel
Published: May 2018

Allostery is a fundamental principle of protein regulation that remains poorly understood and hard to engineer, in particular in ion channels. Here we use human Inward Rectifier K+Channel Kir2.1 to establish domain insertion ‘permissibility’ as a new experimental paradigm to identify engineerable allosteric sites. We find that permissibility is best explained by dynamic protein properties, such as conformational flexibility. Many allosterically regulated sites in Kir2.1 or sites equivalent to those regulated in homologs, such as G-protein-gated inward rectifier K+channels (GIRK), havedifferentialpermissibility; that is, for these sites permissibility depends on the structural properties of the inserted domain. Our data and the well-established link between protein dynamics and allostery led us to propose that differential permissibility is a metric of both existing and latent allostery in Kir2.1. In support of this notion, inserting light-switchable domains into either existing or latent allosteric sites, but not elsewhere, renders Kir2.1 activity sensitive to light.
Vegetation monitoring using multispectral sensors – best practices and lessons learned from high latitudes
Authors: Assmann Jakob J , Kerby Jeffrey T , Cunliffe Andrew M , Myers-Smith Isla H
Published: May 2018

Emerging drone technologies have the potential to revolutionise ecological monitoring. The rapid technological advances in recent years have dramatically increased affordability and ease of use of Unmanned Aerial Vehicles (UAVs) and associated sensors. Compact multispectral sensors, such as the Parrot Sequoia (Paris, France) and MicaSense RedEdge (Seattle WA, USA) capture spectrally accurate high-resolution (fine grain) imagery in visible and near-infrared parts of the electromagnetic spectrum, providing supplement to satellite and aircraft-based imagery. Observations of surface reflectance can be used to calculate vegetation indices such as the Normalised Difference Vegetation Index (NDVI) for productivity estimates and vegetation classification. Despite the advances in technology, challenges remain in capturing consistently high-quality data, particularly when operating in extreme environments such as the high latitudes. Here, we summarize three years of ecological monitoring with drone-based multispectral sensors in the remote Canadian Arctic. We discuss challenges, technical aspects and practical considerations, and highlight best practices that emerged from our experience, including: flight planning, factoring in weather conditions, and geolocation and radiometric calibration. We propose a standardised methodology based on established principles from remote sensing and our collective field experiences, using the Parrot Sequoia sensor as an example. With these good practises, multispectral sensors can provide meaningful spatial data that is reproducible and comparable across space and time.
ESCRT and autophagy cooperate to repair ESX-1-dependent damage to the Mycobacterium-containing vacuole
Authors: López-Jiménez Ana T. , Cardenal-Muñoz Elena , Leuba Florence , Gerstenmaier Lilli , Hagedorn Monica , King Jason S. , Soldati Thierry
Published: May 2018

Phagocytes capture invader microbes within the bactericidal phagosome. Some pathogens subvert killing by damaging and escaping from this compartment. To prevent and fight bacterial escape, cells contain and repair the membrane damage, or finally eliminate the cytosolic escapees. All eukaryotic cells engage highly conserved mechanisms to ensure integrity of membranes in a multitude of physiological and pathological situations, including the Endosomal Sorting Complex Required for Transport (ESCRT) and autophagy machineries. In Dictyostelium discoideum, recruitment of the ESCRT-III protein Snf7/Chmp4/Vps32 and the ATPase Vps4 to sites of membrane repair relies on the ESCRT-I component Tsg101 and occurs in absence of Ca2+. The ESX-1 dependent membrane perforations produced by the pathogen Mycobacterium marinum separately engage both ESCRT and autophagy. In absence of Tsg101, M. marinum escapes earlier to the cytosol, where it is restricted by xenophagy. We propose that ESCRT has an evolutionary conserved function in containing intracellular pathogens in intact compartments.
An Indexing Theory for Working Memory based on Fast Hebbian Plasticity
Authors: Fiebig Florian , Herman Pawel , Lansner Anders
Published: May 2018

Working memory (WM) is a key component of human memory and cognition. Computational models have been used to study the underlying neural mechanisms, but neglected the important role of short- and long-term memory interactions (STM, LTM) for WM. Here, we investigate these using a novel multi-area spiking neural network model of prefrontal cortex (PFC) and two parieto-temporal cortical areas based on macaque data. We propose a WM indexing theory that explains how PFC could associate, maintain and update multi-modal LTM representations. Our simulations demonstrate how simultaneous, brief multi-modal memory cues could build a temporary joint memory representation as an “index” in PFC by means of fast Hebbian synaptic plasticity. This index can then reactivate spontaneously and thereby reactivate the associated LTM representations. Cueing one LTM item rapidly pattern-completes the associated un-cued item via PFC. The PFC-STM network updates flexibly as new stimuli arrive thereby gradually over-writing older representations.
Insights into the mutational burden of human induced pluripotent stem cells using an integrative omics approach
Authors: D’Antonio Matteo , Benaglio Paola , Jakubosky David , Greenwald William W. , Matsui Hiroko , Donovan Margaret K. R. , Li He , Smith Erin N. , D’Antonio-Chronowska Agnieszka , Frazer Kelly A.
Published: May 2018

To understand the mutational burden of human induced pluripotent stem cells (iPSCs), we whole genome sequenced 18 fibroblast-derived iPSC lines and identified different classes of somatic mutations based on structure, origin and frequency. Copy number alterations affected 295 kb in each sample and strongly impacted gene expression. UV-damage mutations were present in ~45% of the iPSCs and accounted for most of the observed heterogeneity in mutation rates across lines. Subclonal mutations (not present in all iPSCs within a line) composed 10% of point mutations, and compared with clonal variants, showed an enrichment in active promoters and increased association with altered gene expression. Our study shows that, by combining WGS, transcriptome and epigenome data, we can understand the mutational burden of each iPSC line on an individual basis and suggests that this information could be used to prioritize iPSC lines for models of specific human diseases and/or transplantation therapy.
Comparative evaluation of the Geenius™ HIV 1/2 Confirmatory Assay and the HIV-1 and HIV-2 Western blots in the Japanese population
Authors: Kondo Makiko , Sudo Koji , Sano Takako , Kawahata Takuya , Itoda Ichiro , Iwamuro Shinya , Yoshimura Yukihiro , Tachikawa Natsuo , Kojima Yoko , Mori Haruyo , Fujiwara Hiroshi , Hasegawa Naoki , Kato Shingo
Published: May 2018

Accurate diagnosis of earlier HIV infection is essential for treatment and prevention. Currently, confirmation tests of HIV infection in Japan are performed using Western blot (WB), but WB has several limitations including low sensitivity and cross-reactivity between HIV-1 and HIV-2 antibodies. To address these problems, a new HIV testing algorithm and a more reliable confirmation and HIV-1/2 differentiation assay are required. The Bio-Rad Geenius™ HIV-1/2 Confirmatory Assay (Geenius) has recently been approved and recommended for use in the revised guidelines for diagnosis of HIV infection by the Center for Disease Control and Prevention (USA). We made comprehensive comparison of the performance of Geenius and the Bio-Rad NEW LAV BLOT 1 and 2 (NLB 1 and 2) which are WB kits for HIV-1 and HIV-2, respectively, to examine if Geenius is a suitable alternative to these WB assays which are now being used in HIV testing in Japan. A total of 166 HIV-1 positive samples (146 from patients with established HIV-1 infection and 20 from patients with acute infection), five HIV-1 seroconversion panels containing 21 samples and 30 HIV-2 positive samples were used. In addition, a total of 140 HIV negative samples containing 10 false-positives on screening tests were examined. The sensitivity of Geenius and NLB 1 for HIV-1 positive samples was 99.3% and 98.6%, respectively. Geenius provided more positive results in the samples from acute infections and detected positivity 0 to 32 days earlier in seroconversion panels than NLB 1. NLB 2 gave positive results in 12.3% of HIV-1 positive samples. The sensitivity of both Geenius and NLB 2 for HIV-2 positive samples was 100%. The specificity of Geenius, NLB 1 and NLB 2 was 98.5%, 81.5% and 90.0%, respectively. Geenius is an attractive alternative to WB for confirmation and differentiation of HIV-1 and HIV-2 infections. The adaptation of Geenius to the HIV testing algorithm may be advantageous for rapid diagnosis and the reduction of testing costs.
Autopsing history: Charlemagne's Mummy (c. 747 - 814 AD)
Authors: Schleifring Joachim H , Galassi Francesco M , Habicht Michael E , Rühli Frank
Published: May 2018

In this article a complete history of Charlemagne's mortal remains is given, including the publication for the first time of the report of the last opening of the tomb in 1988. Besides exclusive bioarchaeological aspects - highlighting that his body was indeed mummified - a full clinical interpretation of the Emperor's final illnesses and death is given: a likely combination of osteoarthritis, gout and a recurrent fever - causing infectious disease.
TMEM135 is an LXR-inducible regulator of peroxisomal metabolism
Authors: Renquist Benjamin J. , Madanayake Thushara W. , Hennebold Jon D. , Ghimire Susma , Geisler Caroline E. , Xu Yafei , Bogan Randy L.
Published: May 2018

The liver x receptors (LXRs) are key regulators of systemic lipid metabolism. We determined whether transmembrane protein 135 (TMEM135) is an LXR target gene and its physiologic function. An LXR agonist increased TMEM135 mRNA and protein in human hepatocyte and macrophage cell lines, which was prevented by LXR knockdown. The humanTMEM135promoter contains an LXR response element that bound the LXRs via EMSA and ChIP, and mediated LXR-induced transcription in reporter assays. Knockdown of TMEM135 in HepG2 cells caused triglyceride accumulation despite reduced lipogenic gene expression, indicating a potential role in β-oxidation. To determine physiologic importance, TMEM135 was knocked-down via siRNA in livers of fed and fasted C57BL/6 mice. Fasting increased hepatic fatty acid and NADH concentrations in control mice, consistent with increased fatty acid uptake and β-oxidation. However, in fasted TMEM135 knockdown mice, there was a further significant increase in hepatic fatty acid concentrations and a significant decrease in NADH, indicating an impairment in β-oxidation by peroxisomes and/or mitochondria. Conversely, hepatic ketones tended to increase in fasted TMEM135 knockdown compared to control mice, and because ketogenesis is exclusively dependent on mitochondrial β-oxidation, this indicates peroxisomal β-oxidation was impaired in knockdown mice. Localization studies demonstrated that TMEM135 co-localized with peroxisomes but not mitochondria. Mechanistically, proteomic and Western blot analyses indicated that TMEM135 regulates concentrations of matrix enzymes within peroxisomes. In conclusion,TMEM135is a novel LXR target gene in humans that mediates peroxisomal metabolism, and thus TMEM135 may be a therapeutic target for metabolic disorders associated with peroxisome dysfunction.
POT1a depletion in the developing brain leads to p53-dependent neuronal cell death and ataxia
Authors: She Robert , Clapp Charlie , Denchi Eros Lazzerini
Published: May 2018

The processes that control genome stability are essential for the development of the Central Nervous System (CNS) and the prevention of neurological disease. Here we investigated whether activation of a DNA damage response by dysfunctional telomeres affects neurogenesis. More specifically, we analyzed ATR-dependent DNA damage response by depletion of POT1a in neural progenitors. These experiments revealed that POT1a inactivation leads to a partially penetrant lethality, and surviving mice displayed ataxia due to loss of neuronal progenitor cells, and died by 3 weeks of age. Inactivation of p53 was sufficient to completely suppress the lethality associated with POT1a depletion and rescued the neuronal defects characterizing POT1a depleted animals. In contrast, activation of ATM by the depletion of the shelterin protein TRF2 resulted in a fully penetrant lethality that could not be rescued by p53 inactivation (Lobanova et al.). This data reveals that activation of distinct types of DNA damage response pathway give rise to different types of neuropathology. Moreover, our data provides an explanation for the heterogeneity of the neurological defects observed in patients affected by telomere biological disorders.
Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains
Authors: Zhao Ying-Tao , Kwon Deborah Y. , Johnson Brian S. , Fasolino Maria , Lamonica Janine M. , Kim Yoon Jung , Zhao Boxuan Simen , He Chuan , Vahedi Golnaz , Kim Tae Hoon , Zhou Zhaolan
Published: May 2018

Genetic variants associated with autism spectrum disorders (ASDs) are enriched in genes encoding synaptic proteins and chromatin regulators. Although the role of synaptic proteins in ASDs is widely studied, the mechanism by which chromatin regulators contribute to ASD risk remains poorly understood. Upon profiling and analyzing the transcriptional and epigenomic features of genes expressed in the cortex, we uncovered a unique set of long genes that contain broad enhancer-like chromatin domains (BELDs) spanning across their entire gene bodies. Analyses of these BELD genes show that they are highly transcribed with frequent RNA polymerase II (Pol II) initiation and low Pol II pausing, and they exhibit frequent chromatin–chromatin interactions within their gene bodies. These BELD features are conserved from rodents to humans, are enriched in genes involved in synaptic function, and appear post-natally concomitant with synapse development. Importantly, we find that BELD genes are highly implicated in neurodevelopmental disorders, particularly ASDs, and that their expression is preferentially down-regulated in individuals with idiopathic autism. Finally, we find that the transcription of BELD genes is particularly sensitive to alternations in ASD-associated chromatin regulators. These findings suggest that the epigenomic regulation of BELD genes is important for post-natal cortical development and lend support to a model by which mutations in chromatin regulators causally contribute to ASDs by preferentially impairing BELD gene transcription.