bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic profiling suggests two sources of organic matter shape microbial activity, but not community composition, in New Zealand fjords
Authors: Tobias-Hünefeldt Sven P. , Wing Stephen R. , Baltar Federico , Morales Sergio E.
Published: August 2019

Fjords are semi-enclosed marine systems with unique physical conditions that influence microbial communities structure. Pronounced organic matter and physical condition gradients within fjords provide a natural laboratory for the study of changes in microbial phylogeny and metabolic potential in response to environmental conditions (e.g. depth). In the open ocean new production from photosynthesis supplies organic matter to deeper aphotic layers, sustaining microbial activity. We measured the metabolic diversity and activity of microbial communities in fjords to determine patterns in metabolic potential across and within fjords, and whether these patterns could be explained by community composition modifications. We demonstrated that metabolic potential and activity are shaped by similar parameters as total (prokaryotic and eukaryotic) microbial communities. However, we identified increases in metabolic diversity and potential (but not in community composition) at near bottom (aphotic) sites consistent with the influence of sediments in deeper waters. Thus, while composition and function of the microbial community in the upper water column was likely shaped by marine snow and sinking POM generated by new production, deeper sites were strongly influenced by sediment resuspension of benthic organic matter generated from this or other sources (terrestrial, chemoautotrophic, microbial carbon loop), uncoupling the community composition and function dynamics.
Proliferative behavior of hematopoietic stem cells revisited: No evidence for mitotic memory
Authors: Morcos Mina N. F. , Zerjatke Thomas , Glauche Ingmar , Munz Clara M. , Ge Yan , Petzold Andreas , Reinhardt Susanne , Dahl Andreas , Anstee Natasha , Bogeska Ruzhica , Milsom Michael , Säwén Petter , Wan Haixia , Bryder David , Roers Axel , Gerbaulet Alexander
Published: August 2019

The proliferative activity of adult hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that the most primitive HSCs divide only four times, to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in primitive HSCs with high repopulation potential. We argue that this background had been misinterpreted as retention of induced label and permanent quiescence. We found cell division-independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support HSC mitotic memory and entry into permanent quiescence after few divisions, but show that primitive HSCs of adult mice continue to cycle rarely.
Host identity and symbiotic association affects the genetic and functional diversity of the clownfish-hosting sea anemone microbiome
Authors: Titus Benjamin M. , Laroche Robert , Rodríguez Estefanía , Wirshing Herman , Meyer Christopher P.
Published: August 2019

All eukaryotic life engages in symbioses with a diverse community of bacteria that are essential for performing basic life functions. In many cases, eukaryotic organisms form additional symbioses with other macroscopic eukaryotes. The tightly-linked physical interactions that characterize many macroscopic symbioses creates opportunities for microbial transfer, which likely affects the diversity and function of individual microbiomes, and may ultimately lead to microbiome convergence between distantly related taxa. Here, we sequence the microbiomes of five species of clownfish-hosting sea anemones that co-occur on coral reefs in the Maldives. We test the importance of evolutionary history, clownfish symbiont association, and habitat on the genetic and predicted functional diversity of the microbiome, and explore signals of microbiome convergence in anemone taxa that have evolved symbioses with clownfishes independently. Our data indicate that host identity shapes the majority of the genetic diversity of the clownfish-hosting sea anemone microbiome, but predicted functional microbial diversity analyses demonstrate a convergence among host anemone microbiomes, which reflect increased functional diversity over individuals that do not host clownfishes. Further, we identify up-regulated microbial functions in host anemones that are likely affected by clownfish presence. Taken together our study reveals an even deeper metabolic coupling between clownfishes and their host anemones, and what could be a previously unknown mutualistic benefit to anemones that are symbiotic with clownfishes.
Inference of Gene Regulatory Network Uncovers the Linkage Between Circadian Clock and Crassulacean Acid Metabolism in Kalanchoë fedtschenkoi
Authors: Moseley Robert C. , Motta Francis , Tuskan Gerald A. , Haase Steve , Yang Xiaohan
Published: August 2019

The circadian clock drives time-specific gene expression, allowing for associated biological processes to be active during certain times of the 24 h day. Crassulacean acid metabolism (CAM) photosynthetic plants represent an interesting case of circadian regulation of gene expression as CO2 fixation and stomatal movement in CAM plants display strong circadian dynamics. The molecular mechanisms behind how the circadian clock enabled these physiological differences is not well understood. Therefore, we set out to investigate whether core circadian elements in CAM plants were re-phased during evolution, or whether networks of phase-specific genes were simply connected to different core elements. We utilized a new metric for identifying candidate core genes of a periodic gene network and then applied the Local Edge Machine (LEM) algorithm to infer regulatory relationships between the candidate core clock genes and orthologs of known core clock genes in K. fedtschenkoi. We also used LEM to identify stomata-related gene targets for K. fedtschenkoi core clock genes and constructed a subsequent gene regulatory network. Our results provide new insights into the mechanism of circadian control of CAM-related genes in K. fedtschenkoi, facilitating the engineering of CAM machinery into non-CAM plants for sustainable crop production in water-limited environments.
Inhibition of Bruton’s tyrosine kinase reduces NF-kB and NLRP3 inflammasome activity preventing insulin resistance and microvascular disease
Authors: Purvis Gareth S. D. , Collino Massimo , Tavio Haidee M. A. , Chiazza Fausto , O’Riodan Caroline E. , Zeboudj Lynda , Guisot Nick , Bunyard Peter , Greaves David R. , Thiemermann Christoph
Published: August 2019

Activation of inflammatory pathways in myeloid cells initiates insulin resistance leading to the development of type-2 diabetes and microvascular disease. Currently, there are no therapies available that target inflammation in T2D or microvascular disease. In the present study we investigate if Bruton’s tyrosine kinase (BTK) may represent a novel therapeutic target using the FDA approved medication ibrutinib. Ibrutinib treatment protected high fat diet (HFD)-fed mice from developing insulin resistance and improved glycaemic control by restoring signalling through IRS-1/Akt/GSK-3β pathway. These improvements were independent of body weight and calorific intake. Treatment with ibrutinib to mice fed a HFD reduced NF-κB and reduced inflammatory gene expression, this was coupled with decreased activation of the NLRP3 inflammasome in the diabetic liver and kidney. Ibrutinib treatment also protected mice from the development of diabetic nephropathy by reducing monocyte/macrophage infiltration due to reduced expression of the pro-inflammatory chemokines. Ibrutinib treatment to human monocyte derived macrophages significantly reduced pro-inflammatory gene expression and a significant reduction in IL-1β and TNFα after LPS stimulation. In the present study we provide ‘proof of concept’ evidence that BTK is a novel therapeutic target for the treatment of T2D and ibrutinib may be a candidate for drug repurposing in T2D.
Electrophysiological correlates of the flexible allocation of visual working memory resources
Authors: Salahub Christine , Lockhart Holly A. , Dube Blaire , Al-Aidroos Naseem , Emrich Stephen M.
Published: August 2019

Visual working memory is a brief, capacity-limited store of visual information that is involved in a large number of cognitive functions. To guide one’s behavior effectively, one must efficiently allocate these limited memory resources across memory items. Previous research has suggested that items are either stored in memory or completely blocked from memory access. However, recent behavioral work proposes that memory resources can be flexibly split across items based on their level of task importance. Here, we investigated the electrophysiological correlates of flexible resource allocation by manipulating the distribution of resources amongst systematically lateralized memory items. We examined the contralateral delay activity (CDA), a waveform typically associated with the number of items held in memory. Across three experiments, we found that, in addition to memory load, the CDA flexibly tracks memory resource allocation. This allocation occurred as early as attentional selection, as indicated by the N2pc. Additionally, CDA amplitude was better-described when fit with a continuous model predicted by load and resources together than when fit with either alone. Our findings show that electrophysiological markers of attentional selection and memory maintenance not only track memory load, but also the proportion of memory resources those items receive.
Galanin inhibits visceral afferent responses to noxious mechanical and inflammatory stimuli
Authors: Taylor Toni S. , Konda Parvesh , John Sarah S. , Bulmer David C. , Hockley James R.F. , Smith Ewan St. John
Published: August 2019

Galanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. Galanin displays inhibitory effects on vagal afferent signalling within the upper GI tract, and the goal of this study was to determine the actions of galanin on colonic spinal afferent function. Specifically, we sought to evaluate the effect of galanin on lumbar splanchnic nerve (LSN) mechanosensitivity to noxious distending pressures and the development of hypersensitivity in the presence of inflammatory stimuli and colitis. Using ex vivo electrophysiological recordings we show that galanin produces a dose-dependent inhibition of colonic LSN responses to mechanical stimuli and prevents the development of hypersensitivity to acutely administered inflammatory mediators. Using galanin receptor (GalR) agonists, we show that GalR1 activation, but not GalR2/3 activation, inhibits mechanosensitivity. The inhibitory effect of galanin on colonic afferent activity was not observed in tissue from mice with dextran sodium sulphate-induced colitis. We conclude that galanin has a marked inhibitory effect on colonic mechanosensitivity at noxious distending pressures and prevents the acute development of mechanical hypersensitivity to inflammatory mediator, an effect not seen in the inflamed colon. These actions highlight a potential role for galanin in the regulation of mechanical nociception from the bowel and the therapeutic potential of targeting galaninergic signalling to treat visceral hypersensitivity.

Key point summary

Galanin inhibits visceral afferent mechanosensitivity to noxious phasic distension of the colon via GalR1.

Galanin attenuates afferent mechanical hypersensitivity induced by the application of inflammatory mediators.

Inhibition of afferent mechanosensitivity by galanin is not observed in tissues isolated from mice undergoing DSS-induced colitis

Galanin inhibits the transmission of noxious mechanical stimuli by colonic afferents and its sensitisation by inflammatory mediators highlighting an antinociceptive role for galanin in the colon.
The enteric nervous system of the human and mouse colon at a single-cell resolution
Authors: Drokhlyansky Eugene , Smillie Christopher S. , Van Wittenberghe Nicholas , Ericsson Maria , Griffin Gabriel K. , Dionne Danielle , Cuoco Michael S. , Goder-Reiser Max N. , Sharova Tatyana , Aguirre Andrew J. , Boland Genevieve M. , Graham Daniel , Rozenblatt-Rosen Orit , Xavier Ramnik J. , Regev Aviv
Published: August 2019

As the largest branch of the autonomic nervous system, the enteric nervous system (ENS) controls the entire gastrointestinal tract, but remains incompletely characterized. Here, we develop RAISIN RNA-seq, which enables the capture of intact single nuclei along with ribosome-bound mRNA, and use it to profile the adult mouse and human colon to generate a reference map of the ENS at a single-cell resolution. This map reveals an extraordinary diversity of neuron subsets across intestinal locations, ages, and circadian phases, with conserved transcriptional programs that are shared between human and mouse. These data suggest possible revisions to the current model of peristalsis and molecular mechanisms that may allow enteric neurons to orchestrate tissue homeostasis, including immune regulation and stem cell maintenance. Human enteric neurons specifically express risk genes for neuropathic, inflammatory, and extra-intestinal diseases with concomitant gut dysmotility. Our study therefore provides a roadmap to understanding the ENS in health and disease.
Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology
Authors: Naikawadi Ram P. , Green Gary , Jones Kirk D. , Achtar-Zadeh Natalia , Mieleszko Julia E. , Kukreja Jasleen , Greenland John , Wolters Paul J.
Published: August 2019

Rationale

Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD) which is a major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology.

Objective

Our objective was to test whether telomere dysfunction contributes to pathologic changes seen in CLAD.

Methods and Results

Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells (AECs), and increased expression of senescence markers (beta-galactosidase, p16, p53 and p21) in lung epithelial cells. Telomere repeat binding factor 1 flox/flox (TRF1F/F) mice were crossed with tamoxifen inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1 F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on micro-computed tomography, a 4-fold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II AEC numbers, expression of senescence-associated beta-galactosidase in epithelial cells and decreased SCGB1a1 expression in airway epithelial cells.

Conclusions

These findings demonstrate that telomere dysfunction isolated to club cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.
Disome-seq reveals widespread ribosome collisions that recruit co-translational chaperones
Authors: Zhao Taolan , Chen Yan-Ming , Li Yu , Wang Jia , Chen Siyu , Gao Ning , Qian Wenfeng
Published: August 2019

Regulation of translation elongation plays a crucial role in determining absolute protein levels and ensuring the correct localization and folding of proteins. Much of our knowledge regarding translation elongation comes from the sequencing of mRNA fragments protected by single ribosomes (ribo-seq). However, larger protected mRNA fragments have been observed, suggesting the existence of an alternative and previously hidden layer of regulation. In this study, we performed disome-seq to sequence mRNA fragments protected by two stacked ribosomes — a product of translational pauses during which the 5′-ribosome collides with the 3′-paused one. We detected widespread ribosome collisions that are missed in traditional ribo-seq. These collisions are due to 1) slow ribosome release when stop codons are at the A-site, 2) slow peptide bond formation from proline, glycine, asparagine, and cysteine when they are at the P-site, and 3) slow leaving of polylysine from the exit tunnel of ribosomes. The paused ribosomes can continue translating after collisions, as suggested by the structure of disomes obtained by cryo-electron microscopy (cryo-EM). Collided ribosomes recruit chaperones, which can aid in the co-translational folding of the nascent peptides. Therefore, cells use regulated ribosome collisions to ensure protein homeostasis.
Spatial Patterns for Discriminative Estimation
Authors: Llera Alberto , Chauvin Roselyne , Mulders Peter , Naaijen Jilly , Mennes Maarten , Beckmann Christian F.
Published: August 2019

Functional connectivity between brain regions is modulated by cognitive states or experimental conditions. A multivariate methodology that can capture fMRI connectivity maps in light of different experimental conditions would be of primary importance to learn about the specific roles of the different brain areas involved in the observed connectivity variations. Here we detail, adapt, optimize and evaluate a supervised dimensionality reduction model to fMRI timeseries. We demonstrate the strength of such an approach for fMRI data using data from the Human Connectome Project to show that the model provides close to perfect discrimination between different fMRI tasks at low dimensionality. The straightforward interpretability and relevance of the model results is demonstrated by the obtained linear filters relating to anatomical areas well known to be involved on each considered task, and its robustness by testing discriminatory generalization and spatial reproducibility with respect to the number of subjects and fMRI time-points acquired. We additionally suggest how such approach can provide a complementary view to traditional task fMRI analyses by looking at changes in the covariance structure as a substitute to changes in the mean signal. We conclude that the presented methodology provides a robust tool to investigate brain connectivity alterations across induced cognitive changes and has the potential to be used in pathological or pharmacological cohort studies. A publicly available toolbox is provided to facilitate the end use and further development of this methodology to extract Spatial Patterns for Discriminative Estimation (SP♠DE).
Genetic screens reveal a central role for heme biosynthesis in artemisinin susceptibility
Authors: Harding Clare R. , Sidik Saima M. , Petrova Boryana , Gnädig Nina F. , Okombo John , Ward Kurt E. , Markus Benedikt M. , Fidock David A. , Lourido Sebastian
Published: August 2019

Artemisinins have revolutionized the treatment ofPlasmodium falciparummalaria, however, resistance threatens to undermine global control efforts. To explore artemisinin resistance in apicomplexan parasites broadly, we used genome-scale CRISPR screens recently developed forToxoplasma gondiito discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncovered the putative porphyrin transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provided evidence that mitochondrial metabolism can modulate resistance. We show that disruption of a top candidate from the screens, the mitochondrial protease DegP2, lowered levels of free heme and decreased DHA susceptibility, without significantly altering fitness in culture. Deletion of the homologous gene inP. falciparum, PfDegP, similarly lowered heme levels and DHA susceptibility. These results expose the vulnerability of the heme biosynthetic pathway for genetic perturbations that can lead to survival in the presence of DHA. We go on to show that chemically reducing heme biosynthesis can decrease the sensitivity of bothT. gondiiandP. falciparumto DHA, suggesting guidelines for developing combination therapies.
Meiotic budding yeast assemble bundled triple helices but not ladders
Authors: Ma Olivia X. , Chong Wen Guan , Lee Joy K.E. , Cai Shujun , Siebert C. Alistair , Howe Andrew , Zhang Peijun , Shi Jian , Surana Uttam , Gan Lu
Published: August 2019

In meiosis, cells undergo two sequential rounds of cell division, termed meiosis I and meiosis II. Textbook models of the meiosis I substage called pachytene show that nuclei have conspicuous 100-nm-wide, ladder-like synaptonemal complexes (SC), which form between homologous chromosomes. It remains unknown if cells have any other large, meiosis-specific nuclear structures. Here we present cryo-ET analysis of frozen-hydrated budding yeast cells before, during, and after pachytene. We found no evidence for the dense ladder-like structures expected of the SC or the ordered chromatin loops expected to project from their sides. Instead, we found large quantities of 12-nm-wide triple-helices that pack into crystalline bundles. These structures are present in meiotic cells, but not in interphase cells, so we call them meiotic triple helices (MTHs). MTHs are enriched in the nucleus but not enriched in the cytoplasm. Bundles of MTHs form at the same time as SCs in wild-type cells and also in mutant cells that are unable to form SCs. These results suggest that in yeast, SCs are not crystalline and that they coexist with large, previously unreported meiotic machines.
NCOR1 and OCT4 Facilitate Early Reprogramming by Co-Suppressing Fibroblast Gene Expression
Authors: Peñalosa-Ruiz Georgina , Mulder Klaas W. , Veenstra Gert Jan C.
Published: August 2019

Reprogramming somatic cells to induced pluripotent stem cells (iPSC) succeeds only in a small fraction of cells within the population. Reprogramming occurs in distinctive stages, each facing its own bottlenecks. It initiates with overexpression of transcription factors OCT4, SOX2, KLF4 and c-MYC (OSKM) in somatic cells such as mouse embryonic fibroblasts (MEFs). OSKM bind chromatin, silencing the somatic identity and starting the stepwise reactivation of the pluripotency program. However, inefficient suppression of the somatic lineage leads to unwanted epigenetic memory from the tissue of origin, even in successfully generated iPSCs. Thus, it is essential to shed more light on chromatin regulators and processes involved in dissolving the somatic identity. Recent work characterized the role of transcriptional co-repressors NCOR1 and NCOR2 (also known as NCoR and SMRT), showing that they cooperate with c-MYC to silence pluripotency genes during late reprogramming stages. NCOR1/NCOR2 were also proposed to be involved in silencing fibroblast identity, however it is unclear how this happens. Here, we shed light on the role of NCOR1 in early reprogramming. We show that siRNA-mediated ablation of NCOR1 and OCT4 results in very similar phenotypes, including transcriptomic changes and highly correlated high content colony phenotypes.. Both NCOR1 and OCT4 bind to promoters co-occupied by c-MYC in MEFs. During early reprogramming, downregulation of one group of somatic MEF-expressed genes requires both NCOR1 and OCT4, whereas another group of MEF-expressed genes is downregulated by NCOR1 but not OCT4. Our data suggest that NCOR1, assisted by OCT4 and c-MYC, facilitates transcriptional inactivation of genes with high expression in MEFs, which need to be suppressed to bypass an early reprogramming block. This way, NCOR1 facilitates early reprogramming progression.
Biphasic Response of Protein Kinase A to Cyclic Adenosine Monophosphate Triggers Distinct Epithelial Phenotypes
Authors: Fonseca João Pedro , Weinberg Zara Y. , Aslankoohi Elham , El-Samad Hana
Published: August 2019

Despite the large diversity of the proteins involved in cellular signaling, many intracellular signaling pathways converge onto one of only dozens of small molecule second messengers. Cyclic adenosine monophosphate (cAMP), one of these second messengers, is known to regulate activity of both Protein Kinase A (PKA) and the Extracellular Regulated Kinase (ERK), among other signaling pathways. In its role as an important cellular signaling hub, intracellular cAMP concentration has long been assumed to monotonically regulate its known effectors.

Using an optogenetictool that can introduce precise amounts of cAMP in MDCKI cells, we identify genes whose expression changes biphasically with monotonically increasing cAMP levels. By examining the behavior of PKA and ERK1/2 in the same dose regime, we find that these kinases also respond biphasically to increasing cAMP levels, with opposite phases. We reveal that this behavior results from an elaborate integration by PKA of many cellular signals triggered by cAMP. In addition to the direct activation of PKA, cAMP also modulates the activity of p38 and ERK, which then converge to inhibit PKA. These interactions and their ensuing biphasic PKA profile have important physiological repercussions, influencing the ability of MDCKI cells to proliferate and form acini. Our data, supported by computational modeling, synthesize a set of network interconnections involving PKA and other important signaling pathways into a model that demonstrates how cells can capitalize on signal integration to create a diverse set of responses to cAMP concentration and produce complex input-output relationships.
Optimization of AsCas12a for combinatorial genetic screens in human cells
Authors: Sanson Kendall R , DeWeirdt Peter C , Sangree Annabel K , Hanna Ruth E , Hegde Mudra , Teng Teng , Borys Samantha M , Strand Christine , Joung J Keith , Kleinstiver Benjamin P , Pan Xuewen , Huang Alan , Doench John G
Published: August 2019

Cas12a enzymes have attractive properties for scalable delivery of multiplexed perturbations, yet widespread usage has lagged behind Cas9-based strategies. Here we describe the optimization of Cas12a from Acidaminococcus (AsCas12a) for use in pooled genetic screens in human cells. By assaying the activity of thousands of guides, we confirm on-target design rules and extend them to an enhanced activity variant, enAsCas12a. We also develop the first comprehensive set of off-target rules for Cas12a, and demonstrate that we can predict and exclude promiscuous guides. Finally, to enable efficient higher-order multiplexing via lentiviral delivery, we screen thousands of direct repeat variants and identify 38 that outperform the wildtype sequence. We validate this optimized AsCas12a toolkit by targeting 12 synthetic lethal gene pairs with up to 400 guide pairs each, and demonstrate effective triple knockout via flow cytometry. These results establish AsCas12a as a robust system for combinatorial applications of CRISPR technology.
Visual working memory representations in visual and parietal cortex do not remap after eye movements
Authors: He Tao , Ekman Matthias , Vandenbroucke Annelinde R.E. , de Lange Floris P.
Published: August 2019

It has been suggested that our visual system does not only process stimuli that are directly available to our eyes, but also has a role in maintaining information in VWM over a period of seconds. It remains unclear however what happens to VWM representations in the visual system when we make saccades. Here, we tested the hypothesis that VWM representations are remapped within the visual system after making saccades. We directly compared the content of VWM for saccade and no-saccade conditions using MVPA of delay-related activity measured with fMRI. We found that when participants did not make a saccade, VWM representations were robustly present in contralateral early visual cortex. When making a saccade, VWM representations degraded in contralateral V1-V3 after the saccade shifted the location of the remembered grating to the opposite visual field. However, contrary to our hypothesis we found no evidence for the representations of the remembered grating at the saccadic target location in the opposite visual field, suggesting that there is no evidence for remapping of VWM in early visual cortex. Interestingly, IPS showed persistent VWM representations in both the saccade and no-saccade condition. Together, our results indicate that VWM representations in early visual cortex are not remapped across eye movements, potentially limiting the role of early visual cortex in VWM storage.

Highlights

Visual working memory (VWM) representations do not remap after making saccades

Eye movement degrade VWM representations in early visual cortex, limiting the role of early visual cortex in VWM storage

Parietal cortex shows persistent VWM representations across saccades
A study of parietal-motor connectivity by intraoperative dual cortical stimulation
Authors: Cattaneo Luigi , Giampiccolo Davide , Meneghelli Pietro , Tramontano Vincenzo , Sala Francesco
Published: August 2019

the function of the primate’s posterior parietal cortex in sensorimotor transformations is well-established, though in humans its complexity is still challenging. Well-established models indicate that the posterior parietal cortex influences motor output indirectly, by means of connections to the premotor cortex, which in turn is directly connected to the motor cortex. The possibility that the posterior parietal cortex could be at the origin of direct afferents to M1 has been suggested in humans but has never been confirmed directly. In the present work we assessed during intraoperative monitoring of the corticospinal tract in brain tumour patients the existence of short-latency effects of parietal stimulation on corticospinal excitability to the upper limb. We identified several foci within the inferior parietal lobule that drove short-latency influences on cortical motor output. Active foci were distributed along the postcentral gyrus and clustered around the anterior intraparietal area and around the parietal operculum. For the first time in humans, the present data show direct evidence in favour of a distributed system of connections from the posterior parietal cortex to the ipsilateral primary motor cortex.
Why are children so distractible? Development of attention and motor control from childhood to adulthood
Authors: Hoyer R. S. , Elshafei H. , Hemmerlin J. , Bouet R. , Bidet-Caulet A.
Published: August 2019

Distractibility is the propensity to behaviorally react to irrelevant information. Though children are more distractible the younger they are, the precise contribution of attentional and motor components to distractibility and their developmental trajectories have not been characterized yet. We used a new behavioral paradigm to identify the developmental dynamics of components contributing to distractibility in a large cohort of French participants balanced, between age groups, in gender and socio-economic status (N=352; age: 6-25). Results reveal that each measure of these components, namely voluntary attention, distraction, impulsivity and motor control, present a distinct maturational timeline. In young children, increased distractibility is mostly the result of reduced sustained attention capacities and enhanced distraction, while in teenagers, it is the result of decreased motor control and increased impulsivity.
Photo sensing and quorum sensing are integrated to control bacterial group behaviors
Authors: Mukherjee Sampriti , Jemielita Matthew , Stergioula Vasiliki , Tikhonov Mikhail , Bassler Bonnie L.
Published: August 2019

Pseudomonas aeruginosatransitions between the free-swimming state and the sessile biofilm mode during its pathogenic lifestyle. We show that quorum sensing repressesP. aeruginosabiofilm formation and virulence by activating expression of genes encoding the KinB-AlgB two-component system. Phospho-AlgB represses biofilm and virulence genes, while KinB dephosphorylates, and thereby, inactivates AlgB. We discover that the photoreceptor BphP is the kinase that, in response to light, phosphorylates and activates AlgB. Indeed, exposingP. aeruginosato light represses biofilm formation and virulence gene expression. To our knowledge,P. aeruginosawas not previously known to detect light. The KinB-AlgB-BphP module is present in all Pseudomonads, and we demonstrate that AlgB is the cognate response regulator for BphP in diverse bacterial phyla. We propose that KinB-AlgB-BphP constitutes a “three-component” system and AlgB is the node at which varied sensory information is integrated. This study sets the stage for light-mediated control ofP. aeruginosainfectivity.
Convergence of DNA methylation profiles in a novel environment in the reef coral Porites astreoides
Authors: Dimond James L. , Roberts Steven B.
Published: August 2019

Phenotypic acclimatization is an organismal response to environmental change that may be rooted in epigenetic mechanisms. In reef building corals, organisms that are severely threatened by environmental change, some evidence suggests that DNA methylation is an environmentally responsive mediator of acclimatization. We investigated changes in DNA methylation of the reef coral Porites astreoides in response to simulated environmental change. Coral colonies were sampled from a variety of habitats on the Belize Barrier Reef and transplanted to a common garden for one year. We used restriction site associated DNA sequencing, including a methylation-sensitive variant, to subsample the genome and assess changes in DNA methylation levels after a year in the common garden. Methylation changes among the 629 CpG loci we recovered were subtle, yet coral methylomes were more similar to each other after a year in the common garden together, indicating convergence of methylation profiles in the common environment. Differentially methylated loci showed matches with both coding and non-coding RNA sequences with putative roles in intracellular signaling, apoptosis, gene regulation, and epigenetic crosstalk. There was a weak but positive and significant relationship between genetic and epigenetic variation, providing evidence of methylation heritability. Altogether, our results suggest that DNA methylation in P. astreoides is at least somewhat responsive to environmental change, reflective of the environment, and heritable, characteristics necessary for methylation to be implicated as part of potential transgenerational acclimatization responses.
Regulation of defeat-induced social avoidance by medial amygdala DRD1 in male and female prairie voles
Authors: Tickerhoof Maria C. , Hale Luanne H. , Smith Adam S.
Published: August 2019

Social interaction with unfamiliar individuals is necessary for species-preserving behaviors such as finding mates and establishing social groups. However, social conflict is a potential negative outcome to interaction with a stranger that can be distressing enough to cause an individual to later avoid interactions with other unfamiliar conspecifics. Unfortunately, stress research using a prominent model of social conflict, social defeat stress, has largely omitted female subjects. This has left a void in the literature regarding social strain on female stress biology and adequate comparison of the effect of sex in stress pathways. The prairie vole (Microtus ochrogaster) exhibits aggressive behavior in both sexes, making voles an attractive candidate to model social defeat in both sexes. This study sought to establish a model of social defeat stress in both male and female prairie voles, characterize behavioral changes in response to this stressor, and investigate the role of dopamine signaling in the response to social defeat stress. Defeated male and female prairie voles displayed social avoidance as well as an increase in expression of dopamine receptor D1 (DRD1) in the medial amygdala (MeA). Pharmacological manipulation of DRD1 signaling in the MeA revealed that increased DRD1 signaling is sufficient to induce a social avoidant state, and could be a necessary component in the defeat-induced social avoidance response. These findings provide the prairie vole as a model of social defeat in both sexes, and implicate the MeA in avoidance of unfamiliar conspecifics after a distressing social encounter.
Structure of LetB reveals a tunnel for lipid transport across the bacterial envelope
Authors: Isom Georgia L. , Coudray Nicolas , MacRae Mark R. , McManus Collin T. , Ekiert Damian C. , Bhabha Gira
Published: August 2019

Gram-negative bacteria are surrounded by an outer membrane composed of phospholipids and lipopolysaccharide (LPS), which acts as a barrier to the environment and contributes to antibiotic resistance. While mechanisms of LPS transport have been well characterised, systems that translocate phospholipids across the periplasm, such as MCE (Mammalian Cell Entry) transport systems, are less well understood. Here we show that E. coli MCE protein LetB (formerly YebT), forms a ∼0.6 megadalton complex in the periplasm. Our cryo-EM structure reveals that LetB consists of a stack of seven modular rings, creating a long hydrophobic tunnel through the centre of the complex. LetB is sufficiently large to span the gap between the inner and outer membranes, and mutations that shorten the tunnel abolish function. Lipids bind inside the tunnel, suggesting that it functions as a pathway for lipid transport. Cryo-EM structures in the open and closed states reveal a dynamic tunnel lining, with implications for gating or substrate translocation. Together, our results support a model in which LetB establishes a physical link between the bacterial inner and outer membranes, and creates a hydrophobic pathway for the translocation of lipids across the periplasm, to maintain the integrity of the outer membrane permeability barrier.
Mitigating memory effects during undulatory locomotion on hysteretic materials
Authors: Schiebel Perrin E. , Astley Henry C. , Rieser Jennifer M. , Agarwal Shashank , Hubicki Christian , Hubbard Alex M. , Cruz Kelimar , Mendelson Joseph , Kamrin Ken , Goldman Daniel I.
Published: August 2019

Undulatory swimming in flowing media like water is well-studied, but little is known about loco-motion in environments that are permanently deformed by body–substrate interactions like snakes in sand, eels in mud, and nematode worms in rotting fruit. We study the desert-specialist snakeChion-actis occipitalistraversing granular matter and find body inertia is negligible despite rapid transit and speed dependent granular reaction forces. New surface resistive force theory (RFT) calculation reveals how this snakes wave shape minimizes memory effects and optimizes escape performance given physiological limitations (power). RFT explains the morphology and waveform dependent performance of a diversity of non-sand-specialist, but overpredicts the capability of snakes with high slip. Robophysical experiments recapitulate aspects of these failure-prone snakes and elucidate how reencountering previously remodeled material hinders performance. This study reveals how memory effects stymied the locomotion of a diversity of snakes in our previous studies [Marvi et al, Science, 2014] and suggests the existence of a predictive model for history-dependent granular physics.
Modeling the assessment of the upper limb motor function impairment in children with cerebral palsy using sEMG and IMU sensors
Authors: Raouafi S. , Raison M. , Sofiane A.
Published: August 2019

Several rehabilitation approaches have shown that robot-assisted therapy (robot-AT) can improve the quality of upper limb movements in children with cerebral palsy (CP). However, there is still no method for assessing upper limb motor function impairment using a combination of surface electromyography (sEMG) and inertial measurement unit (IMU) sensors. The aim of this study was to develop a functional ability model to assess the effectiveness of robot-AT on improving upper limb function in children with CP. Fifteen healthy children and fifteen children with CP were included in this study. Children with CP performed eighteen robot-AT sessions and were evaluated twice, using EMG and three-axis IMU readings from accelerometer (IMU-ACC). Principal component analysis and the RELIEFF algorithm were used for dimensionality reduction of the feature space. The classification was performed by using support vector machines, linear discriminant analysis, and random forest. The proposed assessment method was evaluated by using leave-one-out cross validation. With this approach, it was possible to differentiate between healthy children and children with CP pre-robot-AT and post-robot-AT with an overall accuracy of 97.56%. This study suggests that there is potential for modeling the assessment of the upper limb motor function impairment in children with CP using sEMG and IMU-ACC sensors.
Local design principles at hippocampal synapses revealed by an energy-information trade-off
Authors: Mahajan Gaurang , Nadkarni Suhita
Published: August 2019

Synapses across different brain regions display distinct structure-function relationships. We investigate the interplay of fundamental design principles that shape the transmission properties of the excitatory CA3-CA1 pyramidal cell connection, a prototypic synapse for studying the mechanisms of learning in the hippocampus. This small synapse is characterized by probabilistic release of transmitter, which is markedly facilitated in response to naturally occurring trains of action potentials. Based on a physiologically realistic computational model of the CA3 presynaptic terminal, we show how unreliability and short-term dynamics of vesicle release work together to regulate the trade-off of information transfer versus energy use. We propose that individual CA3-CA1 synapses are designed to operate at close to maximum possible capacity of information transfer in an efficient manner. Experimental measurements reveal a wide range of vesicle release probabilities at hippocampal synapses, which may be a necessary consequence of long-term plasticity and homeostatic mechanisms that manifest as presynaptic modifications of release probability. We show that the timescales and magnitude of short-term plasticity render synaptic information transfer nearly independent of differences in release probability. Thus, individual synapses transmit optimally while maintaining a heterogeneous distribution of presynaptic strengths indicative of synaptically-encoded memory representations. Our results support the view that organizing principles that are evident on higher scales of neural organization percolate down to the design of an individual synapse.
γ–Secretase controls the specification of astrocytes from oligodendrocyte precursor cells via Stat3
Authors: Hou Jinxing , Bi Huiru , Zou Gang , Ye Zhuoyang , Zhao Jing , Hu Yimin , Lu Jun , Chen Guiquan
Published: August 2019

Oligodendrocytes (OLs) and astrocytes play critical roles in a variety of brain functions. OL precursor cells (OPCs) are known to give rise to OLs as well as astrocytes. However, little is known about the mechanism by which OPCs determine their specification choice for OLs versus astrocytes in the central nervous system (CNS). Here we show that genetic inhibition of γ-secretase in OPCs reduces OL differentiation but enhances astrocyte specification. Mechanistic analysis reveals that inhibition of γ-secretase results in decreased levels of Hes1, and that Hes1 down-regulates the expression of signal transducer and activator of transcription3 (Stat3) via binding to specific regions of its promoter. We demonstrate that conditional inactivation of Stat3 in OL lineages restores the number of astrocytes in γ-secretase mutant mice. In summary, this study identifies a key mechanism which controls OPC’s specification choice for OL versus astrocyte during postnatal development. This γ-secretase-dependent machinery may be essential for the CNS to maintain the population balance between OLs and astrocytes.
The CDK Pef1 and Protein Phosphatase 4 oppose each other for regulating cohesin binding to fission yeast chromosomes
Authors: Birot Adrien , Tormos-Pérez Marta , Vaur Sabine , Feytout Amélie , Jaegy Julien , Gil Dácil Alonso , Vazquez Stéphanie , Ekwall Karl , Javerzat Jean-Paul
Published: August 2019

Cohesin has essential roles in chromosome structure, segregation and repair. Cohesin binding to chromosomes is catalyzed by the cohesin loader, Mis4 in fission yeast. How cells fine tune cohesin deposition is largely unknown. Here we provide evidence that Mis4 activity is regulated by phosphorylation of its cohesin substrate. A genetic screen for negative regulators of Mis4 yielded a CDK called Pef1, whose closest human homologue is CDK5. Inhibition of Pef1 kinase activity rescued cohesin loader deficiencies. In an otherwise wild-type background, Pef1 ablation stimulated cohesin binding to its regular sites along chromosomes while ablating Protein Phosphatase 4 had the opposite effect. Pef1 and PP4 control the phosphorylation state of the cohesin kleisin Rad21. The CDK phosphorylates Rad21 on Threonine 262. Pef1 ablation, non phosphorylatable Rad21-T262 or mutations within a Rad21 binding domain of Mis4 alleviated the effect of PP4 deficiency. Such a CDK/PP4 based regulation of cohesin loader activity could provide an efficient mechanism for translating cellular cues into a fast and accurate cohesin response.
RUNX1-ETO induction rapidly alters chromatin landscape and growth of a specific sub-population of hESC-derived myeloid precursor cells by interfering with RUNX1 regulation
Authors: Nafria Monica , Keane Peter , Ng Elizabeth S. , Stanley Edouard G. , Elefanty Andrew G. , Bonifer Constanze
Published: August 2019

Acute myeloid leukemia is a hematopoietic malignancy caused by recurrent mutations in genes encoding transcriptional, epigenetic and/or signaling regulators. The t(8;21) translocation generates the aberrant transcription factor RUNX1-ETO whose expression can be detectedin uterobut is insufficient to cause overt disease. Although patients harboring cells with the t(8;21) translocation have acquired additional mutations and show extensive epigenetic reprogramming, the effects directly attributable to RUNX1-ETO expression are unclear. To address this question, we used a human embryonic stem cell differentiation system capable of forming definitive human myeloid progenitor cells to express RUNX1-ETO in an inducible fashion. Induction of RUNX1-ETO causes extensive chromatin reprogramming by interfering with RUNX1 binding, blocks differentiation and arrests cellular growth, whereby growth arrest is reversible following RUNX1-ETO removal. Single cell gene expression analyses show that RUNX1-ETO induction alters the differentiation of a defined sub-population of progenitors, indicating that oncoprotein-mediated transcriptional reprogramming is highly target cell specific.