bluuebunny/crossref_metadata_2025 huggingface dataset:
Propofol Anesthesia Concentration Rather Than Abrupt Behavioral Unresponsiveness Linearly Degrades Responses in the Rat Primary Auditory Cortex
Authors: Bergman Lottem , Krom Aaron J , Sela Yaniv , Marmelshtein Amit , Hayat Hanna , Regev Noa , Nir Yuval
Published: October 2020

Despite extensive knowledge of its molecular and cellular effects, how anesthesia affects sensory processing remains poorly understood. In particular, it remains unclear whether anesthesia modestly or robustly degrades activity in primary sensory regions, and whether such changes are linked to anesthesia drug concentration vs. behavioral unresponsiveness, since these are typically confounded. Here, we employed slow gradual intravenous propofol anesthesia induction together with auditory stimulation and intermittent assessment of behavioral responsiveness while recording epidural EEG, and neuronal spiking activity in the primary auditory cortex (PAC) of eight rats. We found that all main components of neuronal activity including spontaneous firing rates, onset response magnitudes, onset response latencies, post-onset neuronal silence duration, and late-locking to 40Hz click-trains, gradually deteriorated in a dose- dependent manner with increasing anesthesia levels without showing abrupt changes around loss of righting reflex or other time-points. Thus, the dominant factor affecting PAC responses is the anesthesia drug concentration rather than any sudden, dichotomous behavioral state changes. Our findings explain a wide array of seemingly conflicting results in the literature that, depending on the precise definition of wakefulness (vigilant vs. drowsy) and anesthesia (light vs. deep/surgical), report a spectrum of effects in primary regions ranging from minimal to dramatic differences.
Waffle Method: A general and flexible approach for improving throughput in FIB-milling
Authors: Kelley Kotaro , Raczkowski Ashleigh M. , Klykov Oleg , Jaroenlak Pattana , Bobe Daija , Kopylov Mykhailo , Eng Edward T. , Bhabha Gira , Potter Clinton S. , Carragher Bridget , Noble Alex J.
Published: October 2020

Cryo-FIB/SEM combined with cryo-ET has emerged from within the field of cryo-EM as the method for obtaining the highest resolution structural information of complex biological samplesin-situin native and non-native environments. However, challenges remain in conventional cryo-FIB/SEM workflows, including milling thick specimens that do not vitrify well, specimens with preferred orientation, low-throughput when milling small and/or low concentration specimens, and cellular specimens that distribute poorly across grid squares. Here we present a general approach we call the ‘Waffle Method’ which leverages high-pressure freezing to address these challenges. We illustrate the mitigation of these challenges by applying the Waffle Method and cryo-ET to reveal the macrostructure of the polar tube in microsporidian spores in multiple complementary orientations, which was previously not possible due to preferred orientation of the spores on the grid. We demonstrate the broadness of the Waffle Method by applying it to three additional cellular samples and a single particle sample using a variety of cryo-FIB-milling hardware, with both manual and automated approaches. We also present a unique and critical stress-relief gap designed specifically for waffled lamellae. Additionally, we describe applications of the Waffle Method which are currently being explored. We propose the Waffle Method as a way to achieve many of the advantages of cryo-liftout on the specimen grid while avoiding the long, challenging, and technically-demanding process required for cryo-liftout.
IFN-λ4 may contribute to HCV persistence by increasing ER stress and enhancing IRF1 signaling
Authors: Onabajo Olusegun O. , Wang Fang , Lee Mei-Hsuan , Florez-Vargas Oscar , Obajemu Adeola , Castro Mauro A. A. , Tanikawa Chizu , Vargas Joselin , Liao Shu-Fen , Song Ci , Huang Yu-Han , Shen Chen-Yang , Banday A. Rouf , O’Brien Thomas R. , Hu Zhibin , Matsuda Koichi , Robertson A. Gordon , Prokunina-Olsson Ludmila
Published: October 2020

Chronic hepatitis C virus (HCV) infection and cirrhosis are major risk factors for developing hepatocellular carcinoma (HCC). Genetic polymorphisms in theIFNL3/IFNL4locus have been associated both with impaired clearance of HCV and protection from liver fibrosis, an early stage of cirrhosis. Here, we aimed to address the genetic and functional relationships betweenIFNL3/IFNL4polymorphisms, HCV-related cirrhosis, and HCC risk. We evaluated associations betweenIFNL4genotype, defined as the presence of rs368234815-dG or rs12979860-T alleles, with cirrhosis and HCC risk in patients with chronic HCV - 2,931 from Taiwan and 3,566 from Japan. We detected associations betweenIFNL4genotype and decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwan), but increased risk of HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058, in Japan).In-vitro, IFN-λ4 expression increased ER stress, and enhanced positive regulation of IFN responses via IRF1 induction, which mediated antiproliferative effects in hepatic cells. Our data present novel IFN-λ4-associated pathways that may be contributing to HCV persistence and development of HCC.
Live-dead assay on unlabeled cells using phase imaging with computational specificity
Authors: Hu Chenfei , He Shenghua , Lee Young Jae , He Yuchen , Kong Edward M. , Li Hua , Anastasio Mark A. , Popescu Gabriel
Published: October 2020

Existing approaches to evaluate cell viability involve cell staining with chemical reagents. However, this step of exogenous staining makes these methods undesirable for rapid, nondestructive and long-term investigation. Here, we present instantaneous viability assessment ofunlabeledcells using phase imaging with computation specificity (PICS). This new concept utilizes deep learning techniques to compute viability markers associated with the specimen measured by label-free quantitative phase imaging. Demonstrated on different live cell cultures, the proposed method reports approximately 95% accuracy in identifying live and dead cells. The evolution of the cell dry mass and projected area for the labelled and unlabeled populations reveal that the viability reagents decrease viability. The nondestructive approach presented here may find a broad range of applications, from monitoring the production of biopharmaceuticals, to assessing the effectiveness of cancer treatments.
A novel family of secreted insect proteins linked to plant gall development
Authors: Korgaonkar Aishwarya , Han Clair , Lemire Andrew L. , Siwanowicz Igor , Bennouna Djawed , Kopec Rachel , Andolfatto Peter , Shigenobu Shuji , Stern David L.
Published: October 2020

In an elaborate form of inter-species exploitation, many insects hijack plant development to induce novel plant organs called galls that provide the insect with a source of nutrition and a temporary home. Galls result from dramatic reprogramming of plant cell biology driven by insect molecules, but the roles of specific insect molecules in gall development have not yet been determined. Here we study the aphidHormaphis cornu, which makes distinctive “cone” galls on leaves of witch hazelHamamelis virginiana. We found that derived genetic variants in the aphid genedeterminant of gall color(dgc) are associated with strong downregulation ofdgctranscription in aphid salivary glands, upregulation in galls of seven genes involved in anthocyanin synthesis, and deposition of two red anthocyanins in galls. We hypothesize that aphids inject DGC protein into galls, and that this results in differential expression of a small number of plant genes.Dgcis a member of a large, diverse family of novel predicted secreted proteins characterized by a pair of widely spaced cysteine-tyrosine-cysteine (CYC) residues, which we named BICYCLE proteins.Bicyclegenes are most strongly expressed in the salivary glands specifically of galling aphid generations, suggesting that they may regulate many aspects of gall development.Bicyclegenes have experienced unusually frequent diversifying selection, consistent with their potential role controlling gall development in a molecular arms race between aphids and their host plants.

One Sentence Summary

Aphidbicyclegenes, which encode diverse secreted proteins, contribute to plant gall development.
Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents
Authors: Ramirez David G. , Upadhyay Awaneesh K. , Pham Vinh T. , Ciccaglione Mark , Borden Mark A , Benninger Richard K.P.
Published: October 2020

Type 1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing β-cells within the pancreatic islets of Langerhans (insulitis), resulting in loss of glucose homeostasis. Early diagnosis during pre-symptomatic T1D would allow for therapeutic intervention prior to substantial loss of β-cell mass at T1D onset. There are limited methods to track the progression of insulitis and β-cell mass decline in pre-symptomatic T1D. During insulitis, the islet microvasculature increases permeability, such that sub-micron sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Sub-micron sized nanodroplet (ND) phasechange agents can be vaporized into micron-sized bubbles; serving as a circulating microbubble precursor. We tested if NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in NOD mice and NOD;Rag1ko controls, and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10w NOD mice following ND infusion and vaporization, but was absent in both the non-infiltrated kidney of NOD mice and pancreas of Rag1ko controls. High contrast elevation also correlated with rapid diabetes onset. In pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression to guide and assess preventative therapeutic interventions for T1D.

Significance

There is a need for imaging methods to detect type1 diabetes (T1D) progression prior to clinical diagnosis. T1D is a chronic disease that results from autoreactive T cells infiltrating the islet of Langerhans and destroying insulin-producing β-cells. Overt disease takes years to present and is only diagnosed after significant β-cells loss. As such, the possibility of therapeutic intervention to preserve β-cell mass is hampered by an inability to follow pre-symptomatic T1D progression. There are immunotherapies that can delay T1D development. However identifying ‘at risk’ individuals, and tracking whether therapeutic interventions are impacting disease progression, prior to T1D onset, is lacking. A method to detect insulitis and β-cell mass decline would present an opportunity to guide therapeutic treatments to prevent T1D.
ViMIC: A Database of Human Disease-related Virus Mutations, Integration Sites and Cis-effects
Authors: Wang Ying , Tong Yuantao , Zhang Zeyu , Zheng Rongbin , Huang Danqi , Yang Jinxuan , Zong Hui , Tan Fanglin , Zhang Xiaoyan
Published: October 2020

Molecular mechanisms of virus-related diseases involve multiple factors, including viral mutation accumulation and integration of a viral genome into the host DNA. With increasing attention being paid to virus-mediated pathogenesis and the development of many useful technologies to identify virus mutations (VMs) and viral integration sites (VISs), abundant literatures on these topics are available in PubMed. However, knowledge of VMs and VISs is widely scattered in numerous published papers, and the association of VMs with VISs in the viral genome or the functional annotation of VISs still lacks integration and curation. To address these challenges, we built a database of human disease-related Virus Mutations, Integration sites and Cis-effects (ViMIC), which specialize in three features: virus mutation sites, viral integration sites and target genes. In total, the ViMIC provides information on 6,461 VMs, 79,089 VISs, and 15,056 viral target genes of 8 viruses in 65 human diseases obtained from literatures. Furthermore, in ViMIC, users are allowed to explore the cis-effects of virus-host interactions by surveying 78 histone modifications, binding of 1,358 transcription regulators, and chromatin accessibility on these VISs. We believe ViMIC will become a valuable resource for the virus research community. The database is available at http://bmtongji.cn/ViMIC/index.php.
HEXOKINASE1 interferes with cytokinin synthesis and strigolactone perception during sugar-induced shoot branching
Authors: Barbier Francois F. , Cao Da , Fichtner Franziska , Weiste Christoph , Perez-Garcia Maria-Dolores , Caradeuc Mathieu , Le gourrierec José , Sakr Soulaiman , Beveridge Christine A.
Published: October 2020

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Plant architecture is controlled by several endogenous signals including hormones and sugars. However, only little is known about the nature and roles of the sugar signalling pathways in this process. Here we test whether the sugar pathway mediated by HEXOKINASE1 (HXK1) is involved in the control of shoot branching.

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To test the involvement of HXK1 in the control of shoot architecture we modulated the HXK1 pathway using physiological and genetic approaches in diverse plants, rose, arabidopsis and pea and evaluated impacts of hormonal pathways.

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We show that triggering a hexokinase-dependent pathway was able to promote bud outgrowth in pea and rose. In arabidopsis, both HXK1 deficiency and defoliation led to decreased shoot branching and conferred hypersensitivity to auxin.HXK1expression was positively correlated with sugar availability. HXK1-deficient plants displayed decreased cytokinin levels and increased expression ofMAX2which is required for strigolactone signalling. The branching phenotype of HXK1-deficient plants could be partly restored by cytokinin treatment and strigolactone deficiency could override the negative impact ofHXK1deficiency on shoot branching.

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Our observations demonstrate that a HXK1-dependent pathway contributes to the regulation of shoot branching and interact with hormones to modulate plant architecture.
Dynamical consequences of regional heterogeneity in the brain’s transcriptional landscape
Authors: Deco Gustavo , Aquino Kevin , Arnatkevičiūtė Aurina , Oldham Stuart , Sabaroedin Kristina , Rogasch Nigel C. , Kringelbach Morten L. , Fornito Alex
Published: October 2020

Brain regions vary in their molecular and cellular composition, but how this heterogeneity shapes neuronal dynamics is unclear. Here, we investigate the dynamical consequences of regional heterogeneity using a biophysical model of whole-brain functional magnetic resonance imaging (MRI) dynamics in humans. We show that models in which transcriptional variations in excitatory and inhibitory receptor (E:I) gene expression constrain regional heterogeneity more accurately reproduce the spatiotemporal structure of empirical functional connectivity estimates than do models constrained by global gene expression profiles and MRI-derived estimates of myeloarchitecture. We further show that regional heterogeneity is essential for yielding both ignition-like dynamics, which are thought to support conscious processing, and a wide variance of regional activity timescales, which supports a broad dynamical range. We thus identify a key role for E:I heterogeneity in generating complex neuronal dynamics and demonstrate the viability of using transcriptional data to constrain models of large-scale brain function.
An embryonic zebrafish model to screen disruption of gut-vascular-barriers upon exposure to ambient ultrafine particles
Authors: Baek Kyung In , Qian Yi , Chang Chih-Chiang , O’Donnell Ryan , Soleimanian Ehsan , Sioutas Constantinos , Li Rongsong , Hsiai Tzung K.
Published: October 2020

Epidemiological studies have linked exposure to ambient particulate matter (PM) with gastrointestinal (GI) diseases. Ambient ultrafine particle (UFP) are the redox-active sub-fraction of PM2.5, harboring elemental and polycyclic aromatic hydrocarbons from urban environmental sources including diesel and gasoline exhausts. The gut vascular barrier (GVB) regulates paracellular trafficking and systemic disseminations of ingested microbes and toxins. Here, we posit that acute UFP ingestion disrupts the integrity of the intestinal barrier by modulating intestinal Notch activation. Using zebrafish embryos, we performed micro-gavage with the FITC-conjugated dextran (FD10, 10 kDa) to assess the disruption of GVB integrity upon UFP exposure. Following micro-gavage, FD10 retained in the embryonic GI system, migrated through the cloaca. Conversely, co-gavaging UFP increased transmigration of FD10 across the intestinal barrier, and FD10 fluorescence occurred in the venous capillary plexus. Ingestion of UFP further impaired the mid-intestine morphology. We performed micro-angiogram of FD10 to corroborate acute UFP-mediated disruption of GVB. Transient genetic and pharmacologic manipulations of global Notch activity suggested Notch regulation of the GVB. Overall, our integration of a genetically tractable embryonic zebrafish and micro-gavage technique provided epigenetic insights underlying ambient UFP ingestion disrupts the GVB.

Graphic Abstract
Screening for highly transduced genes inStaphylococcus aureusreveals both lateral and specialized transduction
Authors: Bowring Janine Zara , Su Yue , Alsaadi Ahlam , Svenningsen Sine L. , Parkhill Julian , Ingmer Hanne
Published: October 2020

Bacteriophage-mediated transduction of bacterial DNA is a major route of horizontal gene transfer in the human pathogen,Staphylococcus aureus. Transduction involves packaging of bacterial DNA by viruses and enables transmission of virulence and resistance genes between cells. To learn more about transduction inS. aureus, we searched a transposon mutant library for genes and mutations that enhanced transfer mediated by the temperate phage, φ11. Using a novel screening strategy, we performed multiple rounds of transduction of transposon mutant pools selecting for an antibiotic resistance marker within the transposon element. When determining the locations of transferred mutations, we found that, within each pool of 96 mutants the screen had selected for just 1 or 2 transposon mutant(s). Subsequent analysis showed that the position of the transposon, rather than inactivation of bacterial genes, was responsible for the phenotype. Interestingly, from multiple rounds we identified a pattern of transduction that encompassed mobile genetic elements, as well as chromosomal regions both upstream and downstream of the phage integration site. The latter was confirmed by DNA sequencing of purified phage lysates. Importantly, transduction frequencies were lower for phage lysates obtained by phage infection rather than induction. Our results confirm previous reports of lateral transduction of bacterial DNA downstream of the integrated phage, but also indicate specialized transduction of DNA upstream of the phage, likely involving imprecise excision of the phage from the bacterial genome. These findings illustrate the complexity of transduction processes and increase our understanding of the mechanisms by which phages transfer bacterial DNA.

Importance

Horizontal transfer of DNA between bacterial cells contributes to the spread of virulence and antibiotic resistance genes in human pathogens. ForStaphylococcus aureus, bacterial viruses are particularly important. These viruses, termed bacteriophages, can transfer bacterial DNA between cells by a process known as transduction, which despite of its importance is only poorly characterized. Here, we employed a transposon mutant library to investigate transduction inS. aureus. We show that the location of bacterial DNA in relation to bacteriophages integrated in the bacterial genome is a key decider of how frequently that DNA is transduced. Based on serial transduction of transposon mutant pools and direct sequencing of bacterial DNA in bacteriophage particles, we demonstrate both lateral and specialized transduction. The use of mutant libraries to investigate the patterns of bacterial DNA transfer between cells could help understand how bacteria evolve virulence and resistance and may ultimately lead to new intervention strategies.
Increased orbitofrontal connectivity in misophonia
Authors: Cerliani Leonardo , Rouw Romke
Published: October 2020

For individuals with misophonia, specific innocuous sensory stimuli - such as hearing another person chewing or breathing - evoke strong negative emotional and physiological responses, such as extreme anger, disgust, stress and anxiety. Instead people with misophonia do not experience or display atypical reactions to generic aversive sounds such as screams or nails scratching on a blackboard. Misophonia appears to be unrelated to neurological trauma or hearing deficit, and features a characteristic developmental pattern. Its aetiology is currently unknown.

The few previous fMRI studies on misophonia showed that sufferers feature increased dorsal anterior insula activity during trigger vs. generic aversive sounds. While this effect likely reflects the saliency associated with the perception of trigger sounds in people with misophonia, in the present fMRI study we investigate the neural mechanisms underlying the emotional reaction to trigger stimuli. To this aim, we probe the task-dependent connectivity of mid-cingulate, medial premotor and ventrolateral premotor cortex. We observe that only in participants with misophonia the presentation of trigger audio-visuals prompts an increased interaction of these three brain regions with the lateral orbitofrontal cortex. This brain region is crucial for behavioural inhibition mediated by cognitive and emotional content (such as in reward-reversal learning) and is part of the temporo-amygdala-orbitofrontal network, which integrates visceral and emotional states with cognition and behaviour. We also observe that in people with misophonia trigger sounds prompt a significant increase in the interaction between mid-cingulate and the primary auditory cortex.

Our study replicates previous results and expands the network of brain regions involved in misophonia. The involvement of the orbitofrontal cortex suggests a defective functioning of high-order integrative processes allowing the reappraisal of experience-dependent negative emotional association with harmless sensory stimuli, and sheds light on the mechanisms underlying the compulsive nature of the misophonic reaction. The increased interaction, rather than the overall activity, of the primary auditory cortex with the mid-cingulate supports the hypothesis that the emotional response in misophonia is subserved by an indirect auditory-limbic pathway processing the subjective valence of specific sounds, rather than their physical properties alone.
Heat hypersensitivity of ryanodine receptor type 1 mutants implicated in malignant hyperthermia
Authors: Oyama Kotaro , Zeeb Vadim , Yamazawa Toshiko , Murayama Takashi , Oyamada Hideto , Harada Yoshie , Fukuda Norio , Ishiwata Shin’ichi , Suzuki Madoka
Published: October 2020

Cellular heat-sensing is a universal strategy for avoiding thermal damage and adapting to environments by regulating thermogenic activities. If heat-sensing results in the acceleration of processes governing cellular thermogenesis, hyperthermia can occur. However, how this positive feedback loop contributes to hyperthermia development, especially the gap between heat-sensing and thermogenesis, remains largely unknown. Here, we show that an optically controlled local heat pulse induces an intracellular Ca2+burst in cultured HEK 293 cells overexpressing ryanodine-receptor-type-1 (RyR1) mutants related to the life-threatening illness malignant hyperthermia (MH), and that the Ca2+burst originates from heat-induced Ca2+-release (HICR) because of the mutant channels’ heat hypersensitivity. Furthermore, the heat hypersensitivity of the four RyR1 mutants was ranked, highlighting the complexity of MH. Our findings reveal the novel cellular heat-sensing mechanism, HICR, is essential for the functional positive feedback loop causing MH, suggesting a well-tuned HICR is fundamental for heat-mediated intracellular signaling.
Optogenetic interrogation of the role of striatal patches in habit formation and inhibition of striatal dopamine
Authors: Nadel J.A. , Pawelko S.S. , Scott J.R. , McLaughlin R. , Fox M. , Hollon N.G. , Howard C.D.
Published: October 2020

Habits are inflexible behaviors that can be maladaptive in diseases including drug addiction. The striatum is integral to habit formation, and interspersed throughout the striatum are patches, or striosomes, which are characterized by unique gene expression relative to the surrounding matrix. Recent work has indicated that patches are necessary for habit formation, but how patches contribute to habits remains partially understood. Here, using optogenetics, we modulated striatal patches in Sepw1-NP67 mice during habit formation. We find that patch activation during operant training impairs habit formation, and conversely, that acute patch stimulation after reward devaluation can drive habitual reward seeking. Patch stimulation invigorates general locomotion but is not inherently rewarding. Finally, we use fast-scan cyclic voltammetry to demonstrate that patch stimulation suppresses dopamine release in dorsal striatumin vivo. Overall, this work provides novel insight into the role of the patch compartment in habit formation, and potential interactions with dopamine signaling.
Role of an Atypical Cadherin Gene,Cdh23in Prepulse Inhibition and Implication ofCDH23in Schizophrenia
Authors: Balan Shabeesh , Ohnishi Tetsuo , Watanabe Akiko , Ohba Hisako , Iwayama Yoshimi , Toyoshima Manabu , Hara Tomonori , Hisano Yasuko , Miyasaka Yuki , Toyota Tomoko , Shimamoto-Mitsuyama Chie , Maekawa Motoko , Numata Shusuke , Ohmori Tetsuro , Shimogori Tomomi , Kikkawa Yoshiaki , Hayashi Takeshi , Yoshikawa Takeo
Published: October 2020

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reportedFabp7as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest LOD score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in theCdh23gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression-QTL) effect imparted by the c.753G>A variant for theCdh23expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) inCDH23showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleteriousCDH23variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulatingCdh23variant and a possible contribution ofCDH23to schizophrenia susceptibility.
Liquid condensates increase potency of amyloid fibril inhibitors
Authors: Michaels Thomas C. T. , Mahadevan L. , Weber Christoph A.
Published: October 2020

In living cells, liquid condensates form in the cytoplasm and nucleoplasm via phase separation and regulate physiological processes. They also regulate aberrant aggregation of amyloid fibrils, a process linked to Alzheimer’s and Parkinson’s diseases. In the absence of condensates it has been shown that amyloid aggregation can be inhibited by molecular chaperones and rationally designed drugs. However it remains unknown how this drug- or chaperone-mediated inhibition of amyloid fibril aggregation is affected by phase-separated condensates. Here we study the interplay between protein aggregation, its inhibition and liquid-liquid phase separation. Our key finding is that the potency of inhibitors of amyloid formation can be strongly enhanced. We show that the corresponding mechanism relies on the colocalization of inhibitors and aggregates inside the liquid condensate. We provide experimentally testable physicochemical conditions under which the increase of inhibitor potency is most pronounced. Our work highlights the role of spatio-temporal heterogeneity in curtailing aberrant protein aggregation and suggests design principles for amyloid inhibitors accounting for partitioning of drugs into liquid condensates.
Human temporal voice areas are sensitive to chimpanzee vocalizations
Authors: Ceravolo Leonardo , Debracque Coralie , Gruber Thibaud , Grandjean Didier
Published: October 2020

In recent years, research on voice processing, particularly the study of temporal voice areas (TVA), was dedicated almost exclusively to human voice. To characterize commonalities and differences regarding primate vocalization representations in the human brain, the inclusion of closely related primates, especially chimpanzees and bonobos, is needed. We hypothesized that commonalities would depend on both phylogenetic and acoustic proximity, with chimpanzees ranking the closest toHomo. Presenting human participants with four primate species vocalizations (rhesus macaques, chimpanzees, bonobos and humans) and taking into account acoustic distance or removing voxels explained solely by vocalization low-level acoustics, we observed within-TVA enhanced left and right anterior superior temporal gyrus activity for chimpanzee compared to all other species, and chimpanzee compared to human vocalizations. Our results provide evidence for a common neural basis in the TVA for the processing of phylogenetically and acoustically close vocalizations, namely those of humans and chimpanzees.
An aminoacylation independent activity of PheRS/FARS promotes growth and proliferation
Authors: Ho Manh Tin , Lu Jiongming , Suter Beat
Published: October 2020

Summary / Abstract

Aminoacyl-tRNA synthetases (aaRSs) not only load the appropriate amino acid onto their cognate tRNA, but many of them perform additional functions that are not necessarily related to their canonical activities. Phenylalanyl-tRNA synthetase (PheRS/FARS) levels are elevated in various cancer cells compared to their normal cell counterparts. However, whether and how these levels might contribute to tumor formation was not clear. Here, we show that PheRS is required for cell growth and proliferation. Interestingly, elevated expression of the α-PheRS subunit alone stimulates cell growth and proliferation. In the wing discs system, this leads to a strong increase of mitotic cells. Clonal analysis of twin spots in dividing follicle cells revealed that elevated expression of theα-PheRSsubunit causes cells to grow and proliferate about 25% faster than their normal twin cells. Importantly, this stimulation of growth and proliferation neither required the β-PheRS subunit nor the aminoacylation activity, and it did not visibly stimulate translation. These results, therefore, revealed a non-canonical function of an ancient housekeeping enzyme, providing novel insight into its roles in health and diseases.
Dynamic influences on static measures of metacognition
Authors: Desender Kobe , Vermeylen Luc , Verguts Tom
Published: October 2020

Humans differ in their capability to judge the accuracy of their own choices via confidence judgments. Signal detection theory has been used to quantify the extent to which confidence tracks accuracy via M-ratio, often referred to as metacognitive efficiency. This measure, however, is static in that it does not consider the dynamics of decision making. This could be problematic because humans may shift their level of response caution to alter the tradeoff between speed and accuracy. Such shifts could induce unaccounted-for sources of variation in the assessment of metacognition. Instead, evidence accumulation frameworks consider decision making, including the computation of confidence, as a dynamic process unfolding over time. We draw on evidence accumulation frameworks to examine the influence of response caution on metacognition. Simulation results demonstrate that response caution has an influence on M-ratio. We then tested and confirmed that this was also the case in human participants who were explicitly instructed to either focus on speed or accuracy. We next demonstrated that this association between M-ratio and response caution was also present in an experiment without any reference towards speed. The latter finding was replicated in an independent dataset. In contrast, when data were analyzed with a novel dynamic measure of metacognition, which we refer to as v-ratio, in all of the three studies there was no effect of speed-accuracy tradeoff. These findings have important implications for research on metacognition, such as its measurement, domain-generality, individual differences, and neural correlates.
Low nitrogen availability inhibits the phosphorus starvation response in maize (Zea maysssp.maysL.)
Authors: Vladimir Torres-Rodríguez J. , Nancy Salazar-Vidal M. , Montes Ricardo A. Chávez , Massange-Sánchez Julio A. , Gillmor C. Stewart , Sawers Ruairidh J. H.
Published: October 2020

Background

Nitrogen (N) and phosphorus (P) are macronutrients essential for crop growth and productivity. In cultivated fields, N and P levels are rarely sufficient, contributing to the yield gap between realized and potential production. Fertilizer application increases nutrient availability, but not all farmers have access to fertilizers, nor are current rates of application sustainable or environmentally desirable. Transcriptomic studies of cereal crops have revealed dramatic responses to either low N or low P single stress treatments. In the field, however, levels of both N and P may be suboptimal. The interaction between N and P starvation responses remains to be fully characterized.

Results

We characterized growth and root and leaf transcriptomes of young maize plants under nutrient replete, low N, low P or combined low NP conditions. We identified 1,555 genes to respond to our nutrient treatments, in one or both tissues. A large group of genes, including many classical P starvation response genes, were regulated antagonistically between low N and P conditions. An additional experiment over a range of N availability indicated that a mild reduction in N levels was sufficient to repress the low P induction of P starvation genes. Although expression of P transporter genes was repressed under low N or low NP, we confirmed earlier reports of P hyper accumulation under N limitation.

Conclusions

Transcriptional responses to low N or P were distinct, with few genes responding in a similar way to the two single stress treatments. In combined NP stress, the low N response dominated, and the P starvation response was largely suppressed. A reduction in N availability was sufficient to repress the induction of P starvation associated genes. We conclude that activation of the transcriptional response to P starvation in maize is contingent on sufficient N availability.
Crystal structure of the GDP-bound GTPase domain of Rab5a fromLeishmania donovani
Authors: Zohib Muhammad , Maheshwari Diva , Pal Ravi Kant , Freitag-Pohl Stefanie , Biswal Bichitra Kumar , Pohl Ehmke , Arora Ashish
Published: October 2020

Eukaryotic Rab5s are highly conserved small GTPase-family proteins that are involved in the regulation of early endocytosis.Leishmania donovaniRab5a regulates the sorting of early endosomes that are involved in the uptake of essential nutrients through fluid-phase endocytosis. Here, the 1.80 Å resolution crystal structure of the N-terminal GTPase domain ofL. donovaniRab5a in complex with GDP is presented. The crystal structure determination was enabled by the design of specific single-site mutations and two deletions that were made to stabilize the protein for previous NMR studies. The structure of LdRab5a shows the canonical GTPase fold, with a six-stranded central mixed β-sheet surrounded by five α-helices. The positions of the Switch I and Switch II loops confirm an open conformation, as expected in the absence of the γ-phosphate. However, in comparison to other GTP-bound and GDP-bound homologous proteins, the Switch I region traces a unique disposition in LdRab5a. One magnesium ion is bound to the protein at the GTP-binding site. Molecular-dynamics simulations indicate that the GDP-bound structure exhibits higher stability than the apo structure. The GDP-bound LdRab5a structure presented here will aid in efforts to unravel its interactions with its regulators, including the guanine nucleotide-exchange factor, and will lay the foundation for a structure-based search for specific inhibitors
Expatriate demographic characteristics and host country national support: an empirical investigation in Central/South America
Authors: Varma Arup , Yoon Young-Jae , Froese Fabian Jintae
Published: October 2020

Purpose

The support of host country nationals (HCNs) is critical for expatriate adjustment and performance. Drawing from social identity theory and self-categorization theory, this study investigates the antecedents of HCNs' support toward expatriates in Central/South America, focusing on cultural similarities and expatriate race.

Design/methodology/approach

We conducted a quasi-experimental study to understand the antecedents that promote the willingness of HCNs to offer required support to expatriates. Data were gathered from 117 Latin American participants, who were asked to respond to questions about their perceptions of expatriates from the USA and their willingness to offer support to those expatriates.

Findings

Overall, our findings suggest that HCNs are likely to provide support to expatriates when they perceive the expatriates as similar in terms of culture and race. Specifically, African Americans received more positive attitudes and support than White Americans in South/Central America. The effect of cultural similarity on HCN willingness to support expatriates was mediated by perceived trustworthiness.

Originality/value

The present study extends the research on HCN support to expatriates, to Central/South America, an important region that has been under-studied in the expatriate–HCN context. Another novel feature of our study is that we investigate the role of expatriate race and cultural similarity and illuminate the underlying mechanism of the relationship between expatriate race and HCN support.
Technical trends of artificial intelligence in standard-essential patents
Authors: Chang Shu-Hao
Published: October 2020

Purpose

Defining key artificial intelligence (AI) technologies is especially fundamental because AI applications involve the development of multiple technical fields and have the potential to generate numerous business opportunities in the future. However, most related studies have examined patent grants granted by or patent applications filed to major patent offices; few studies have employed the perspective of standard-essential patents (SEPs) from a holistic technical view. In addition, because few studies have explored the status signals of countries in relation to SEPs, the present study integrated “country” into the model and determined differences among countries in terms of their technological focus.

Design/methodology/approach

In this study, through patent technological network analysis in various periods, the author not only observed the focus fields of AI-related SEPs but also examined temporal trends to determine technical development trends.

Findings

This study identified technologies that have been key players in the SEP network in recent years; these technologies were centered on electric digital data processing, recognition of data and transmission of digital information. Moreover, many of these technologies have been applied in areas such as management and commerce and radio navigation. Furthermore, the USA plays a crucial role in the global development of AI technical network.

Originality/value

This study constructs a technical network model to identify key technologies and trends that can serve as a reference for national research and development resource allocation.
Experimental investigation and modeling study of the fiber orientation behavior
Authors: Li Maoyuan , Zhang Yun , Zhang Shi , Hou Binkui , Zhou Huamin
Published: October 2020

Purpose

The orientation behavior of fiber is of great significance in improving the performance of fiber-reinforced polymer products. Generally, the Folgar–Tucker equation can accurately describe the variation of orientation vector of fiber, whereas the stability of numerical algorithms was the major challenge. This paper aims to propose an accurate, stable algorithm to solve the Folgar–Tucker equation for the fiber orientation behavior.

Design/methodology/approach

First, the mismatch problem between the strain rate and the pressure field was solved by using the integral transformation method. Then, an accurate, stable algorithm to solve the Folgar–Tucker equation based on the invariant-based optimal fitting method was proposed. The equation was discretized by finite element/finite difference method, and the Lagrange multiplier method was applied to ensure stability.

Findings

The proposed algorithm is proven to accurately and steadily coincide with the experimental results for different cases, including the fiber orientation behaviors under combined flow field, rectangular sheet, three-dimensional computed tomography imaging of tensile specimen and box cases.

Originality/value

The fiber orientation behavior during the injection molding can be accurately predicted, which plays a significant role in determining the mechanical properties of products.
Optimising social procurement policy outcomes through cross-sector collaboration in the Australian construction industry
Authors: Loosemore Martin , Denny-Smith George , Barraket Jo , Keast Robyn , Chamberlain Daniel , Muir Kristy , Powell Abigail , Higgon Dave , Osborne Jo
Published: October 2020

Purpose

Social procurement policies are an emerging policy instrument being used by governments around the world to leverage infrastructure and construction spending to address intractable social problems in the communities they represent. The relational nature of social procurement policies requires construction firms to develop new collaborative partnerships with organisations from the government, not-for-profit and community sectors. The aim of this paper is to address the paucity of research into the risks and opportunities of entering into these new cross-sector partnerships from the perspectives of the stakeholders involved and how this affects collaborative potential and social value outcomes for intended beneficiaries.

Design/methodology/approach

This case study research is based on a unique collaborative intermediary called Connectivity Centre created by an international contractor to coordinate its social procurement strategies. The findings draw on a thematic analysis of qualitative data from focus groups with 35 stakeholders from the construction, government, not-for-profit, social enterprise, education and employment sectors.

Findings

Findings indicate that potentially enormous opportunities which social procurement offers are being undermined by stakeholder nervousness about policy design, stability and implementation, poor risk management, information asymmetries, perverse incentives, candidate supply constraints, scepticism, traditional recruitment practices and industry capacity constraints. While these risks can be mitigated through collaborative initiatives like Connectivity Centres, this depends on new “relational” skills, knowledge and competencies which do not currently exist in construction. In conclusion, when social procurement policy requirements are excessive and imposed top-down, with little understanding of the construction industry's compliance capacity, intended social outcomes of these policies are unlikely to be achieved.

Originality/value

This research draws on theories of cross-sector collaboration developed in the realm of public sector management to address the lack of research into how the new cross-sector partnerships encouraged by emerging social procurement policies work in the construction industry. Contributing to the emerging literature on cross-sector collaboration, the findings expose the many challenges of working in cross-sector partnerships in highly transitionary project-based environments like construction.
Smart and learning campus as living lab to foster education for sustainable development: an experience with air quality monitoring
Authors: Mazutti Janaina , Londero Brandli Luciana , Lange Salvia Amanda , Fritzen Gomes Bárbara Maria , Damke Luana Inês , Tibola da Rocha Vanessa , Santos Rabello Roberto dos
Published: October 2020

Purpose

Higher education institutions are widely known both for their promotion to education for sustainable development (ESD) and for their contribution as living labs to urban management strategies. As for strategies, smart and learning campuses have recently gained significant attention. This paper aims to report an air quality monitoring experience with focus on the smart and learning campus and discuss its implications for the university context with regard to ESD and sustainable development goal (SDG) integration.

Design/methodology/approach

The air quality monitoring was held at the main campus of University of Passo Fundo and focused on three pollutants directly related to vehicle emissions. The air quality index (AQI) was presented on a website, along with information regarding health problems caused by air pollution, main sources of emissions and strategies to reduce it.

Findings

The results showed how the decrease in air quality is related to the traffic emissions and the fact that exposing students to a smart and learning environment could teach them about sustainability education.

Practical implications

This case study demonstrated how monitoring air quality in a smart environment could highlight and communicate the impact of urban mobility on air quality and alerted to the need for more sustainable choices, including transports.

Originality/value

This paper contributes to the literature by showing the potential of a smart-learning campus integration and its contribution towards the ESD and the UN SDGs.