bluuebunny/crossref_metadata_2025 huggingface dataset:
Ginsenoside Rd attenuates blood-brain barrier damage by suppressing proteasome-mediated signaling after transient forebrain ischemia
Authors: Zhang Xiao , Liu Xuedong , Hu Gengyao , Zhang Guangyun , Zhao Gang , Shi Ming
Published: March 2020

Ischemic stroke damages the blood-brain barrier (BBB), which leads to brain edema and increases the risk of intracranial hemorrhage. Proteasome inhibition has been found to protect the BBB against cerebral ischemia by suppressing neuroinflammation-mediated matrix metalloproteases-9 (MMP-9) activation. We recently showed that ginsenoside Rd (Rd), a major active ingredient of Panax ginseng, could suppress proteasome-mediated inflammation and be efficient for treating ischemic stroke but downstream mechanisms were still unidentified. For this purpose, Sprague–Dawley rats were subjected to focal cerebral ischemic injury. The activity of proteasome and its downstream effectors nuclear factor-kappa B (NF-κB) and MMP-9 were evaluated. Rd reduced the activity of 20S proteasome in a cell-free assay and inhibited proteasome activity in brain lysates after ischemic stroke. Rd administration suppressed ischemic injury-induced NF-κB activity and IκB degradation mediated by the proteasome. Moreover, Rd reduced the activity and level of MMP-9, a downstream effector of NF-κB, and protected against BBB damage as evidenced by reduced Evan’s Blue leakage and brain edema after cerebral ischemic injury. Jointly, these data demonstrate that ginsenoside Rd attenuates the pathogenesis of cerebral ischemia-induced BBB damage, probably by inhibiting proteasome activity and sequentially suppressing NF-κB/MMP-9 pathway.
Association of SAPAP3 allelic variants with symptom dimensions and pharmacological treatment response in obsessive-compulsive disorder
Authors: Naaz Safoora , Balachander Srinivas , Murthy Nithyananda Srinivasa , Bhagyalakshmi MS , Sud Reeteka , Saha Priyanka , Narayanaswamy Janardhanan C , Janardhan Reddy YC , Jain Sanjeev , Purushottam Meera , Viswanath Biju
Published: March 2020

Background

Though several SAPAP3 gene knockout studies in mice have implicated its role in compulsivity, human studies have failed to demonstrate its association with obsessive-compulsive disorder (OCD). We examined the association between allelic variants of a single nucleotide polymorphism in the SAPAP3 gene (rs6662980) with specific aspects of the OCD phenotype.

Methods

A total of 200 subjects with OCD were genotyped using the TaqMan assay. All subjects were assessed using Mini International Neuropsychiatric Interview, the Yale-Brown Obsessive-Compulsive Scale, and their treatment response was evaluated over naturalistic treatment and follow-up.

Results

After correcting for multiple comparisons, G-allele at rs6662980 was found to be associated with contamination/washing symptoms (p=0.003). Logistic regression analysis also showed that presence of G allele predicted poor response to serotonin reuptake inhibitors [odds ratio = 2.473 (95% CI = 1.157 - 5.407), p=0.021]. Interaction between presence of G-allele and contamination factor score predicted SRI resistance (B= 1.197, p = 0.006).

Limitations

We did not use a dimensional measure for assessing OCD symptoms. Treatment response was assessed over naturalistic follow-up.

Conclusion

Specific phenotypic manifestations of OCD, which include contamination and washing-related symptoms along with resistance to serotonin reuptake inhibitors, may be related to alterations in the SAPAP3 gene.

Public Significance Statement

“This study finds that a specific polymorphism in the SAPAP3 gene, was found to be associated with the contamination/washing symptoms of OCD and was also found to predict resistance to pharmacological treatment”

Highlights

SAPAP3 gene is implicated in OCD

Association of SAPAP3 gene (rs6662980) with OCD phenotypes was examined

Presence of the minor (G) allele predicted contamination & washing symptoms

SAPAP3 polymorphism had a significant association with treatment response

Interaction between presence of G-allele and contamination factor score predicted treatment resistance
Analysis clinical features of COVID-19 infection in secondary epidemic area and report potential biomarkers in evaluation
Authors: Ji Weiping , Bishnu Gautam , Cai Zhenzhai , Shen Xian
Published: March 2020

Objective

Based on the clinical characteristics of infected patients with novel coronavirus in secondary epidemic areas, we aimed to identify potential biomarkers for the evaluation of novel coronavirus-infected patients, guide the diagnosis and treatment of this disease in secondary epidemic areas and provide a reference for the clinical prevention and control of this epidemic situation.

Methods

The clinical data of 33 patients with respiratory symptoms caused by the novel coronavirus in Wenzhou city from January 15 to February 12, 2020, were thoroughly reviewed. At the onset of the disease, we found that the primary symptoms were fever, cough, fatigue, chest tightness, chest pain and specific blood test results. According to the patients’ histories, the patients were divided into two groups: those who spent time in the main epidemic area and those who did not spend time in the main epidemic area. The differences in the clinical manifestations between these two groups were analyzed.

Results

The main clinical symptoms of patients infected with novel coronavirus in the secondary epidemic area were respiratory tract ailments and systemic symptoms. After grouping patients based on the presence or absence of residency in or travel history to the main epidemic area, there was no significant difference between the baseline data of these two groups, and there were no significant differences in symptoms and signs between the two groups (P>0.05). Some patients had abnormally increased serum amyloid protein A (SAA). There were statistically significant differences in the leukocyte count/C-reactive protein, monocyte ratio/C-reactive protein, neutrophil count/C-reactive protein, monocyte count/C-reactive protein and hemoglobin/C-reactive protein values between the two groups (P < 0.05).

Conclusion

Respiratory tract ailments and systemic symptoms were the primary symptoms of novel coronavirus infection in the secondary epidemic area; these symptoms are not typical. The abnormal increase in serum amyloid protein (SAA) may be used as an auxiliary index for diagnosis and treatment. CRP changes before other blood parameters and thus may be an effective evaluation index for patients with COVID-19 infection.
Inferring the number of COVID-19 cases from recently reported deaths
Authors: Jombart Thibaut , van Zandvoort Kevin , Russell Timothy W , Jarvis Christopher I , Gimma Amy , Abbott Sam , Clifford Sam , Funk Sebastian , Gibbs Hamish , Liu Yang , Pearson Carl A. B. , Bosse Nikos I ,   Centre for the Mathematical Modelling of Infectious Diseases COVID-19 Working Group, Eggo Rosalind M , Kucharski Adam J , Edmunds W John
Published: March 2020

We estimate the number of COVID-19 cases from newly reported deaths in a population without previous reports. Our results suggest that by the time a single death occurs, hundreds to thousands of cases are likely to be present in that population. This suggests containment via contact tracing will be challenging at this point, and other response strategies should be considered. Our approach is implemented in a publicly available, user-friendly, online tool.
Belowground changes to community structure alter methane-cycling dynamics in Amazonia
Authors: Meyer Kyle M. , Morris Andrew H. , Webster Kevin , Klein Ann M. , Kroeger Marie E. , Meredith Laura K. , Brændholt Andreas , Nakamura Fernanda , Venturini Andressa , de Souza Leandro Fonseca , Shek Katherine L. , Danielson Rachel , van Haren Joost , de Camargo Plinio Barbosa , Tsai Siu Mui , Dini-Andreote Fernando , de Mauro José M. S. , Nüsslein Klaus , Saleska Scott , Rodrigues Jorge L. M. , Bohannan Brendan J. M.
Published: March 2020

Amazonian rainforest is undergoing increasing rates of deforestation, driven primarily by cattle pasture expansion. Forest-to-pasture conversion has been associated with changes to ecosystem processes, including substantial increases in soil methane (CH4) emission. The drivers of this change in CH4flux are not well understood. To address this knowledge gap, we measured soil CH4flux, environmental conditions, and belowground microbial community attributes across a land use change gradient (old growth primary forest, cattle pasture, and secondary forest regrowth) in two Amazon Basin regions. Primary forest soils exhibited CH4uptake at modest rates, while pasture soils exhibited CH4emission at high but variable rates. Secondary forest soils exhibited low rates of CH4uptake, suggesting that forest regrowth following pasture abandonment could reverse the CH4sink-to-source trend. While few environmental variables were significantly associated with CH4flux, we identified numerous microbial community attributes in the surface soil that explained substantial variation in CH4flux with land use change. Among the strongest predictors were the relative abundance and diversity of methanogens, which both increased in pasture relative to forests. We further identified individual taxa that were associated with CH4fluxes and which collectively explained ~50% of flux variance. These taxa included methanogens and methanotrophs, as well as taxa that may indirectly influence CH4flux through acetate production, iron reduction, and nitrogen transformations. Each land type had a unique subset of taxa associated with CH4fluxes, suggesting that land use change alters CH4cycling through shifts in microbial community composition. Taken together, our results suggest that changes in CH4flux from agricultural conversion could be driven by microbial responses to land use change in the surface soil, with both direct and indirect effects on CH4cycling. This demonstrates the central role of microorganisms in mediating ecosystem responses to land use change in the Amazon Basin.
Third generation sequencing revises the molecular karyotype forToxoplasma gondiiand identifies emerging copy number variants in sexual recombinants
Authors: Xia Jing , Venkat Aarthi , Reese Michael L. , Le Roch Karine , Ay Ferhat , Boyle Jon P.
Published: March 2020

Toxoplasma gondiiis an obligate intracellular parasite that has a significant impact on human health, especially in the immunocompromised. This parasite is also a useful genetic model for intracellular parasitism given its ease of culture in the laboratory and relevant animal models. However, as for many other eukaryotes, theT. gondiigenome is incomplete, containing hundreds of sequence gaps due to the presence of repetitive and/or uncloneable sequences that prevent complete telomere-to-telomere de novo chromosome assembly. Here, we report the first use of single molecule DNA sequencing to generate near complete de novo genome assemblies forT. gondiiand its near relative,N. caninum. Using the Oxford Nanopore Minion platform, we dramatically improved the contiguity of theT. gondiigenome (N50 of ∼6.6Mb) and increased overall assembled sequence compared to current reference sequences by ∼2 Mb. Multiple complete chromosomes were fully assembled as evidenced by clear telomeric repeats on the end of each contig. Interestingly, for all of theToxoplasma gondiistrains that we sequenced (RH, CTG, II×III F1 progeny clones CL13, S27, S21, and S26), the largest contig ranged in size between 11.9 and 12.1 Mb in size, which is larger than any previously reportedT. gondiichromosome. This was due to a repeatable and consistent fusion of chromosomes VIIb and VIII. These data were further validated by mapping existingT. gondiiME49 Hi-C data to our assembly, providing parallel lines of evidence that theT. gondiikaryotype consists of 13, rather than 14, chromosomes. In addition revising the molecular karyotype we were also able to resolve hundreds of repeats derived from both coding and non-coding tandem sequence expansions. For well-known host-targeting effector loci like rhoptry protein 5 (ROP5) and ROP38, we were also able to accurately determine the precise gene count, order and orientation using established assembly approaches and the most likely primary sequence of each using our own assembly correction scripts tailored to correcting homopolymeric run errors in tandem sequence arrays. Finally, when we compared theT. gondiiandN. caninumassemblies we found that while the 13 chromosome karyotype was conserved, we determined that previously unidentified large scale translocation events occurred inT. gondiiandN. caninumsince their most recent common ancestry.
Molecular identification of sixty-three amacrine cell types completes a mouse retinal cell atlas
Authors: Yan Wenjun , Laboulaye Mallory A. , Tran Nicholas M. , Whitney Irene E. , Benhar Inbal , Sanes Joshua R.
Published: March 2020

Amacrine cells (ACs) are a diverse class of interneurons that modulate input from photoreceptors to retinal ganglion cells (RGCs), rendering each RGC type selectively sensitive to particular visual features, which are then relayed to the brain. While many AC types have been identified morphologically and physiologically, they have not been comprehensively classified or molecularly characterized. We used high-throughput single-cell RNA sequencing (scRNA-seq) to profile >32,000 ACs from mouse retina, and applied computational methods to identify 63 AC types. We identified molecular markers for each type, and used them to characterize the morphology of multiple types. We show that they include nearly all previously known AC types as well as many that had not been described. Consistent with previous studies, most of the AC types express markers for the canonical inhibitory neurotransmitters GABA or glycine, but several express neither or both. In addition, many express one or more neuropeptides, and two express glutamatergic markers. We also explored transcriptomic relationships among AC types and identified transcription factors expressed by individual or multiple closely related types. Noteworthy among these wereMeis2andTcf4, expressed by most GABAergic and most glycinergic types, respectively. Together, these results provide a foundation for developmental and functional studies of ACs, as well as means for genetically accessing them. Along with previous molecular, physiological and morphological analyses, they establish the existence of at least 130 neuronal types and nearly 140 cell types in mouse retina.

SIGNIFICANCE STATEMENT

The mouse retina is a leading model for analyzing the development, structure, function and pathology of neural circuits. A complete molecular atlas of retinal cell types provides an important foundation for these studies. We used high-throughput single-cell RNA sequencing (scRNA-seq) to characterize the most heterogeneous class of retinal interneurons, amacrine cells, identifying 63 distinct types. The atlas includes types identified previously as well as many novel types. We provide evidence for use of multiple neurotransmitters and neuropeptides and identify transcription factors expressed by groups of closely related types. Combining these results with those obtained previously, we proposed that the mouse retina contains 130 neuronal types, and is therefore comparable in complexity to other regions of the brain.
Ventral tegmental dopamine neurons control the impulse vector during motivated behavior
Authors: Hughes Ryan N. , Bakhurin Konstantin I. , Petter Elijah A. , Watson Glenn D.R. , Kim Namsoo , Friedman Alexander D. , Yin Henry H.
Published: March 2020

The Ventral Tegmental Area (VTA) is a major source of dopamine, especially to the limbic brain regions. Despite decades of research, the function of VTA dopamine neurons remains controversial. Here, using a novel head-fixed behavioral system with five orthogonal force sensors, we show for the first time that distinct populations of VTA dopamine activity precisely represent the impulse vector (force exerted over time) generated by the animal. Optogenetic excitation of VTA dopamine neurons quantitatively determines impulse in the forward direction, and optogenetic inhibition produces impulse in the backward direction. At the same time, these neurons also regulate the initiation and execution of anticipatory licking. Our results indicate that VTA controls the magnitude, direction, and duration of force used to move towards or away from any motivationally relevant stimuli.

One Sentence Summary

VTA dopamine bidirectionally controls impulse vector and anticipatory behavior
Controlling the Growth of the Skin CommensalStaphylococcus epidermidisUsing D-Alanine Auxotrophy
Authors: Dodds David , Bose Jeffrey L. , Deng Ming-De , Dubé Gilles , Grossman Trudy , Kaiser Alaina , Kulkarni Kashmira , Leger Roger , Mootien-Boyd Sara , Munivar Azim , Oh Julia , Pestrak Matthew , Rajpura Komal , Tikhonov Alex , Turecek Traci , Whitfill Travis
Published: March 2020

Using live microbes as therapeutic candidates is a strategy that has gained traction across multiple therapeutic areas. In the skin, commensal microorganisms play a crucial role in maintaining skin barrier function, homeostasis, and cutaneous immunity. Alterations of the homeostatic skin microbiome are associated with a number of skin diseases. Here, we present the design of an engineered commensal organism,Staphylococcus epidermidis, for use as a live biotherapeutic product (LBP) candidate for skin diseases. The development of novel bacterial strains whose growth can be controlled without the use of antibiotics, or genetic elements conferring antibiotic resistance, enables modulation of therapeutic exposure and improves safety. We therefore constructed an auxotrophic strain ofS. epidermidisthat requires exogenously supplied D-alanine. TheS. epidermidisstrain, NRRL B-4268 Δalr1Δalr2Δdat(SEΔΔΔ) contains deletions of three biosynthetic genes: two alanine racemase genes,alr1andalr2(SE1674 and SE1079), and the D-alanine aminotransferase gene,dat(SE1423). These three deletions restricted growth in D-alanine deficient media, pooled human blood, and skin. In the presence of D-alanine, SEΔΔΔcolonized and increased expression of human β-defensin 2 in cultured human skin modelsin vitro. SEΔΔΔ, showed a low propensity to revert to D-alanine prototrophy, and did not form biofilms on plasticin vitro. These studies support the potential safety and utility of SEΔΔΔas a live biotherapeutic strain whose growth can be controlled by D-alanine.
Plastidic Δ6 fatty-acid desaturases with distinctive substrate specificity regulate the pool of c18-pufas in the ancestral picoalgaostreococcus tauri
Authors: Degraeve-Guilbault C. Charlotte , Gomez Rodrigo E. , Lemoigne Cécile. , Pankansem Nattiwong , Morin Soizic , Tuphile Karine , Joubès Jérôme , Jouhet Juliette , Gronnier Julien , Suzuki Iwane , Domergue Frédéric , Corellou Florence
Published: March 2020

Eukaryotic Δ6-desaturases are microsomal enzymes which balance the synthesis of ω-3 and ω-6 C18-polyunsaturated-fatty-acids (PUFA) accordingly to their specificity. In several microalgae, includingO. tauri, plastidic C18-PUFA are specifically regulated by environmental cues suggesting an autonomous control of Δ6-desaturation of plastidic PUFA. Sequence retrieval fromO. tauridesaturases, highlighted two putative Δ6/Δ8-desaturases sequences clustering, with other microalgal homologs, apart from other characterized Δ-6 desaturases. Their overexpression in heterologous hosts, includingN. benthamianaandSynechocystis, unveiled their Δ6-desaturation activity and plastid localization.O. taurilines overexpressing these Δ6-desaturases no longer adjusted their plastidic C18-PUFA amount under phosphate starvation but didn’t show any obvious physiological alterations. Detailed lipid analyses from the various overexpressing hosts, unravelled that the substrate features involved in the Δ6-desaturase specificity importantly involved the lipid head-group and likely the non-substrate acyl-chain, in addition to the overall preference for the ω-class of the substrate acyl-chain. The most active desaturase displayed a broad range substrate specificity for plastidic lipids and a preference for ω-3 substrates, while the other was selective for ω-6 substrates, phosphatidylglycerol and 16:4-galactolipid species specific to the native host. The distribution of plastidial Δ6-desaturase products in eukaryotic hosts suggested the occurrence of C18-PUFA export from the plastid.

One sentence summary

Osteococcus tauri plastidic lipid C18-PUFA remodelling involves two plastid-located cytochrome-b5 fused Δ6-desaturases with distinct preferences for both head-group and acyl-chain.
Hydrogel mechanical properties are more important than osteoinductive growth factors for bone formation with MSC spheroids
Authors: Whitehead Jacklyn , Griffin Katherine H. , Vorwald Charlotte E. , Gionet-Gonzales Marissa , Cinque Serena E. , Leach J. Kent
Published: March 2020

Mesenchymal stromal cells (MSCs) can promote tissue repair in regenerative medicine, and their therapeutic potential is further enhancedviaspheroid formation. We demonstrated that intraspheroidal presentation of Bone Morphogenetic Protein-2 (BMP-2) on hydroxyapatite (HA) nanoparticles resulted in more spatially uniform MSC osteodifferentiation, providing a method to internally influence spheroid phenotype. Stress relaxation of hydrogels has emerged as a potent stimulus to enhance monodispersed MSC spreading and osteogenic differentiation, but the effect of hydrogel viscoelasticity on MSC spheroids has not been reported. Herein, we describe a materials-based approach to augment the osteogenic potential of entrapped MSC spheroids by leveraging the mechanical properties of alginate hydrogels. Compared to spheroids entrapped in covalently crosslinked, elastic alginate, calcium deposition of MSC spheroids was consistently increased in ionically crosslinked, viscoelastic alginate. We observed significant increases in calcium deposition by MSC spheroids loaded with BMP-2-HA in viscoelastic gels compared to soluble BMP-2, which was higher than all elastic alginate gels. Upon implantation in critically sized calvarial bone defects, we observed enhanced bone formation in all animals treated with viscoelastic hydrogels. Increases in bone formation were evident in viscoelastic gels, regardless of the mode of presentation of BMP-2 (i.e., soluble delivery or HA nanoparticles). These studies demonstrate that the dynamic mechanical properties of viscoelastic alginate are an effective strategy to enhance the therapeutic potential of MSC spheroids for bone formation and repair.
Hierarchical effects of choice-related activity and neural encoding during feature selective attention
Authors: Mohn Jennifer L. , Downer Joshua D. , O’Connor Kevin N. , Johnson Jeffrey S. , Sutter Mitchell L.
Published: March 2020

Selective attention is necessary to sift through, form a coherent percept of, and make behavioral decisions on the vast amount of information present in most sensory environments. How and where selective attention is employed in cortex and how this perceptual information then informs the relevant behavioral decisions is still not well understood. Studies probing selective attention and decision making in visual cortex have been enlightening as to how sensory attention might work in that modality; whether or not similar mechanisms are employed in auditory attention is not yet clear. Therefore, we trained rhesus macaques on a feature selective attention task, where they switched between reporting changes in temporal (amplitude modulation, AM) and spectral (carrier bandwidth) features of a broadband noise stimulus. We investigated how the encoding of these features by single neurons in primary (A1) and secondary (lateral belt, ML) auditory cortex were affected by the different attention conditions. We found that neurons in A1 and ML showed mixed-selectivity to the sound and task features. We found no difference in AM encoding between the attention conditions. We found that choice-related activity in both A1 and ML neurons shifts between attentional conditions. This finding suggests that choice-related activity in auditory cortex does not simply reflect motor preparation or action, and supports the relationship between reported choice-related activity and the decision and perceptual process.

New & Noteworthy

We recorded from primary and secondary auditory cortex while monkeys performed a non-spatial feature attention task. Both areas exhibited rate-based choice-related activity. The manifestation of choice-related activity was attention-dependent, suggesting that choice-related activity in auditory cortex does not simply reflect arousal or motor influences, but relates to the specific perceptual choice. The lack of temporal-based choice activity is consistent with growing evidence that subcortical, but not cortical, single neurons inform decisions through temporal envelope following.
An empirical examination of sample size effects on population demographic estimates in birds using single nucleotide polymorphism (SNP) data
Authors: McLaughlin Jessica F. , Winker Kevin
Published: March 2020

Sample size is a critical aspect of study design in population genomics research, yet few empirical studies have examined the impacts of small sample sizes. We used datasets from eight diverging bird lineages to make pairwise comparisons at different levels of taxonomic divergence (populations, subspecies, and species). Our data are from loci linked to ultraconserved elements (UCEs) and our analyses used one SNP per locus. All individuals were genotyped at all loci (McLaughlin et al. 2020). We estimated population demographic parameters (effective population size, migration rate, and time since divergence) in a coalescent framework using Diffusion Approximation for Demographic Inference (δaδi; Gutenkunst et al. 2009), an allele frequency spectrum (AFS) method. Using divergence-with-gene-flow models optimized with full datasets, we subsampled at sequentially smaller sample sizes from full datasets of 6 – 8 diploid individuals per population (with both alleles called) down to 1:1, and then we compared estimates and their changes in accuracy. Accuracy was strongly affected by sample size, with considerable differences among estimated parameters and among lineages. Effective population size parameters (ν) tended to be underestimated at low sample sizes (fewer than 3 diploid individuals per population, or 6:6 haplotypes in coalescent terms). Migration (m) was fairly consistently estimated until ≤ 2 individuals per population, and no consistent trend of over- or underestimation was found in either time since divergence (T) orΘ(4Nrefμ). Lineages that were taxonomically recognized above the population level (subspecies and species pairs; i.e., deeper divergences) tended to have lower variation in scaled root mean square error (SMRSE) of parameter estimation at smaller sample sizes than population-level divergences, and many parameters were estimated accurately down to 3 diploid individuals per population. Shallower divergence levels (i.e., populations) often required at least 5 individuals per population for reliable demographic inferences using this approach. Although divergence levels might be unknown at the outset of study design, our results provide a framework for planning appropriate sampling and for interpreting results if smaller sample sizes must be used.
Bayesian estimation on logarithmic scales as an explanation for spatiotemporal interferences with a tendency of deceleration
Authors: Chen Youguo , Avitt Andrew , Cui Minghui , Peng Chunhua
Published: March 2020

Spatial and temporal information processing interfere with each other. Kappa effect is a famous spatiotemporal interference, in which the estimated time between two lights increases as an increase of distance between the lights, showing a tendency of deceleration. A classical model attributes the interference to constant speeds and predicts a linear relation, whereas a slowness model attributes the interference to slow speeds and proposes the tendency is the result of the variance of stimuli locations. The present study developed a logarithmic version of the classical model and asserts that the tendency is the result of the Web-Fechner law. These hypotheses were tested in two time discrimination tasks by manipulating the variance of stimuli locations and distance between stimuli. The results demonstrate that estimated time was not modulated by the variance of stimuli locations, and increased as an increase of distance with a tendency of deceleration. The Bayesian model on logarithmic scales made more accurate behavioral predictions than the linear model; the estimated constant speed of the logarithmic Bayesian model was equal to the absolute threshold of speed; the strength of the Kappa effect positively correlated with the variability of time perception. Findings suggest that the interference in the Kappa effect is driven by slow speeds, the strength of the interference is influenced by the variability of time perception, and the tendency of deceleration is the result of the Weber-Fechner law. This Bayesian framework may be useful when applied in the field of time perception and other types of cross-dimensional interferences.
Isopropoxy benzene guanidine killsStaphylococcus aureuswithout detectable resistance
Authors: Zhang Xiufeng , Peng Xianfeng , Lu Yixing , Hao Jie , Li Fangping , Qin Zonghua , Xiong Wenguang , Zeng Zhenling
Published: March 2020

Antibiotic resistance is a serious public health crisis. The challenge caused byStaphylococcus aureusinfections clearly urges the development of novel antimicrobial therapy. Drug repurposing has emerged as an alternative approach to rapidly identify effective drugs against multidrug-resistant bacteria. Recently, substituted benzene guanidine compounds have been used as leading structures to discover new promising drugs in both synthetic and medicinal chemistry. We investigated the antimicrobial activity of an analog of substituted benzene guanidine compounds (isopropoxy benzene guanidine) and further explored its antibacterial mechanism againstS. aureus. Isopropoxy benzene guanidine had a MIC of 0.125-4μg/ml againstS. aureusand displayed potent activity againstS. aureusby disrupting cell membrane. Unlike conventional antibiotics, repeated use of isopropoxy benzene guanidine had a low probability of resistance section. The most substantial isopropoxy benzene guanidine-induced changes occurred in transcript levels of membrane transport functions-regulated genes, and genes involved in purine- and pyrimidine-synthesis pathway and virulence factors. Furthermore,in vivostudies demonstrated that isopropoxy benzene guanidine is capable of treating invasive MRSA infections. These findings provided strong evidence that isopropoxy benzene guanidine represents a new chemical lead for novel antibacterial agent against multidrug-resistantS. aureusinfections.
Weakest link dynamics predict apparent antibiotic interactions in a model cross-feeding community
Authors: Adamowicz Elizabeth M. , Harcombe William R.
Published: March 2020

With the growing global threat of antimicrobial resistance, novel strategies are required for combatting resistant pathogens. Combination therapy, wherein multiple drugs are used to treat an infection, has proven highly successful in the treatment of cancer and HIV. However, this practice has proven challenging for the treatment of bacterial infections due to difficulties in selecting the correct combinations and dosages. An additional challenge in infection treatment is the polymicrobial nature of many infections, which may respond to antibiotics differently than a monoculture pathogen. This study tests whether patterns of antibiotic interactions (synergy, antagonism, or independence/additivity) in monoculture can be used to predict antibiotic interactions in an obligate cross-feeding co-culture. Using our previously described weakest link hypothesis, we hypothesized antibiotic interactions in co-culture based on the interactions we observed in monoculture. We then compared our predictions to observed antibiotic interactions in co-culture. We tested the interactions between ten previously identified antibiotic combinations using checkerboard assays. Although our antibiotic combinations interacted differently than predicted in our monocultures, our monoculture results were generally sufficient to predict co-culture patterns based solely on the weakest link hypothesis. These results suggest that combination therapy for cross-feeding multispecies infections may be successfully designed based on antibiotic interaction patterns for their component species.
Identification ofCandida glabrataTranscriptional Regulators that Govern Stress Resistance and Virulence
Authors: Filler Elan E. , Liu Yaoping , Solis Norma V. , Diaz Luis F. , Edwards John E. , Filler Scott G. , Yeaman Michael R.
Published: March 2020

The mechanisms by whichCandida glabrataresists host defense peptides and caspofungin are incompletely understood. To identify transcriptional regulators that enableC. glabratato withstand these classes of stressors, a library of 215C. glabratatranscriptional regulatory deletion mutants was screened for susceptibility to both protamine and caspofungin. We identified 8 mutants that had increased susceptibility to both host defense peptides and caspofungin. Of these mutants, 6 were deleted for genes that were predicted to specify proteins involved in histone modification. These genes wereADA2, GCN5, SPT8, HOS2, RPD3, andSPP1. Theada2Δ andgcn5Δ mutants also had increased susceptibility to other stressors such as H2O2and SDS. In theGalleria mellonellamodel of disseminated infection, theada2Δ andgcn5Δ mutants had attenuated virulence, whereas in neutropenic mice, the virulence of theada2Δ andrpd3Δ mutants was decreased. Thus, histone modification plays a central role in enablingC. glabratato withstand host defense peptides and caspofungin, and Ada2 is essential for the maximal virulence of this organism during disseminated infection.
Death in Venice: A Digital Reconstruction of a Large Plague Outbreak During 1630-1631
Authors: Lazzari Gianrocco , Colavizza Giovanni , Bortoluzzi Fabio , Drago Davide , Erboso Andrea , Zugno Francesca , Kaplan Frédéric , Salathé Marcel
Published: March 2020

The plague, an infectious disease caused by the bacterium Yersinia pestis, is widely considered to be responsible for the most devastating and deadly pandemics in human history. Starting with the infamous Black Death, plague outbreaks are estimated to have killed around 100 million people over multiple centuries, with local mortality rates as high as 60%. However, detailed pictures of the disease dynamics of these outbreaks centuries ago remain scarce, mainly due to the lack of high-quality historical data in digital form. Here, we present an analysis of the 1630-31 plague outbreak in the city of Venice, using newly collected daily death records. We identify the presence of a two-peak pattern, for which we present two possible explanations based on computational models of disease dynamics. Systematically digitized historical records like the ones presented here promise to enrich our understanding of historical phenomena of enduring importance. This work contributes to the recently renewed interdisciplinary foray into the epidemiological and societal impact of pre-modern epidemics.
Genomic signals of admixture and reinforcement between two closely related species of European sepsid flies
Authors: Giesen Athene , Blanckenhorn Wolf U. , Schäfer Martin A. , Shimizu Kentaro K. , Shimizu-Inatsugi Rie , Misof Bernhard , Niehuis Oliver , Podsiadlowski Lars , Lischer Heidi E. L. , Aeschbacher Simon , Kapun Martin
Published: March 2020

Interspecific gene flow by hybridization may weaken species barriers and adaptive divergence, but can also initiate reinforcement of reproductive isolation trough natural and sexual selection. The extent of interspecific gene flow and its consequences for the initiation and maintenance of species barriers in natural systems remain poorly understood, however. To assess genome-wide patterns of gene flow between the two closely related European dung fly speciesSepsis cynipseaandSepsis neocynipsea(Diptera: Sepsidae), we tested for historical gene flow with the aid of ABBA-BABA test using whole-genome resequencing data from pooled DNA of male specimens originating from natural and laboratory populations. We contrasted genome-wide variation in DNA sequence differences between samples from sympatric populations of the two species in France and Switzerland with that of interspecific differences between pairs of samples involving allopatric populations from Estonia and Italy. In the French Cevennes, we detected a relative excess of DNA sequence identity, suggesting interspecific gene flow in sympatry. In contrast, at two sites in Switzerland, we observed a relative depletion of DNA sequence identity compatible with reinforcement of species boundaries in sympatry. Our results suggest that the species boundaries betweenS. cynipseaandS. neocynipseain Europe depend on the eco-geographic context.
Lipids as currency in ecological interactions: Competition and facilitation between two lipid scavenging parasitoids
Authors: Lammers Mark , van Gorkum Tim A. M. , Hoeijmans Stefanie , Kraaijeveld Ken , Harvey Jeffrey A. , Ellers Jacintha
Published: March 2020

Interspecific interactions in nature often revolve around the acquisition of nutrients. Depending on the organisms’ metabolic requirements, competition for specific essential nutrients may occur, which selects for increased abilities to monopolize, consume and store these nutrients. Lipid scavengers are organisms that rely on exogenous lipid acquisition as they lack the ability to synthesize fatty acidsde novoor in sufficient quantity. Most parasitoid insects are lipid scavengers: they obtain all required lipids by feeding on their hosts as larvae. Here we study the nutritional ecology of competitive interactions between nativeNasonia vitripennisand introducedTachinaephagus zealandicus. While the former was already known to lack lipogenesis, we show thatT. zealandicusalso relies on host lipids. The interactions between the two species were studied using competition experiments, in which oviposition ofT. zealandicuson a host was followed by multiparasitism byN. vitripennis. The outcome of competition was determined by the duration of the time lag between oviposition events.N. vitripenniswas superior when arriving 3 days after oviposition byT. zealandicus. In contrast, 9 days after oviposition ofT. zealandicuswe observed complete reversal, and noN. vitripennisoffspring were able to develop. Only whenN. vitripennislaid eggs 15 days afterT. zealandicusoviposition, both species could emerge from the same host. However,N. vitripennisrealizes only 10% of its potential fitness at this time point because prior parasitization by the gregariousT. zealandicuscompartmentalizes the host resources, limiting the spread ofN. vitripennis’venom. This study shows that successful reproduction ofN. vitripennisat 15 days was achieved by hyperparasitizing, a capability that provides a fitness benefit toN. vitripennis, as it extends the time window that hosts are available for parasitization. Choice tests with hosts at different time intervals afterT. zealandicusoviposition revealed a partial mismatch inN. vitripennisfemales between competition avoidance and offspring performance, which may be linked to the limited co-evolutionary time between native and introduced species. We discuss our results in the context of nutritional ecology and, specifically, the role of lipids in ecological interactions.
Replacing the Calvin cycle with the reductive glycine pathway inCupriavidus necator
Authors: Claassens Nico J. , Bordanaba-Florit Guillermo , Cotton Charles A. R. , De Maria Alberto , Finger-Bou Max , Friedeheim Lukas , Giner-Laguarda Natalia , Munar-Palmer Martí , Newell William , Scarinci Giovanni , Verbunt Jari , de Vries Stijn T. , Yilmaz Suzan , Bar-Even Arren
Published: March 2020

Formate can be directly produced from CO2and renewable electricity, making it a promising microbial feedstock for sustainable bioproduction.Cupriavidus necatoris one of the few biotechnologically-relevant hosts that can grow on formate, but it uses the inefficient Calvin cycle. Here, we redesignC. necatormetabolism for formate assimilation via the highly efficient synthetic reductive glycine pathway. First, we demonstrate that the upper pathway segment supports glycine biosynthesis from formate. Next, we explore the endogenous route for glycine assimilation and discover a wasteful oxidation-dependent pathway. By integrating glycine biosynthesis and assimilation we are able to replaceC. necator’s Calvin cycle with the synthetic pathway and achieve formatotrophic growth. We then engineer more efficient glycine metabolism and use short-term evolution to optimize pathway activity, doubling the growth yield on formate and quadrupling the growth rate. This study thus paves the way towards an ideal microbial platform for realizing the formate bioeconomy.
Ursolic acid inhibits cell migration and promotes JNK-dependent lysosomal associated cell death in Glioblastoma multiforme cells
Authors: Conway Gillian E. , Zizyte Deimante , Mae Mondala Julie Rose , He Zhonglei , Lynam Lorna , Lecourt Mathilde , Barcia Carlos , Howe Orla , Curtin James F
Published: March 2020

Ursolic acid (UA) is a bioactive compound which has demonstrated therapeutic efficacy in a variety of cancer cell lines. UA activates various signalling pathways in Glioblastoma multiforme (GBM), however, the relationship between cell death and migration has yet to be elucidated. UA induces a dose dependent cytotoxic response demonstrated by flow cytometry and biochemical cytotoxicity assays. Inhibitor and fluorescent probe studies demonstrated that UA induces a caspase independent, JNK dependent, mechanism of cell death. Migration studies established that UA inhibits GBM cell migration in a time dependent manner that is independent of the JNK signalling pathway. The cytotoxic insult induced by UA resulted in the formation of acidic vesicle organelles (AVOs), speculating activation of autophagy. However, inhibitor and spectrophotometric analysis demonstrated that autophagy was not responsible for the formation of the AVOs and confocal microscopy identified the AVO’s as lysosomes. Further investigation using isosurface visualisation of confocal imaging determined co-localisation of lysosomes with the previously identified acidic vesicles, thus providing evidence that lysosomes are likely to be playing a role in UA induced cell death.

Collectively, our data identifies that UA rapidly induces a lysosomal associated mechanism of cell death in addition to UA acting as an inhibitor of GBM cell migration.

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Role of syndecan-1 in the interaction between dendritic cells and T cells
Authors: Kouwenberg M , Rops A , Bakker-van Bebber M , Diepeveen L , Götte M , Hilbrands L , van der Vlag J
Published: March 2020

Syndecan-1 (Sdc-1) is a heparan sulfate proteoglycan that can bind cytokines and chemokines via its heparan sulfate side chains, and has immunomodulatory properties in experimental models. Sdc-1 expression has been reported on dendritic cells (DC) and T cells. The potential role of Sdc-1 in DC - T cell interaction has not been investigated yet. We postulate that Sdc-1 is involved in DC – T cell interaction and may influence graft survival in an allogeneic transplant model.

Sdc-1 expression on bone marrow-derived DC and T cells was analyzed by flow cytometry. Unstimulated and LPS stimulated Sdc-1 deficient DC were evaluatedin vitrofor phenotype and stimulatory capacity in mixed lymphocyte reaction. Sdc-1 deficient T cells were evaluated for proliferative capacity and differentiation in a mixed lymphocyte reaction and a proliferation assay. Allograft survival was evaluated in a fully MHC mismatched heterotopic heart transplant model, with either Sdc-1 deficient donors or recipients.

Sdc-1 is expressed on the cell surface of unstimulated and LPS matured DC. Sdc-1 deficiency had no effect on expression of co-stimulatory molecules, cytokine production or T cell stimulatory capacity as compared to WT DC. Sdc-1 expression was not detectable on WT T cells, although intracellular Sdc-1 expression could be demonstrated after ConA activation. Sdc-1 deficient T cells showed reduced proliferation upon DC or ConA stimulation and reduced IL-17 production upon ConA stimulation, compared to WT T cells. Sdc-1 deficiency of either allograft or recipient did not prolong allograft survival.

In conclusion, Sdc-1 is expressed on the cell surface of DC, where its absence does not affect DC phenotype or T cell stimulatory capacity. Sdc-1 is intracellularly expressed in ConA activated T cells. Sdc-1 deficiency in T cells results in a reduced proliferative responsein vitro, as induced by DC and ConA. Sdc-1 deficiency in donor or recipient does not affect allograft survival.
Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis
Authors: Wu M , Minkowicz S , Dumrongprechachan V , Hamilton P , Xiao L , Kozorovitskiy Y
Published: March 2020

Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters plasticity, neuromodulatory signaling, and neuronal activity in distributed networks, yet the field lacks a unifying framework for its varied consequences. Here we describe neuromodulatory and plasticity changes following aversive learning by using a learned helplessness paradigm, where ketamine restores escape behavior. Dopaminergic neuron activity in the ventral tegmental area systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine’s effects are blocked by chemogenetic inhibition of dopamine signaling and mimicked by optogenetic activation. We use 2-photon glutamate uncaging/imaging to interrogate structural plasticity in medial prefrontal cortex, revealing that dendritic spinogenesis on pyramidal neurons is both regulated by aversive experience and recovered by ketamine in a dopamine-dependent manner. Together, these data describe recurrent circuits that causally link neuromodulatory dynamics, aversive learning, and plasticity enhancements driven by a therapeutically promising antidepressant.
Soil-microbes-mediated invasional meltdown in plants
Authors: Zhang Zhijie , Liu Yanjie , Brunel Caroline , van Kleunen Mark
Published: March 2020

While most alien species fail to establish, some invade native communities and become widespread. Many of these communities have been invaded by multiple aliens, suggesting that aliens may cause invasional meltdowns. Here, we tested whether and how a third plant species affects the competitive outcome between alien and native plants through its soil legacy. We first conditioned soil with one of ten species (six natives and four aliens) or without plants. Then, we grew on these 11 soils, five aliens and five natives without competition, and with intra- or interspecific competition (all pairwise alien-native combinations). We found that aliens were not more competitive than natives when grown on soil conditioned by other natives or on non-conditioned soil. However, aliens were more competitive than natives on soil conditioned by other aliens. Although soil conditioning rarely affected the strength of competition between later plants, soil conditioned by aliens changed the competitive outcomes by affecting growth of aliens less negatively than that of natives. Microbiome analysis confirmed this finding by showing that the soil-legacy effects of one species on later species were less negative when their fungal endophyte communities were less similar; and that fungal endophyte communities were less similar between two aliens than between aliens and natives. Our study suggests that coexistence between aliens and natives is less likely with more alien species. Such invasional meltdown is likely mediated by spill-over of fungal endophytes, some of which are pathogenic.