bluuebunny/crossref_metadata_2025 huggingface dataset:
Organic matter removal from mother liquor of gas field wastewater by electro-Fenton process with the addition of H
2
O
2
: effect of initial pH
Authors: Wang Yan , Li Hui-qiang , Ren Li-ming
Published: December 2019

The electro-Fenton (EF) process was applied to treat mother liquor of gas field wastewater (ML-GFW). The Fe-Fe electrodes were used and H
2
O
2
was added to the EF system. Effect of initial pH on chemical oxygen demand (COD) removal efficiency, specific electrical energy consumption (SEEC), specific electrode plate consumption (SEPC) and organic matter removal mechanism was investigated. The results showed that COD removal efficiency reached the maximum (71.9%) at initial pH of 3 after reaction for 3 h. Besides, considering with the SEEC and SEPC, pH of 3 was also the best choice, at which SEEC was 4.7 kW h kg
COD
−1
, SEPC was 0.82 kgFe kg
COD
−1
. Organic matter removal was achieved by two ways: oxidation and flocculation, and oxidation played a major role. With the analysis of GC-MS, the possible degradation pathways of the representative contaminants in the ML-GFW were given.
Social inhibition maintains adaptivity and consensus of honeybees foraging in dynamic environments
Authors: Bidari Subekshya , Peleg Orit , Kilpatrick Zachary P.
Published: December 2019

To effectively forage in natural environments, organisms must adapt to changes in the quality and yield of food sources across multiple timescales. Individuals foraging in groups act based on both their private observations and the opinions of their neighbours. How do these information sources interact in changing environments? We address this problem in the context of honeybee colonies whose inhibitory social interactions promote adaptivity and consensus needed for effective foraging. Individual and social interactions within a mathematical model of collective decisions shape the nutrition yield of a group foraging from feeders with temporally switching quality. Social interactions improve foraging from a single feeder if temporal switching is fast or feeder quality is low. When the colony chooses from multiple feeders, the most beneficial form of social interaction is direct switching, whereby bees flip the opinion of nest-mates foraging at lower-yielding feeders. Model linearization shows that effective social interactions increase the fraction of the colony at the correct feeder (consensus) and the rate at which bees reach that feeder (adaptivity). Our mathematical framework allows us to compare a suite of social inhibition mechanisms, suggesting experimental protocols for revealing effective colony foraging strategies in dynamic environments.
Disrupted white matter integrity in treatment-resistant schizophrenia
Authors: McNabb Carolyn B. , McIlwain Meghan E. , Anderson Valerie M. , Kydd Robert R. , Sundram Frederick , Russell Bruce R.
Published: December 2019

Treatment response in schizophrenia is heterogeneous and has been posited to divide into three distinct subcategories: treatment-responsive (first-line responders; FLR), treatment-resistant (TRS, responding to clozapine), and ultra-treatment-resistant schizophrenia (UTRS, requiring augmented antipsychotic therapy). Previous work suggests that white matter abnormalities drive antipsychotic resistance but little work has been carried out to identify differences between those with TRS and those with UTRS. The current study aimed to establish whether differences in white matter structure are present across both treatment-resistant subtypes of schizophrenia or if UTRS is distinct from TRS. Diffusion-weighted images were acquired for 18 individuals with TRS, 14 with UTRS, 18 FLR and 20 healthy controls. Measures of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and parallel diffusivity (PD) were obtained using tract-based spatial statistics. Analysis of variance (ANOVA) and post-hoc between-groups t-tests interrogating differences were conducted for each white matter measure. Those with TRS had lower FA than healthy controls across widespread regions of the brain, including the superior longitudinal fasciculus, corpus callosum, thalamic radiation, corticospinal tract, internal capsule, corona radiata and fronto-occipital fasciculus (p<.05 FWE-corrected). Lower FA was also observed in those with TRS compared with UTRS in the superior longitudinal fasciculus (p<.05 FWE-corrected). However, post-hoc tests failed to survive corrections for multiple comparisons across the 12 post-hoc contrasts. No differences in MD, PD or RD were observed between groups. These data suggest that TRS is distinct from UTRS and that lower FA could act as a biomarker of treatment resistance in people with schizophrenia.
Distinct temporal trends in breast cancer incidence from 1997 to 2016 by molecular subtypes: A population-based study of Scottish cancer registry data
Authors: Mesa-Eguiagaray Ines , Wild Sarah H , Rosenberg Philip S. , Bird Sheila M , Brewster David H , Hall Peter S , Cameron David , Morrison David , Figueroa Jonine D
Published: December 2019

Background

Strategies for breast cancer prevention are informed by assessing whether incidence differs by tumour biology. We describe temporal trends of breast cancer incidence by molecular subtypes in Scotland.

Methods

Population-based cancer registry data on 72,217 women diagnosed with incident primary breast cancer from 1997 to 2016 were analysed. Age-standardised rates (ASR) and age-specific incidence were estimated by tumour subtype after imputing the 8% of missing oestrogen receptor (ER) status. Joinpoint regression and age- period- cohort models were used to assess whether significant differences were observed in incidence trends by ER status.

Results

ER positive tumour incidence steadily increased particularly for women of screening age 50 to 69 years from 1997 till around 2011 (1.6%/year, 95%CI: 1.2 to 2.1). ER negative incidence decreased among all ages at a consistent rate of −0.7%/year (95%CI: −1.5, 0) from around 2000-2016. Compared to the 1941-1959 central birth cohort, women born 1912-1940 had lower incidence rate ratios (IRR) for ER+ tumours and women born 1960- 1986 had higher IRR for ER- tumours.

Conclusions

We show evidence of aetiologic heterogeneity of breast cancer. Future incidence and survival reporting should be monitored by molecular subtypes.
Rate of Force Development is Related to Maximal Force, Muscle Quality and Physical Function in Patients With Chronic Kidney Disease Predialysis
Authors: Gollie Jared M. , Harris-Love Michael O. , Patel Samir S. , Blackman Marc R.
Published: December 2019

Background

Physical function is severely compromised in people with chronic kidney disease (CKD) and worsens with continued decreases in kidney function. Neuromuscular force capacity is a key determinant of physical function in healthy older adults, though its importance in persons with CKD is less understood.

Methods

This study aimed to determine the relationships among rate of force development (RFD), muscle quality and physical function in a group of community-dwelling, middle-aged and older men (n=14; age=71.2±6.2 years) with CKD stages 3 and 4 (eGFR=37.5±10.4 ml/min per 1.73 m2). Force characteristics were determined from maximal knee extensor isometric contractions and muscle quality was estimated using ultrasound grayscale analysis. Physical function was assessed by the Short Physical Performance Battery (SPPB) and 5-repetition sit-to-stand (STS) test.

Results

eGFR was directly related to SPPB (r=0.54, p=0.044) and inversely related to STS (r=-0.62, p=0.029). RFD was positively related to SPPB at time points 0-50 ms, 50-100 ms, and 0-300 ms (RFD0-50, r=0.73, p=0.010; RFD50-100, r=0.67, p=0.022 and RFD0-300 r=0.61, p=0.045); and inversely related to STS at time points 0-50 ms, 50-100 ms, and 0-300 ms (RFD0-50, r=-0.78, p=0.007; RFD50-100, r=-0.78, p=0.006 and RFD0-300 r=-0.76, p=0.009), respectively. RFD was positively associated with maximal voluntary force (MVF) at times 50-100 ms, 100-200 ms, and 0-300 ms (RFD50-100, r=0.72, p=0.011; RFD100-200, r=0.66, p=0.025; and RFD0-300 r=0.70, p=0.016), respectively. Neither MVF nor muscle quality was significantly associated with functional measures.

Conclusions

RFD is an important determinant of physical function in middle-aged and older men with CKD stages 3 and 4.
The epidemiology of systematic review updates: a longitudinal study of updating of Cochrane reviews, 2003 to 2018
Authors: Bastian Hilda , Doust Jenny , Clarke Mike , Glasziou Paul
Published: December 2019

Background

The Cochrane Collaboration has been publishing systematic reviews in the Cochrane Database of Systematic Reviews (CDSR) since 1995, with the intention that these be updated periodically.

Objectives

To chart the long-term updating history of a cohort of Cochrane reviews and the impact on the number of included studies.

Methods

The status of a cohort of Cochrane reviews updated in 2003 was assessed at three time points: 2003, 2011, and 2018. We assessed their subject scope, compiled their publication history using PubMed and CDSR, and compared them to all Cochrane reviews available in 2002 and 2017/18.

Results

Of the 1,532 Cochrane reviews available in 2002, 11.3% were updated in 2003, with 16.6% not updated between 2003 and 2011. The reviews updated in 2003 were not markedly different to other reviews available in 2002, but more were retracted or declared stable by 2011 (13.3% versus 6.3%). The 2003 update led to a major change of the conclusions of 2.8% of updated reviews (n = 177). The cohort had a median time since publication of the first full version of the review of 18 years and a median of three updates by 2018 (range 1–11). The median time to update was three years (range 0–14 years). By the end of 2018, the median time since the last update was seven years (range 0–15). The median number of included studies rose from eight in the version of the review before the 2003 update, to 10 in that update and 14 in 2018 (range 0–347).

Conclusions

Most Cochrane reviews get updated, however they are becoming more out-of-date over time. Updates have resulted in an overall rise in the number of included studies, although they only rarely lead to major changes in conclusion.
[Knowledge and attitudes regarding infant BLS among babysitters and nursemaids in north rural Jordan]
Authors: Raffee Liqaa , Hamadneh Shereen , Kassab Manal , Almomani Fidaa , Hamadneh Jehan , AlBashtawy Mohammed , Obeidat Rawan A. , Almazloom Othman
Published: December 2019

Background

There is a lack of national data related to the public knowledge and attitudes concerning Basic Life Support (BLS) for an infant. This study is the first to assess the knowledge and attitude regarding infant BLS among babysitters and nursemaids who are working in registered nurseries in North Jordan.

Methods

A semi-structured questionnaire was conducted among a convenience sample of 77 child caretakers (babysitters and nursemaids) who were looking after infants in registered nurseries in north of Jordan.

Results

The findings show that the majority of participants were not aware of skills for managing foreign body aspiration (or CPR) among infants, while more than two-thirds of them never attended training and or education sessions regarding managing foreign body aspiration among infants.

Conclusions

This research strongly recommends training for babysitters and care center staff. The findings of this study indicated that caregivers in Jordanian kindergartens and nurseries lack awareness regarding safe infant care. As such, there is a lack of basic skills for resuscitation in urgent cases; which can increase the risk of sudden and unexpected child death. Accordingly, the infant life support course is highly recommended for babysitters and nursemaids. Health care professionals could help to implement infant basic life support training courses through local community basic service centers, non-governmental organizations, local associations, universities and health colleges through providing workshops that aim at enhancing knowledge and skills for infant BLS among caregivers and babysitters.
Dissecting intratumor heterogeneity of nodal B cell lymphomas on the transcriptional, genetic, and drug response level
Authors: Roider Tobias , Seufert Julian , Uvarovskii Alexey , Frauhammer Felix , Bordas Marie , Abedpour Nima , Stolarczyk Marta , Mallm Jan-Philipp , Rabe Sophie , Bruch Peter-Martin , Balke-Want Hyatt , Hundemer Michael , Rippe Karsten , Goeppert Benjamin , Seiffert Martina , Brors Benedikt , Mechtersheimer Gunhild , Zenz Thorsten , Peifer Martin , Chapuy Björn , Schlesner Matthias , Müller-Tidow Carsten , Fröhling Stefan , Huber Wolfgang , Anders Simon , Dietrich Sascha
Published: December 2019

Tumor heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is well-known to affect the efficacy of anti-cancer drugs, most personalized treatment approaches do not account for intratumor heterogeneity. We addressed this issue by studying the heterogeneity of lymph node-derived B cell non-Hodgkin lymphoma (B-NHL) by single cell RNA-sequencing (scRNA-seq) and transcriptome-informed flow cytometry. We identified transcriptionally distinct malignant subclones and compared their drug response and genomic profiles. Malignant subclones of the same patient responded strikingly different to anti-cancer drugs ex vivo, which recapitulated subclone-specific drug sensitivity during in vivo treatment. Tumor infiltrating T cells represented the majority of non-malignant cells, whose gene expression signatures were similar across all donors, whereas the frequencies of T cell subsets varied significantly between the donors. Our data provide new insights into the heterogeneity of B-NHL and highlight the relevance of intratumor heterogeneity for personalized cancer therapies.
Neurobehavioural signatures in race car driving
Authors: Lima Ines Rito , Haar Shlomi , Di Grassi Lucas , Faisal A. Aldo
Published: December 2019

Recent technological developments in mobile brain and body imaging are enabling new frontiers of real-world neuroscience. Simultaneous recordings of body movement and brain activity from highly skillful individuals as they demonstrate their exceptional skills in real-world settings, can shed new light on neurobehavioural structure of human expertise. Driving is a real-world skill which many of us acquire on different levels of expertise. Here we ran a case-study on a subject with the highest level of driving expertise - a Formula E Champion. We studied the expert driver’s neural and motor patterns while he drove a sports car in the “Top Gear” race track under extreme conditions (high speed, low visibility, low temperature, wet track). His brain activity, eye movements and hand/foot movements were recorded. Brain activity in the delta, alpha, and beta frequency bands showed causal relation to hand movements. We demonstrate, here in summary, that even in extreme situations (race track driving) a method for conducting human ethomic (Ethology + Omics) data that encompasses information on the sensory inputs and motor outputs outputs of the brain as well as brain state to characterise complex human skills.
Diffusion Weighted Image Co-registration: Investigation of Best Practices
Authors: Chen David Qixiang , Dell’Acqua Flavio , Rokem Ariel , Garyfallidis Eleftherios , Hayes David J. , Zhong Jidan , Hodaie Mojgan
Published: December 2019

1.

The registration or alignment of diffusion weighted images (DWI) with other imaging modalities is a critical step in neuroimaging analysis. Within-subject T1-DWI co-registration is particularly instrumental. DWI-derived scalar images are commonly used as intermediates for T1-DWI co-registration, and the resulting registration transforms are applied to all other scalar images for analysis. The ideal registration intermediate should register well to T1 and other multimodal images and be practically easy to obtain. It is however, currently unclear which DWI-derived scalar image serves as the best intermediate. We aim to determine the best, practical, intermediate for image co-registration. T1 and DWI images were acquired from 20 healthy subjects. DWIs were acquired with 60 directions. Six DWI-derived scalar images were compared including: 1) fractional anisotropy (FA); 2) generalized FA (GFA); 3) B0 images; 4) mean DWIs with the B0 image (MDWI); 5) anisotropic power (AP) images. AP showed the smallest variability in registration improvements across all the tested DWI derived scalar images, and show the highest average percent changes with CC registration cost function (CC=1.2%, MI=15%). In contrast, the FA and GFA transforms resulted in significantly poorer registration across DWI types. The AP image was the DWI-derived scalar image that provided the most consistent registration to all other images. Practically, it is generated easily and so could be implemented in basic and clinical research pipelines currently using other intermediates. Given these findings, it is recommended that AP images be used for T1–DWI co-registration, and that FA and GFA images in particular be avoided.
A Comparison of fMRI and Behavioral Models for Predicting Inter-Temporal Choices
Authors: Knorr Felix G. , Neukam Philipp T. , Fröhner Juliane H. , Mohr Holger , Smolka Michael N. , Marxen Michael
Published: December 2019

In an inter-temporal choice (IteCh) task, subjects are offered a smaller amount of money immediately or a larger amount at a later time point. Here, we are using trial-by-trial fMRI data from 363 recording sessions and machine learning in an attempt to build a classifier that would ideally outperform established behavioral model given that it has access to brain activity specific to a single trial. Such methods could allow for future investigations of state-like factors that influence IteCh choices.

To investigate this, coefficients of a GLM with one regressor per trial were used as features for a support vector machine (SVM) in combination with a searchlight approach for feature selection and cross-validation. We then compare the results to the performance of four different behavioral models.

We found that the behavioral models reached mean accuracies of 90% and above, while the fMRI model only reached 54.84% at the best location in the brain with a spatial distribution similar to the well-known value-tracking network. This low, though significant, accuracy is in line with simulations showing that classifying based on signals with realistic correlations with subjective value produces comparable, low accuracies. These results emphasize the limitations of fMRI recordings from single events to predict human choices, especially when compared to conventional behavioral models. Better performance may be obtained with paradigms that allow the construction of miniblocks to improve the available signal-to-noise ratio.
Diaci v3.0: Chromosome-level assembly,de novotranscriptome and manual annotation ofDiaphorina citri,insect vector of Huanglongbing
Authors: Shippy Teresa D. , Hosmani Prashant S. , Flores-Gonzalez Mirella , Mann Marina , Miller Sherry , Weirauch Matthew T. , Vosburg Chad , Massimino Crissy , Tank Will , de Oliveira Lucas , Chen Chang , Hoyt Stephanie , Adams Rebekah , Adkins Samuel , Bailey Samuel T. , Chen Xiaoting , Davis Nina , DeLaFlor Yesmarie , Espino Michelle , Gervais Kylie , Grace Rebecca , Harper Douglas , Hasan Denisse L. , Hoang Maria , Holcomb Rachel , Jernigan Margaryta R. , Kemp Melissa , Kennedy Bailey , Kercher Kyle , Klaessan Stefan , Kruse Angela , Licata Sophia , Lu Andrea , Masse Ron , Mathew Anuja , Michels Sarah , Michels Elizabeth , Neiman Alan , Norman Seantel , Norus Jordan , Ortiz Yasmin , Panitz Naftali , Paris Thomson , Perentesis Kitty M. R. , Perry Michael , Reynolds Max , Sena Madison M. , Tamayo Blessy , Thate Amanda , Vandervoort Sara , Ventura Jessica , Weis Nicholas , Wise Tanner , Shatters Robert G. , Heck Michelle , Benoit Joshua B. , Hunter Wayne B. , Mueller Lukas A. , Brown Susan J. , D’Elia Tom , Saha Surya
Published: December 2019

Background

Diaphorina citriis a vector of “CandidatusLiberibacter asiaticus” (CLas), the gram-negative bacterial pathogen associated with citrus greening disease. Control measures rely on pesticides with negative impacts on the environment, natural ecosystems and human and animal health. In contrast, gene-targeting methods have the potential to specifically target the vector species and/or reduce pathogen transmission.

Results

To improve the genomic resources needed for targeted pest control, we assembled aD. citrigenome based on PacBio long reads followed by proximity ligation-based scaffolding. The 474 Mb genome has 13 chromosomal-length scaffolds. 1,036 genes were manually curated as part of a community annotation project, composed primarily of undergraduate students. We also computationally identified a total of 1,015 putative transcription factors (TFs) and were able to infer motifs for 337 TFs (33 %). In addition, we produced a genome-independent transcriptome and genomes forD. citriendosymbionts.

Conclusions

Manual annotation provided more accurate gene models for use by researchers and also provided an excellent training opportunity for students from multiple institutions. All resources are available onCitrusGreening.organd NCBI. The chromosomal-lengthD. citrigenome assembly serves as a blueprint for the development of collaborative genomics projects for other medically and agriculturally significant insect vectors.
EcDBS1R6: A new broad-spectrum cationic antibacterial peptide derived from a signal peptide sequence
Authors: Porto William F. , Irazazabal Luz N. , Humblot Vincent , Haney Evan F. , Ribeiro Suzana M. , Hancock Robert E. W. , Ladram Ali , Franco Octavio L.
Published: December 2019

Bacterial infections represent a major worldwide health problem, with an special highlight on Gram-negative bacteria, which were assigned by the World Health Organization (WHO) as the most critical priority for development of novel antimicrobial compounds. Antimicrobial peptides (AMPs) have been considered as potential alternative agents for treating these infections. Here we demonstrated the broad-spectrum activity of EcDBS1R6, a peptide derived from a signal peptide sequence ofEscherichia colithat we previously turned into an AMP by making changes predicted through the Joker algorithm. Signal peptides are known to naturally interact with membranes; however, the modifications introduced by Joker made this peptide capable of killing bacteria. Membrane damage of the bacterial cells was observed by measuring membrane integrity using fluorescent probes and through scanning electron microscopy imaging. Structural analysis revealed that the C-terminus was unable to fold into an α-helix, indicating that the EcDBS1R6 antibacterial activity core was located at the N-terminus, corresponding to the signal peptide portion of the parent peptide. Therefore, the strategy of transforming signal peptides into AMPs seems to be promising and could be used for producing novel antimicrobial agents.
O-GlcNAcylation of small heat shock proteins enhances their anti-amyloid chaperone activity
Authors: Balana Aaron T. , Levine Paul M. , Mukherjee Somnath , Pedowitz Nichole J. , Moon Stuart P. , Takahashi Terry T. , Becker Christian F. W. , Pratt Matthew R.
Published: December 2019

A major role for the intracellular posttranslational modification O-GlcNAc appears to be the inhibition of protein aggregation. Most of the previous studies in this area have focused on O-GlcNAcylation of the amyloid-forming proteins themselves. Here, we use synthetic protein chemistry to discover that O-GlcNAc also activates the anti-amyloid activity of certain small heat shock proteins (sHSPs), a potentially more important modification event that can act broadly and substoichiometrically. More specifically, we find that O-GlcNAcylation increases the ability of sHSPs to block the amyloid formation of both α-synuclein and Aβ. Mechanistically, we show that O-GlcNAc near the sHSP IXI-domain prevents its ability to intramolecularly compete with substrate binding. Our results have important implications for neurodegenerative diseases associated with amyloid formation and potentially other areas of sHSP biology.
Sex differences in traumatic stress reactivity of rats with a history of alcohol drinking
Authors: Albrechet-Souza Lucas , Schratz Connor L. , Gilpin Nicholas W.
Published: December 2019

Background

Alcohol misuse and post-traumatic stress disorder (PTSD) are highly comorbid and treatment outcomes are worse in individuals with both conditions. Although more men report experiencing traumatic events than women, the lifetime prevalence of PTSD is twice as high in females. Despite these data trends in humans, preclinical studies of traumatic stress reactivity have been performed almost exclusively in male animals.

Methods

This study was designed to examine sex differences in traumatic stress reactivity in alcohol-naïve rats and rats given intermittent access to 20% ethanol in a 2-bottle choice paradigm for 5 weeks. Rats were exposed to predator odor (bobcat urine) and tested for avoidance of the odor-paired context 24 hours later; unstressed Controls were never exposed to odor. Two days after stress, we measured physiological arousal using the acoustic startle response (ASR) test. We also measured anxiety-like behavior using the elevated plus-maze (EPM) and circulating corticosterone levels before and immediately after odor exposure.

Results

Male and female rats exposed to predator odor displayed blunted weight gain 24 hours post-stress, but only a subset of stressed animals exhibited avoidance behavior. Chronic intermittent alcohol drinking increased the proportion of Avoiders in males and predator odor exposure increased ASR in these animals. Predator odor stress reduced ASR in females relative to unstressed females and stressed males, regardless of alcohol drinking history. Bobcat urine exposure did not promote persistent anxiety-like behavior, but alcohol-experienced males exhibited reduced activity in the EPM in comparison to alcohol-experienced females.

Furthermore, predator odor increased circulating corticosterone levels in females relative to males and baseline.

Conclusions

We report robust sex differences in behavioral and endocrine responses to bobcat urine exposure in adult Wistar rats. Also, chronic moderate alcohol drinking increased traumatic stress reactivity in males but not females. Our findings emphasize the importance of considering sex as a biological variable in the investigation of traumatic stress effects on physiology and behavior.
RNA-Seq Analysis Illuminates the Early Stages ofPlasmodiumLiver Infection
Authors: Toro-Moreno Maria , Sylvester Kayla , Srivastava Tamanna , Posfai Dora , Derbyshire Emily R.
Published: December 2019

The apicomplexan parasitesPlasmodiumspp. are the causative agents of malaria, a disease that poses a significant global health burden.Plasmodiumspp. initiate infection of the human host by transforming and replicating within hepatocytes. This liver stage (LS) is poorly understood when compared to otherPlasmodiumlife stages, which has hindered our ability to target these parasites for disease prevention. We conducted an extensive RNA-seq analysis throughout thePlasmodium bergheiLS, covering as early as 2 hours post infection (hpi) and extending to 48 hpi. Our data revealed that hundreds of genes are differentially expressed at 2 hpi, and that multiple genes shown to be important for later infection are upregulated as early as 12 hpi. Using hierarchical clustering along with co-expression analysis, we identified clusters functionally enriched for important liver-stage processes such as interactions with the host cell and redox homeostasis. Furthermore, some of these clusters were highly correlated to the expression of ApiAP2 transcription factors, while showing enrichment of mostly uncharacterized DNA binding motifs. This finding presents potential LS targets for these transcription factors, while also hinting at alternative uncharacterized DNA binding motifs and transcription factors during this stage. Our work presents a window into the previously undescribed transcriptome ofPlasmodiumupon host hepatocyte infection to enable a comprehensive view of the parasite’s LS. These findings also provide a blueprint for future studies that extend hypotheses concerning LS gene function inP. bergheito human-infectivePlasmodiumparasites.

IMPORTANCE

The LS ofPlasmodiuminfection is an asymptomatic yet necessary stage for producing blood-infective parasites, the causative agents of malaria. Blocking the liver stage of the life cycle can prevent clinical malaria, but relatively less is known about the parasite’s biology at this stage. Using the rodent modelP. berghei, we investigated whole-transcriptome changes occurring as early as 2 hpi of hepatocytes. The transcriptional profiles of early time points (2, 4, 12, and 18 hpi) have not been accessible before due to the technical challenges associated with liver-stage infections. Our data now provides insights into these early parasite fluxes that may facilitate establishment of infection, transformation and replication in the liver.
Identification of Microorganisms by Liquid Chromatography-Mass Spectrometry (LC-MS1) and in silico Peptide Mass Data
Authors: Lasch Peter , Schneider Andy , Blumenscheit Christian , Doellinger Joerg
Published: December 2019

1.

Over the past decade, modern methods of mass spectrometry (MS) have emerged that allow reliable, fast and cost-effective identification of pathogenic microorganisms. While MALDI-TOF MS has already revolutionized the way microorganisms are identified, recent years have witnessed also substantial progress in the development of liquid chromatography (LC)-MS based proteomics for microbiological applications. For example, LC-tandem mass spectrometry (LC-MS2) has been proposed for microbial characterization by means of multiple discriminative peptides that enable identification at the species, or sometimes at the strain level. However, such investigations can be very time-consuming, especially if the experimental LC-MS2 data are tested against sequence databases covering a broad panel of different microbiological taxa.

In this proof of concept study, we present an alternative bottom-up proteomics method for microbial identification. The proposed approach involves efficient extraction of proteins from cultivated microbial cells, digestion by trypsin and LC-MS measurements. MS1 data are then extracted and systematically tested against an in silico library of peptide mass data compiled in house. The library has been computed from the UniProt Knowledgebase Swiss-Prot and TrEMBL databases and comprises more than 12,000 strain-specific in silico profiles, each containing tens of thousands of peptide mass entries. Identification analysis involves computation of score values derived from spectral distances between experimental and in silico peptide mass data and compilation of score ranking lists. The taxonomic positions of the microbial samples are then determined by using the best-matching database entries. The suggested method is computationally efficient – less than two minutes per sample - and has been successfully tested by a set of 19 different microbial pathogens. The approach is rapid, accurate and automatable and holds great potential for future microbiological applications.
Shotgun metagenomics and metabolomics reveal glyphosate alters the gut microbiome of Sprague-Dawley rats by inhibiting the shikimate pathway
Authors: Mesnage Robin , Teixeira Maxime , Mandrioli Daniele , Falcioni Laura , Ducarmon Quinten Raymond , Zwittink Romy Daniëlle , Amiel Caroline , Panoff Jean-Michel , Belpoggi Fiorella , Antoniou Michael N
Published: December 2019

There is intense debate as to whether glyphosate can interfere with aromatic amino acid biosynthesis in microorganisms inhabiting the gastrointestinal tract, which could potentially lead to negative health outcomes. We have addressed this major gap in glyphosate toxicology by using a multi-omics strategy combining shotgun metagenomics and metabolomics. We tested whether glyphosate (0.5, 50, 175 mg/kg bw/day), or its representative EU commercial herbicide formulation MON 52276 at the same glyphosate equivalent doses, has an effect on the rat gut microbiome in a 90-day subchronic toxicity test. Clinical biochemistry measurements in blood and histopathological evaluations showed that MON 52276 but not glyphosate was associated with statistically significant increase in hepatic steatosis and necrosis. Similar lesions were also present in the liver of glyphosate-treated groups but not in the control group. Caecum metabolomics revealed that glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase in the shikimate pathway as evidenced by an accumulation of shikimic acid and 3-dehydroshikimic acid. Levels of caecal microbiome dipeptides involved in the regulation of redox balance (γ-glutamylglutamine, cysteinylglycine, valylglycine) had their levels significantly increased. Shotgun metagenomics showed that glyphosate affected caecum microbial community structure and increased levels of Eggerthella spp. and Homeothermacea spp.. MON 52276, but not glyphosate, increased the relative abundance of Shinella zoogleoides. Since Shinella spp. are known to degrade alkaloids, its increased abundance may explain the decrease in solanidine levels measured with MON 52776 but not glyphosate. Other glyphosate formulations may have different effects since Roundup® GT Plus inhibited bacterial growth in vitro at concentrations at which MON 52276 did not present any visible effect. Our study highlights the power of a multiomics approach to investigate effects of pesticides on the gut microbiome. This revealed the first biomarker of glyphosate effects on rat gut microbiome. Although more studies will be needed to ascertain if there are health implications arising from glyphosate inhibition of the shikimate pathway in the gut microbiome, our findings can be used in environmental epidemiological studies to understand if glyphosate can have biological effects in human populations.

Graphical Abstract
GIV•Kindlin interaction is required for Kindlin-Mediated Integrin Recognition and Activation
Authors: Rohena Cristina , Kalogriopoulos Nicholas , Rajapakse Navin , Roy Suchismita , Lopez-Sanchez Inmaculada , Ablack Jailal , Sahoo Debashis , Ghosh Pradipta
Published: December 2019

Cells perceive and respond to the extracellular matrix (ECM)viaintegrin receptors; their dysregulation has been implicated in inflammation and cancer metastasis. Here we show that a guanine nucleotide exchange modulator of trimeric-GTPase Gαi, GIV (a.k.aGirdin), directly binds the integrin adaptor Kindlin-2. A non-canonical short linear motif within GIV’s C-terminus binds Kindlin-2-FERM3 domain at a site that is distinct from the binding site for the canonical NPxY motif on the -integrin tail. Binding of GIV to Kindlin-2 allosterically enhances Kindlin-2’s affinity for β1-integrin. Consequently, integrin activation and clustering are maximized, which augments cell adhesion, spreading and invasion. Findings elucidate how the GIV•Kindlin-2 complex has a two-fold impact: it allosterically synergizes integrin activation and enables β1-integrins to indirectly access and modulate trimeric GTPasesviathe complex. Furthermore, Cox proportional-hazard models on tumor transcriptomics provide trans-scale evidence of synergistic interactions between GIV•Kindlin-2•β1-integrin on time to progression to metastasis.

The eTOC blurb

Integrins mediate cell adhesion to the extracellular matrix; their dysregulation fuels inflammation, cancer cell invasion and metastasis. Authors show how two pro-metastatic scaffold proteins, Kindlin and GIV/Girdin bind and cooperatively enhance their allosteric coupling to integrins, and their subsequent activation. Findings reveal novel interfaces in integrin signaling for pharmacologic manipulation.

HIGHLIGHTS

GIV and Kindlin(K2), two integrin adaptors that promote metastasis, bind each other

Binding of GIV or integrin to K2 allosterically enhances GIV•K2•integrin complexes

Binding is required for the maximal recruitment of GIV and K2 to active integrins

Binding facilitates integrin clustering, activation, tumor cell adhesion, invasion.
InhibitingMycobacterium tuberculosisCoaBC by targeting a new allosteric site
Authors: Mendes Vitor , Green Simon R. , Evans Joanna C. , Hess Jeannine , Blaszczyk Michal , Spry Christina , Bryant Owain , Cory-Wright James , Chan Daniel S-H. , Torres Pedro H.M. , Wang Zhe , O’Neill Sandra , Damerow Sebastian , Post John , Bayliss Tracy , Lynch Sasha L. , Coyne Anthony G. , Ray Peter C. , Abell Chris , Rhee Kyu Y. , Boshoff Helena I. M. , Barry Clifton E. , Mizrahi Valerie , Wyatt Paul G. , Blundell Tom L.
Published: December 2019

Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens includingMycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, includingM. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal inM. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organismMycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent inhibitors ofM. tuberculosisCoaB, which we show to bind to a novel cryptic allosteric site within CoaB.
A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression
Authors: Di-Luoffo Mickaël , Pirenne Sophie , Saandi Thoueiba , Loriot Axelle , Gérard Claude , Dauguet Nicolas , Lamoline Florence , Konobrocka Katarzyna , De Greef Vitaline , Komuta Mina , Jacquemin Patrick , Lemaigre Frédéric P.
Published: December 2019

Background & Aims

Although earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) is necessary to improve therapy, there is still limited information available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression towards invasive tumor using experimental models that faithfully recapitulate human tumorigenesis.

Methods

We generated a new mouse model which combines cholangiocyte-specific expression ofKrasG12Dwith 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines.

Results

Mice expressingKrasG12Din cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs) and eventually iCCAs. The histology of mouse and human IPNBs were highly similar, and mouse iCCAs displayed histological characteristics of human mucin-producing large duct type iCCA. Signaling pathways activated in human iCCA were activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We provide evidence that a gene cascade which comprisesKRASG12D, SRY-related HMG box transcription factor 17 (SOX17) and Tensin 4 (TNS4), and which is activated by epidermal growth factor, promotes tumor progression.

Conclusions

We developed a novel mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade promoting tumor progression.
Discrete virus factories form in the cytoplasm of cells co-infected with two strains of the segmented dsRNA virus, infectious bursal disease virus (IBDV), that subsequently coalesce
Authors: Campbell Elle A. , Gray Alice G. , Wells Joanna , Simpson Jennifer , Hawes Pippa C. , Broadbent Andrew J.
Published: December 2019

TheBirnaviridaefamily, responsible for major economic losses to poultry and aquaculture, are non-enveloped viruses with a segmented double-stranded (ds)RNA genome that replicate in discrete cytoplasmic virus factories (VFs). Reassortment is common, however, the underlying mechanism remains unknown given that VFs may act as a barrier to genome mixing. In order to provide new information on VF trafficking during dsRNA virus co-infection, we rescued two recombinant infectious bursal disease viruses (IBDVs) of strain PBG98 containing either a split GFP11- or Tetracysteine (TC)- tag fused to the VP1 polymerase (PBG98-VP1-GFP11 and PBG98-VP1-TC). DF-1 cells transfected with GFP1-10 prior to PBG98-VP1-GFP11 infection, or stained with ReAsH following PBG98-VP1-TC infection, had green or red foci in the cytoplasm respectively that co-localised with VP3 and dsRNA, consistent with VFs. The average number of VFs decreased from a mean of 60 to 5 per cell between 10 and 24 hours post infection (hpi) (p<0.001), while the average area increased from 1.24 μm2to 45.01μm2(p<0.001), and live cell imaging revealed that the VFs were highly dynamic structures that coalesced in the cytoplasm. Small VFs moved faster than large (average 0.57μm/s at 16 hpi compared to 0.22 μm/s at 22 hpi), and VF coalescence was dependent on an intact microtubule network and actin cytoskeleton. During co-infection with PBG98-VP1-GFP11 and PBG98-VP1-TC viruses, discrete VFs initially formed from each input virus that subsequently coalesced 10-16 hours post-infection. We speculate that dsRNA virus reassortment requires VF coalescence, and the potential for reassortment increases at later time points in infection.

Importance

Reassortment is common in viruses with segmented double stranded (ds)RNA genomes. However, these viruses typically replicate within discrete cytoplasmic virus factories (VFs) that may represent a barrier to genome mixing. We generated the first replication competent tagged reporter birnaviruses, infectious bursal disease viruses (IBDVs) containing a split GFP11 or tetracysteine (TC) tag and used the viruses to track the location and movement of IBDV VFs, in order to better understand the intracellular dynamics of VFs from two different strains of dsRNA virus during a co-infection. Discrete VFs initially formed from each virus that subsequently coalesced from 10 hours pi. We hypothesise that VF coalescence is required for the reassortment of dsRNA viruses and the potential for reassortment increases later in the replication cycle. This study provides new information that adds to our understanding of dsRNA virus VF trafficking.
The Glyco-enzyme adaptor GOLPH3 Links Intra-Golgi Transport Dynamics to Glycosylation Patterns and Cell Proliferation
Authors: Rizzo Riccardo , Russo Domenico , Kurokawa Kazuo , Sahu Pranoy , Lombardi Bernadette , Supino Domenico , Zhukovsky Mikhail , Vocat Anthony , Pothukuchi Prathyush , Kunnathully Vidya , Capolupo Laura , Boncompain Gaelle , Vitagliano Carlo , Marino Federica Zito , Aquino Gabriella , Montariello Daniela , Henklein Petra , Mandrich Luigi , Botti Gerardo , Clausen Henrik , Mandel Ulla , Yamaji Toshiyuki , Hanada Kentaro , Budillon Alfredo , Perez Franck , Parashuraman Seetharaman , Hannun Yusuf A , Nakano Akihiko , Corda Daniela , D’Angelo Giovanni , Luini Alberto
Published: December 2019

Glycans are ubiquitous sugar polymers with major biological functions that are assembled by glyco-enzymes onto cargo molecules during their transport through the Golgi complex. How the Golgi determines glycan assembly is poorly understood. By relying on the Golgi cisternal maturation model and using the glyco-enzyme adaptor and oncoprotein GOLPH3 as a molecular tool, we define the first example of how the Golgi controls glycosylation and associated cell functions. GOLPH3, acting as a component of the cisternal maturation mechanism, selectively binds and recycles a subset of glyco-enzymes of the glycosphingolipid synthetic pathway, hinders their escape to the lysosomes and hence increases their levels through a novel lysosomal degradation-regulated mechanism. This enhances the production of specific growth-inducing glycosphingolipids and reprograms the glycosphingolipid pathway to potentiate mitogenic signaling and cell proliferation. These findings unravel unforeseen organizing principles of Golgi-dependent glycosylation and delineate a paradigm for glycan assembly by the Golgi transport mechanisms. Moreover, they indicate a new role of cisternal maturation as a regulator of glycosylation, and outline a novel mechanism of action for GOLPH3-induced proliferation.
Human Skeletal Muscle has Large Capacity to Increase Carnosine Content in Response to Beta-Alanine Supplementation. A Systematic Review with Bayesian Individual and Aggregate Data E-Max Model and Meta-Analysis
Authors: Rezende Nathalia Saffioti , Swinton Paul , de Oliveira Luana Farias , da Silva Rafa Pires , da Silva Vinicius Eira , Nemezio Kleiner , Yamaguchi Guilherme , Artioli Guilherme G , Gualano Bruno , Saunders Bryan , Dolan Eimear
Published: December 2019

Beta-alanine (BA) supplementation increases muscle carnosine content (MCarn), and is ergogenic in many situations. Currently, many questions on the nature of the Mcarn response to supplementation are open, and the response to these has considerable potential to enhance the efficacy and applications of this supplementation strategy.

Objective

To conduct a Bayesian analysis of available data on the Mcarn response to BA supplementation.

Methods

A systematic review with meta-analysis of individual and published aggregate data using a dose response (Emax) model was conducted. The protocol was designed according to PRISMA guidelines. A three-step screening strategy was undertaken to identify studies that measured the Mcarn response to BA supplementation. In addition, individual data from 5 separate studies conducted in the authors’ laboratory were analysed. Data were extracted from all controlled and uncontrolled supplementation studies conducted on healthy humans. Meta-regression was used to consider the influence of potential moderators (including dose, sex, age, baseline Mcarn and analysis method used) on the primary outcome.

Results and Conclusion

The Emax model indicated that human skeletal muscle has large capacity for non-linear Mcarn accumulation, and that commonly used BA supplementation protocols may not come close to saturating muscle carnosine content. Neither baseline values, nor sex, appear to influence subsequent response to supplementation. Analysis of individual data indicated that Mcarn is relatively stable in the absence of intervention, and effectually all participants respond to BA supplementation (99.3% response [95%CrI: 96.2 – 100]).
Natural scene statistics predict how humans pool information across space in the estimation of surface tilt
Authors: Kim Seha , Burge Johannes
Published: December 2019

Visual systems estimate the three-dimensional (3D) structure of scenes from information in two-dimensional (2D) retinal images. Visual systems use multiple sources of information to improve the accuracy of these estimates, including statistical knowledge of the probable spatial arrangements of natural scenes. Here, we examine how 3D surface tilts are spatially related in real-world scenes, and show that humans pool information across space when estimating surface tilt in accordance with these spatial relationships. We develop a hierarchical model of surface tilt estimation that is grounded in the statistics of tilt in natural scenes and images. The model computes a global tilt estimate by pooling local tilt estimates within an adaptive spatial neighborhood. The spatial neighborhood in which local estimates are pooled changes according to the value of the local estimate at a target location. The hierarchical model provides more accurate estimates of groundtruth tilt in natural scenes and provides a better account of human performance than the local model. Taken together, the results imply that the human visual system pools information about surface tilt across space in accordance with natural scene statistics.