bluuebunny/crossref_metadata_2025 huggingface dataset:
Henry Taube. 30 November 1915—16 November 2005
Authors: Ford Peter C. , Meyer Thomas J.
Published: December 2020

Through a lifetime of increasingly broad and significant experiments and discoveries, Henry Taube became the world's premier mechanistic inorganic chemist (one who focuses on reaction pathways and reaction mechanisms produced during inorganic chemical changes). In his first faculty appointment, he examined the oxidation–reduction reaction and identified questions that could only be answered through precise experimentation. He then focused on the chemistry of transition metal complexes, laying out the details of what he called ‘inner sphere electron transfer’. He went on to compile a broad range of findings, leading to the elevation of inorganic chemistry to a major field of study.

Taube earned bachelor's and master's degrees at the University of Saskatchewan and a PhD from UC Berkeley. After receiving his doctorate in 1941, he took a position as an instructor at Cornell University, where he remained until 1946. He then joined the faculty of the University of Chicago, where he carried out seminal investigations of the electron transfer reactions between metal ion complexes. In 1962 he moved to Stanford, where he continued studies of electron transfer mechanisms. He also twice served as chair (1972–74; 1978–79) of the Stanford Department of Chemistry and subsequently was appointed the Marguerite Blake Wilbur Professor in 1976. He formally retired from the faculty in 1986, but continued as an active scientist long afterward.
A COVID-19 transmission model informing medication development and supply chain needs
Authors: Lemenuel-Diot Annabelle , Clinch Barry , Hurt Aeron C. , Boutry Paul , Laurent Johann , Leddin Mathias , Frings Stefan , Charoin Jean Eric
Published: December 2020

Accurate prediction of COVID-19 cases can optimize clinical trial recruitment, inform mitigation strategies and facilitate rapid medication development. Here we present a country-specific, modified Susceptible, Exposed, Infectious, Removed (SEIR) model of SARS-CoV-2 transmission using data from the Johns Hopkins University COVID-19 Dashboard. Inter-country differences in initial exposure, cultural/environmental factors, reporting requirements and stringency of mitigation strategies were incorporated. Asymptomatic patients and super-spreaders were also factored into our model. Using these data, our model estimated 65.8% of cases as asymptomatic; symptomatic and asymptomatic people were estimated to infect 2.12 and 5.83 other people, respectively. An estimated 9.55% of cases were super-spreaders with a 2.11-fold higher transmission rate than average. Our model estimated a mean maximum infection rate of 0.927 cases/day (inter-country range, 0.63–1.41) without mitigation strategies. Mitigation strategies with a stringency index value of ≥60% were estimated to be required to reduce the reproduction ratio below 1. It was predicted that cases over the next 2 months would differ between countries, with certain countries likely to experience an accelerated accumulation of cases. Together, results from our model can guide distribution of diagnostic tests, impact clinical trial development, support medication development and distribution and inform mitigation strategies to reduce COVID-19 spread.

Key Findings

Predicting COVID-19 cases can inform medication development and mitigation strategies

We created a modified SEIR model of SARS-CoV-2 transmission

We integrated asymptomatic cases, super-spreaders and hotspots that drive viral spread

Mitigation strategies with a stringency index of ≥60% are required to reduce the RR below 1

Some countries may experience an accelerated accumulation of cases in the coming months
The attitudes of Greeks towards second-hand smoke and the anti-tobacco legislation
Authors: Passa Anna , Agtzidis Ioannis , Tsaousidou Maria , Passa Katalin Fekete
Published: December 2020

Greece had according to Eurobarometer 2017 the highest rates of secondhand smoke exposure in the European Union (87%). The main aim of this study was to understand the reasons for the non-enforcement of the anti-tobacco legislation. To do this, we created two different questionnaires, one for smokers and one for non-smokers, and we collected epidemiological data, data about the attitudes of Greeks towards smoking, second-hand smoke, and the smoke-free legislation, as well as data about some relevant behavioural patterns. In total 597 non-smoker questionnaires and 366 smoker questionnaires were collected, with the mean age of the participants being 40 years old. The majority of people claimed that smoke disturbs them and, interestingly, smokers responded that they consider disturbing others with their smoke, and especially when children are present. Additionally, smokers said they would slightly reduce going out if the smoke-free legislation was strictly enforced, while non-smokers would respectively slightly increase going out. Based on this observation and given the higher proportion of non-smokers than smokers, we can assume that there will be no negative impact to the eating and drinking establishments, as many people were speculating, but to the opposite, there might even be a small benefit from the implementation of smoke-free measures. Since 2019 the relevant legislation has been enforced, but due to the COVID-19 pandemic, the long-term implementation and the true outcomes of the relevant legislation are more difficult to study.
The iPSYCH2015 Case-Cohort sample: updated directions for unravelling genetic and environmental architectures of severe mental disorders
Authors: Bybjerg-Grauholm Jonas , Bøcker Pedersen Carsten , Bækvad-Hansen Marie , Giørtz Pedersen Marianne , Adamsen Dea , Søholm Hansen Christine , Agerbo Esben , Grove Jakob , Als Thomas Damm , Schork Andrew Joseph , Buil Alfonso , Mors Ole , Nordentoft Merete , Werge Thomas , Børglum Anders Dupont , Hougaard David Michael , Mortensen Preben Bo
Published: December 2020

The Lundbeck Foundation Integrative Psychiatric Research (iPSYCH) consortium has almost doubled its Danish population-based Case–Cohort sample (iPSYCH2012). The newly updated cohort, named iPSYCH2015, expands the study base with 56,233 samples, to a combined total of 141,265 samples. The cohort is nested within the Danish population born between 1981 and 2008 and is a Case-Cohort design including 50,615 population controls. We added more cases to the existing phenotypes identified with, schizophrenia (Nnew=4,131/Ntotal=8,113), autism (Nnew=8,056 / Ntotal=24,975), attention-deficit/hyperactivity disorder (Nnew=10,026/Ntotal=29,668) and affective disorder (Nnew=13,999/Ntotal=40,482) of which a subset has bipolar affective disorder (N-new=1,656/Ntotal=3,819). We also added two additional focus phenotypes, schizophrenia spectrum disorder (N=16,008) and post-partum disorder (N=3,421). In total, the expanded iPSYCH2015 sample consists of 93,608 unique individuals in the case groups and 50,615 population controls. For the sample expansion, DNA was extracted and amplified from dried blood spots samples stored within the Danish Neonatal Screening Biobank and genotyped using the Illumina Global Screening Array. The Biobank sample retrieval rate was 95%, and the genotyping success rate was 92% (97% of retrieved). We expanded the follow-up period by three years, including data such as longitudinal information on health, prescribed medicine, social and socioeconomic information.
Lost in time: temporal monitoring elicits clinical decrements in sustained attention post-stroke
Authors: Brosnan MB , Dockree PM , Harty S , Pearce DJ , Levenstein JM , Gillebert CR , Bellgrove MA , O’Connell RG , Robertson IH , Demeyere N
Published: December 2020

Objective

Mental fatigue, ‘brain fog’ and difficulties maintaining engagement are commonly reported issues in a range of neurological and psychiatric conditions. Traditional sustained attention tasks commonly measure this capacity as the ability to detect target stimuli based on sensory features in the auditory or visual domains. However, with this approach, discrete target stimuli may exogenously capture attention to aid detection, thereby masking deficits in the ability to endogenously sustain attention over time.

Method

To address this, we developed the continuous temporal expectancy test (CTET) where individuals continuously monitor a stream of patterned stimuli alternating at a fixed temporal interval (690ms) and detect an infrequently occurring target stimulus defined by a prolonged temporal duration (1020ms or longer). As such, sensory properties of target and non-target stimuli are perceptually identical and differ only in temporal duration. Using the CTET, we assessed stroke survivors with unilateral right hemisphere damage (N=14), a cohort in which sustained attention deficits have been extensively reported.

Results

Stroke survivors had overall lower target detection accuracy compared to neurologically-healthy age-matched older controls (N=18). In addition, performance of the stroke survivors was characterised by significantly steeper within-block performance decrements which occurred within short temporal windows (~3 ½ minutes) and were restored by the break periods between blocks.

Conclusion

These findings outline a precise measure of the endogenous processes hypothesized to underpin sustained attention deficits following right hemisphere stroke and suggest that continuous temporal monitoring taxes sustained attention process to capture clinical deficits in this capacity over time.
Genetic maternal effects contributes to the risk of Tourette’s disorder
Authors: Mahjani Behrang , Klei Lambertus , Hultman Christina M. , Larsson Henrik , Sandin Sven , Devlin Bernie , Buxbaum Joseph D. , Grice Dorothy E.
Published: December 2020

Background

Risk for Tourette’s and related tic disorders (CTD) derives from a combination of genetic and environmental factors. While multiple studies have demonstrated the importance of direct additive genetic variation for CTD, little is known about the role of cross-generational transmission of genetic risks, such as maternal effects. Here, we partition sources of variation on CTD risk into direct additive genetic effect and maternal effects.

Methods

The study population consists of 2,522,677 individuals from the Swedish Medical Birth Register, born in Sweden between January 1, 1982, to December 31, 1990, and followed for a diagnosis of CTD through December 31, 2013.

Results

We identified 6,227 (0.25%) individuals in the birth cohort diagnosed with CTD. Using generalized linear mixed models, we estimated 4.7% (95% CrI, 4.4%-4.8%) genetic maternal effects, 0.5% (95% CrI, 0.2%-7%) environmental maternal effects, and 61% (95% CrI, 59%-63%) direct additive genetic effects. Around 1% of genetic maternal effects were due to maternal effects from the individual with comorbid obsessive-compulsive disorder.

Conclusions

Our results demonstrate genetic maternal effects contributing to the risk of CTD in offspring and also highlight new sources of overlapping risk between CTD and obsessive-compulsive disorder.
Missed childhood immunizations during the COVID-19 pandemic in Brazil: analyses of routine statistics and of a national household survey
Authors: Silveira Mariangela F , Tonial Cristian T , Maranhão Ana Goretti K , Teixeira Antonia MS , Hallal Pedro C , Menezes Ana Maria B , Horta Bernardo L , Hartwig Fernando P , Barros Aluisio JD , Victora Cesar G
Published: December 2020

Introduction

There is widespread concern that disruption to health services during the COVID-19 pandemic has led to declines in immunization coverage among young children, but there is limited information on the magnitude of such impact.

Methods

We used data from two nationwide sources covering the whole of Brazil. Data from the Information System of the National Immunization Program (SIPNI) on the monthly number of vaccine doses administered to young children were analyzed. The second source was a survey in 133 large cities in the 27 states in the country, carried out from August 24-27. Respondents answered a question on whether children under the age of three years had missed any scheduled vaccinations during the pandemic, and available vaccination cards were photographed for later examination.

Results

SIPNI data showed that, relative to January and February 2020, there was a decline of about 20% in vaccines administered to children aged two months or older during March and April, when social distancing was at the highest level in the country. After May, vaccination levels returned to pre-pandemic values. Survey data, based on the interviews and on examination of the vaccine cards, showed that 19.0% (95% CI 17.0;21.1%) and 20.6% (95% CI 19.0;23.1%) of children, respectively, had missed immunizations. Missed doses were most common in the North (Amazon) region and least common in the South and Southeast, and also more common among children from poor than from wealthy families.

Interpretation

Our results show that the pandemic was associated with a reduction of about 20% in child vaccinations, but this was reverted in recent months. Children from poor families and from the least developed regions of the country were most affected. There is an urgent need to booster immunization activities in the country to compensate for missed doses, and to reduce geographic and socioeconomic inequalities.
Smoking increases the risk of COVID-19 positivity, while Never-smoking reduces the risk
Authors: Barasa Samson , Kiage-Mokaya Josephine , Cruz-Madrid Katya , Friedlander Michael
Published: December 2020

Introduction

Does smoking decrease the risk of testing positive for COVID-19 because the never-smokers (84%) prevalence is high and the current-smokers prevalence is low among COVID-19 positive patients?1,2,3,4,5,6We sought to determine whether never smoking increases the risk of COVID-19 positivity among the 50 to 69-year old patients because they are more likely to test positive for COVID-19.7

Method

We conducted a retrospective chart review of COVID-19 Polymerase chain reaction, in-hospital tested ≥18-year-old patients. A Poisson regression analysis stratified into never-smokers and history of smoking (current + former smokers) was conducted.

Results

277 COVID-19 negative and 117 COVID-19 positive patients’ charts with a never-smokers prevalence of 42.32% and 54% respectively were analyzed. The never-smokers prevalence was 54%, 20-39-years; 61 %, 40 -49-years; 41%, 50 – 69-years; and 43%, 70 – 100-years.

The 40-49-year-old current and former smokers were more likely to test positive for COVID-19 [1.309 (1.047 - 1.635)], unlike the 40-49-year-old never-smokers [0.976 (0.890-1.071)] who had a lower risk.

Regardless of their smoking status, males [1.084(1.021 - 1.151)] and the 50-69-year-old patients [1.082 (1.014 -1.154)] were more likely to test positive for COVID-19, while end stage renal disease [0.908(0.843-0.978)] and non-COVID-19 respiratory viral illness [0.907 (0.863 - 0.953)] patients had a lower risk of COVID-19 positivity.

Heart failure [0.907 (0.830 - 0.991)], chronic obstructive pulmonary disease (COPD) [0.842 (0.745 - 0.952)] and Parkinson’s disease [0.823 (0.708 - 0.957)] never-smokers were less likely to test positive for COVID-19.

Conclusion

This is the first study to show that smoking increases the risk of COVID-19 positivity among the 40-49-year-old patients, while not smoking reduces the risk of COVID-19 positivity among the heart failure, COPD and Parkinson’s disease patients. This study emphasizes that COVID-19 positivity risk is not reduced by smoking and not increased by not smoking.
Ste20-like kinase is critical for inhibitory synapse maintenance and its deficiency confers a developmental dendritopathy
Authors: Schoch Susanne , Quatraccioni Anne , Robens Barbara K. , Maresch Robert , van Loo Karen M.J. , Kelly Tony , Opitz Thoralf , Borger Valeri , Dietrich Dirk , Pitsch Julika , Beck Heinz , Becker Albert J.
Published: December 2020

The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output. The regulatory mechanisms governing the development of dendrites, however, are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. However, its function in neurons is unknown. We show that during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, ≥ 3rd, order dendrites. Moreover, we demonstrate that SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown caused a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, while excitatory neurotransmission was unaffected. Finally, we show that this mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations revealed significant loss of SLK expression. Overall, the present data identify SLK as a key regulator of both dendritic complexity during development and of inhibitory synapse maintenance.
NGScloud2: optimized bioinformatic analysis using Amazon Web Services
Authors: Mora-Márquez Fernando , Vázquez-Poletti José Luis , de Heredia Unai López
Published: December 2020

NGScloud was a bioinformatic system developed to performde novoRNAseq analysis of non-model species by exploiting the cloud computing capabilities of Amazon Web Services. The rapid changes undergone in the way this cloud computing service operates, along with the continuous release of novel bioinformatic applications to analyze next generation sequencing data, have made the software obsolete. NGScloud2 is an enhanced and expanded version of NGScloud that permits the access toad hoccloud computing infrastructure, scaled according to the complexity of each experiment. NGScloud2 presents major technical improvements, such as the possibility of running spot instances and the most updated AWS instances types, that can lead to significant cost savings. As compared to its initial implementation, this improved version updates and includes common applications forde novoRNAseq analysis, and incorporates tools to operate workflows of bioinformatic analysis of reference-based RNAseq, RADseq and functional annotation. NGScloud2 optimizes the access to Amazon’s large computing infrastructures to easily run popular bioinformatic software applications, otherwise inaccessible to non-specialized users lacking suitable hardware infrastructures. The correct performance of the pipelines forde novoRNAseq, reference-based RNAseq, RADseq and functional annotation was tested with real experimental data. NGScloud2 code, instructions for software installation and use are available athttps://github.com/GGFHF/NGScloud2. NGScloud2 includes a companion package, NGShelper that contains python utilities to post-process the output of the pipelines for downstream analysis athttps://github.com/GGFHF/NGShelper.
The generation of cortical novelty responses through inhibitory plasticity
Authors: Schulz Auguste , Miehl Christoph , Berry Michael J. , Gjorgjieva Julijana
Published: December 2020

Animals depend on fast and reliable detection of novel stimuli in their environment. Indeed, neurons in multiple sensory areas respond more strongly to novel in comparison to familiar stimuli. Yet, it remains unclear which circuit, cellular and synaptic mechanisms underlie those responses. Here, we show that inhibitory synaptic plasticity readily generates novelty responses in a recurrent spiking network model. Inhibitory plasticity increases the inhibition onto excitatory neurons tuned to familiar stimuli, while inhibition for novel stimuli remains low, leading to a network novelty response. Generated novelty responses do not depend on the exact temporal structure but rather on the distribution of presented stimuli. By including tuning of inhibitory neurons, the network further captures stimulus-specific adaptation. Finally, we suggest that disinhibition can control the amplification of novelty responses. Therefore, inhibitory plasticity provides a flexible, biologically-plausible mechanism to detect the novelty of bottom-up stimuli, enabling us to make numerous experimentally testable predictions.
Reproductive proteins evolve faster than non-reproductive proteins amongSolanumspecies
Authors: Moyle Leonie C. , Wu Meng , Gibson Matthew J. S.
Published: December 2020

Elevated rates of evolution in reproductive proteins are commonly observed in animal species, and are thought to be driven by the action of sexual selection and sexual conflict acting specifically on reproductive traits. Whether similar patterns are broadly observed in other biological groups is equivocal. Here we examine patterns of protein divergence among wild tomato species (SolanumsectionLycopersicon), to understand forces shaping the evolution of reproductive genes in this diverse, rapidly evolving plant clade. By comparing rates of molecular evolution among loci expressed in reproductive and non-reproductive tissues, our aims were to test if: a) reproductive-specific loci evolve more rapidly, on average, than non-reproductive loci; ‘male’-specific loci evolve at different rates than ‘female’-specific loci; c) genes expressed exclusively in gametophytic (haploid) tissue evolve differently from genes expressed in sporophytic (diploid) tissue or in both tissue types; and d) mating system variation (a potential proxy for the expected strength of sexual selection and/or sexual conflict) affects patterns of protein evolution. We observed elevated evolutionary rates in reproductive proteins. However this pattern was most evident for female- rather than male-specific loci, both broadly and for individual loci inferred to be positively selected. These elevated rates might be facilitated by greater tissue-specificity of reproductive proteins, as faster rates were also associated with more narrow expression domains. In contrast we found little evidence that evolutionary rates are consistently different in loci experiencing haploid selection (gametophytic-exclusive loci), or in lineages with quantitatively different mating systems. Overall while reproductive protein evolution is generally elevated in this diverse plant group, some specific patterns of evolution are more complex than those reported in other (largely animal) systems, and include a more prominent role for female-specific loci among adaptively evolving genes.
Multigenerational exposure to heat stress induces phenotypic resilience, and genetic and epigenetic variations inArabidopsis thalianaoffspring
Authors: Yadav Narendra Singh , Titov Viktor , Ayemere Ivie , Byeon Boseon , Ilnytskyy Yaroslav , Kovalchuk Igor
Published: December 2020

Plants are sedentary organisms that constantly sense changes in their environment and react to various environmental cues. On a short-time scale, plants respond through alterations in their physiology, and on a long-time scale, plants alter their development and pass on the memory of stress to the progeny. The latter is controlled genetically and epigenetically and allows the progeny to be primed for future stress encounters, thus increasing the likelihood of survival. The current study intended to explore the effects of multigenerational heat stress inArabidopsis thaliana.25 generations ofArabidopsis thalianawere propagated in the presence of heat stress. The multigenerational stressed lineage F25H exhibited a higher tolerance to heat stress and elevated frequency of homologous recombination, as compared to the parallel control progeny F25C. A comparison of genomic sequences revealed that the F25H lineage had a three-fold higher number of mutations (SNPs and INDELs) as compared control lineages, suggesting that heat stress induced genetic variations in the heat-stressed progeny. The F25H stressed progeny showed a 7-fold higher number of non-synonymous mutations than the F25C line. Methylome analysis revealed that the F25H stressed progeny showed a lower global methylation level in the CHH context than the control progeny. The F25H and F25C lineages were different from the parental control lineage F2C by 66,491 and 80,464 differentially methylated positions (DMPs), respectively. F25H stressed progeny displayed higher frequency of methylation changes in the gene body and lower in the body of transposable elements (TEs). Gene Ontology analysis revealed that CG-DMRs were enriched in processes such as response to abiotic and biotic stimulus, cell organizations and biogenesis, and DNA or RNA metabolism. Hierarchical clustering of these epimutations separated the heat stressed and control parental progenies into distinct groups which revealed the non-random nature of epimutations. We observed an overall higher number of epigenetic variations than genetic variations in all comparison groups, indicating that epigenetic variations are more prevalent than genetic variations. The largest difference in epigenetic and genetic variations was observed between control plants comparison (F25C vs F2C), which clearly indicated that the spontaneous nature of epigenetic variations and heat-inducible nature of genetic variations. Overall, our study showed that progenies derived from multigenerational heat stress displayed a notable adaption in context of phenotypic, genotypic and epigenotypic resilience.
Prospective mapping of viral mutations that escape antibodies used to treat COVID-19
Authors: Starr Tyler N. , Greaney Allison J. , Addetia Amin , Hannon William W. , Choudhary Manish C. , Dingens Adam S. , Li Jonathan Z. , Bloom Jesse D.
Published: December 2020

Antibodies are becoming a frontline therapy for SARS-CoV-2, but the risk of viral evolutionary escape remains unclear. Here we map how all mutations to SARS-CoV-2’s receptor-binding domain (RBD) affect binding by the antibodies in Regeneron’s REGN-COV2 cocktail and Eli Lilly’s LY-CoV016. These complete maps uncover a single amino-acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2, as well as in lab viral escape selections. Finally, the maps reveal that mutations escaping each individual antibody are already present in circulating SARS-CoV-2 strains. Overall, these complete escape maps enable immediate interpretation of the consequences of mutations observed during viral surveillance.
Automatic Reconstruction of Cerebellar Cortex from Standard MRI Using Diffeomorphic Registration of a High-Resolution Template (ARCUS)
Authors: Samuelsson John G. , Rosen Bruce , Hämäläinen Matti S.
Published: December 2020

As cumulating evidence points to a wider range of functional tasks and neurological conditions that involve the cerebellum than previously known, the interest for examining the cerebellum with non-invasive neuroimaging techniques is growing. However, the standard methods of computational neuroanatomy for segmenting and reconstructing the cerebral cortex work poorly for the cerebellar cortex at the resolutions attainable with contemporary MRI technology because of its extremely intricate folding, making detailed and topologically correct reconstructions of the geometry of the cerebellar cortical surface unfeasible. Recently, a detailed surface reconstruction of the human cerebellar cortex was achieved from an ex-vivo specimen. These novel anatomical data enable a new reconstruction technique where this detailed surface reconstruction is morphed to subject space based on standard in-vivo MRI data. The result is an approximate reconstruction of the cerebellar cortex that requires only standard-resolution MRI data and can be used e.g., in functional neuroimaging, for integrating topographic population data or for visualizing topographic data on flattened surface patches.
KDClassifier: Urinary Proteomic Spectra Analysis Based on Machine Learning for Classification of Kidney Diseases
Authors: Zhao Wanjun , Zhang Yong , Li Xinming , Mao Yonghong , Wu Changwei , Zhao Lijun , Liu Fang , Zhu Jingqiang , Cheng Jingqiu , Yang Hao , Li Guisen
Published: December 2020

Background

By extracting the spectrum features from urinary proteomics based on an advanced mass spectrometer and machine learning algorithms, more accurate reporting results can be achieved for disease classification. We attempted to establish a novel diagnosis model of kidney diseases by combining machine learning with an extreme gradient boosting (XGBoost) algorithm with complete mass spectrum information from the urinary proteomics.

Methods

We enrolled 134 patients (including those with IgA nephropathy, membranous nephropathy, and diabetic kidney disease) and 68 healthy participants as a control, and for training and validation of the diagnostic model, applied a total of 610,102 mass spectra from their urinary proteomics produced using high-resolution mass spectrometry. We divided the mass spectrum data into a training dataset (80%) and a validation dataset (20%). The training dataset was directly used to create a diagnosis model using XGBoost, random forest (RF), a support vector machine (SVM), and artificial neural networks (ANNs). The diagnostic accuracy was evaluated using a confusion matrix. We also constructed the receiver operating-characteristic, Lorenz, and gain curves to evaluate the diagnosis model.

Results

Compared with RF, the SVM, and ANNs, the modified XGBoost model, called a Kidney Disease Classifier (KDClassifier), showed the best performance. The accuracy of the diagnostic XGBoost model was 96.03% (CI = 95.17%-96.77%; Kapa = 0.943; McNemar’s Test, P value = 0.00027). The area under the curve of the XGBoost model was 0.952 (CI = 0.9307-0.9733). The Kolmogorov-Smirnov (KS) value of the Lorenz curve was 0.8514. The Lorenz and gain curves showed the strong robustness of the developed model.

Conclusions

This study presents the first XGBoost diagnosis model, i.e., the KDClassifier, combined with complete mass spectrum information from the urinary proteomics for distinguishing different kidney diseases. KDClassifier achieves a high accuracy and robustness, providing a potential tool for the classification of all types of kidney diseases.
Parallel Hippocampal-Parietal Circuits for Self- and Goal-oriented Processing
Authors: Zheng Annie , Montez David F. , Marek Scott , Gilmore Adrian W. , Newbold Dillan J. , Laumann Timothy O. , Kay Benjamin P. , Seider Nicole A. , Van Andrew N. , Hampton Jacqueline M. , Alexopolous Dimitrios , Schlaggar Bradley L. , Sylvester Chad M. , Greene Deanna J. , Shimony Joshua S. , Nelson Steven M. , Wig Gagan S. , Gratton Caterina , McDermott Kathleen B. , Raichle Marcus E. , Gordon Evan M. , Dosenbach Nico U.F.
Published: December 2020

The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. The human hippocampus has been thought of as being solely functionally connected to a set of neocortical regions known as the default mode network (DMN), which supports self-referential cognition. Using individual-specific precision functional mapping of resting state fMRI data, we found the anterior hippocampus (head and body) to be preferentially connected to the DMN as expected. The hippocampal tail, however, was strongly preferentially connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This resting state functional connectivity (RSFC) anterior-posterior dichotomy was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the head and body of the hippocampus (DMN), relatively sparing the tail (PMN). Anterior and posterior hippocampal connectivity was network-specific even though the DMN and PMN are interdigitated in medial parietal cortex. The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel, but distinct circuits between the hippocampus and medial parietal cortex for self vs. goal-oriented processing.
Multiple variants of the blast fungus effector AVR-Pik bind the HMA domain of the rice protein OsHIPP19 with high affinity
Authors: Maidment Josephine H. R. , Franceschetti Marina , Maqbool Abbas , Saitoh Hiromasa , Jantasuriyarat Chatchawan , Kamoun Sophien , Terauchi Ryohei , Banfield Mark J.
Published: December 2020

Microbial plant pathogens secrete effector proteins which manipulate the host to promote infection. Effectors can be recognised by plant intracellular nucleotide-binding leucine-rich repeat (NLR) receptors, initiating an immune response. The AVR-Pik effector from the rice blast fungusMagnaporthe oryzaeis recognised by a pair of rice NLR receptors, Pik-1 and Pik-2. Pik-1 contains a non-canonical integrated heavy metal-associated (HMA) domain, which directly binds AVR-Pik to activate plant defences. Non-canonical integrated domains are widespread in plant NLRs and are thought to resemble the host target of the recognised effector. AVR-Pik interacts with specific rice HMA domain-containing proteins, namely heavy metal-associated isoprenylated plant proteins (HIPPs) and heavy metal-associated plant proteins (HPPs). Here, we define the biochemical and structural basis of the interaction between AVR-Pik and OsHIPP19, and compare the interaction with the HMA domain of Pik-1. Using analytical gel filtration and surface plasmon resonance, we show that multiple AVR-Pik variants, including the stealthy variants AVR-PikC and AVR-PikF which do not interact with any characterised Pik-1 alleles, bind to OsHIPP19 with nanomolar affinity. The crystal structure of OsHIPP19 in complex with AVR-PikF reveals differences at the interface that underpin high-affinity binding of OsHIPP19-HMA to a wider set of AVR-Pik variants than achieved by the integrated HMA domain of Pik-1. Our results provide a foundation for engineering the HMA domain of Pik-1 to extend binding to currently unrecognised AVR-Pik variants and expand disease resistance in rice to divergent pathogen strains.
Myotube hypertrophy is associated with cancer-like metabolic reprogramming and limited by PHGDH
Authors: Stadhouders Lian E.M. , Verbrugge Sander A.J. , Smith Jonathon A.B. , Gabriel Brendan M. , Hammersen Tim D. , Kolijn Detmar , Vogel Ilse S.P. , Mohamed Abdalla D. , de Wit Gerard M.J. , Offringa Carla , Hoogaars Willem M. , Gehlert Sebastian , Wackerhage Henning , Jaspers Richard T.
Published: December 2020

Muscle fiber size and oxidative metabolism are inversely related, suggesting that a glycolytic metabolism may offer a growth advantage in muscle fibers. However, the mechanisms underlying this advantage remains unknown. Nearly 100 years ago, Warburg reported that cancer cells take up more glucose to produce glycolytic intermediates for anabolic reactions such as amino acid-protein synthesis. The aim of this study was to test whether glycolysis contributes to anabolic signalling responses and hypertrophy in post-mitotic muscle cells. Skeletal muscle hypertrophy was induced in vitro by treating mouse C2C12 myotubes with IGF-1.14C glucose was added to differentiation medium and radioactivity in isolated protein was measured. We exposed differentiated C2C12 and primary mouse myotubes, to 2-deoxyglucose (2DG) and PHGDH siRNA upon which we assessed myotube diameter and signaling pathways involved in the regulation of muscle fiber size. Here, we present evidence that, hypertrophying C2C12 myotubes undergo a cancer-like metabolic reprogramming. First, IGF-1-induced C2C12 myotube hypertrophy increases shunting of carbon from glucose into protein. Second, reduction of glycolysis through 2-deoxy-D-glucose (2DG) lowers C2C12 and primary myotube size 16-40%. Third, reducing the cancer metabolism-associated enzyme PHGDH decreases C2C12 and primary myotube size 25-52%, whereas PHGDH overexpression increases C2C12 myotube size ≈20%. Fourth, the muscle hypertrophy-promoting kinase AKT regulates PHGDH expression. Together these results suggest that glycolysis is important for hypertrophying C2C12 myotubes by reprograming their metabolism similar to cancer cells.
Differential integrin adhesome expression defines human natural killer cell residency and developmental stage
Authors: Solloa Everardo Hegewisch , Seo Seungmae , Mundy-Bosse Bethany L. , Mishra Anjali , Waldman Erik , Maurrasse Sarah , Grunstein Eli , Connors Thomas J. , Freud Aharon G. , Mace Emily M.
Published: December 2020

Natural killer (NK) cells are innate immune cells that reside within tissue and circulate in peripheral blood. As such, they interact with a variety of complex microenvironments, yet how NK cells engage with these varied microenvironments is not well documented. The integrin adhesome represents a molecular network of defined and predicted integrin-mediated signaling interactions. Here, we define the integrin adhesome expression profile of NK cells from tonsil, peripheral blood and those derived from hematopoietic precursors through stromal cell coculture systems. We report that the site of cell isolation and NK cell developmental stage dictate differences in expression of adhesome associated genes and proteins. Furthermore, we define differences in cortical actin content associated with differential expression of actin regulating proteins, suggesting that differences in adhesome expression are associated with differences in cortical actin homeostasis. Together, these data provide new understanding into the diversity of human NK cell populations and how they engage with their microenvironment.
Interactions Between SQUAMOSA and SVP MADS-box Proteins Regulate Meristem Transitions During Wheat Spike Development
Authors: Li Kun , Debernardi Juan M. , Li Chengxia , Lin Huiqiong , Zhang Chaozhong , Dubcovsky Jorge
Published: December 2020

A better understanding of spike development can contribute to improving wheat productivity. MADS-box genesVRN1andFUL2(SQUAMOSA-clade) play critical and redundant roles in wheat spike and spikelet development, where they act as repressors of MADS-box genes of theSHORT VEGETATIVE PHASE(SVP) clade (VRT2,SVP1andSVP3). Here, we show that wheatvrt2 svp1mutants are late flowering, have shorter stems, increased number of spikelets per spike and unusual axillary inflorescences in nodes of the elongating stem. Constitutive expression ofVRT2resulted in leafy glumes and lemmas, reversion of basal spikelets to spikes, and down-regulation of MADS-genes involved in floral development. Moreover, constitutive expression ofVRT2enhanced spikelet defects offul2, whereasvrt2reduced vegetative characteristics in the spikelets ofvrn1 ful2mutants heterozygous forVRN-A1. TheseSVP-SQUAMOSAgenetic interactions were paralleled by physical interactions among their encoded proteins. SVP proteins were able to reduce SQUAMOSA-SEPALLATA interactions in yeast-three-hybrid experiments. We propose that SQUAMOSA-SVP complexes act during the early reproductive phase to promote heading, formation of the terminal spikelet, and stem elongation, but that down-regulation ofSVPgenes is then necessary for the formation of SQUAMOSA-SEPALLATA complexes that are required for normal spikelet and floral development.
A small-scale shRNA screen in primary mouse macrophages identifies a role for the Rab GTPase Rab1b in controlling Salmonella Typhi growth
Authors: Solano-Collado Virtu , Colamarino Rosa Angela , Calderwood David A , Baldassarre Massimiliano , Spanò Stefania
Published: December 2020

Salmonella Typhi, the causative agent of typhoid fever, a life-threatening systemic infection, is a human restricted bacterial pathogen. A fundamental aspect of S. Typhi pathogenesis is its ability to survive in human macrophages but not in macrophages from other animals (i.e. mice). Despite the importance of macrophages in establishing systemic S. Typhi infection, the mechanisms that macrophages use to control the growth of S. Typhi and the role of these mechanisms in the bacterium’s adaptation to the human host are mostly unknown. To facilitate unbiased identification of genes involved in controlling the growth of S. Typhi in macrophages, we report optimized experimental conditions required to perform loss-of function pooled shRNA screens in primary mouse bone-marrow derived macrophages. Following infection with a fluorescently-labeled S. Typhi, cells defective in genes important for controlling S. Typhi growth (and therefore unable to kill S. Typhi) are sorted based on the intensity of fluorescence (i.e. number of intracellular fluorescent bacteria). shRNAs enriched in the fluorescent population are identified by next-generation sequencing. A proof-of-concept screen targeting the mouse Rab GTPases confirmed Rab32 as important to restrict S. Typhi in mouse macrophages. Interestingly and rather unexpectedly, this screen also revealed that Rab1b controls S. Typhi growth in mouse macrophages. This constitutes the first report of a Rab GTPase other than Rab32 involved in S. Typhi host-restriction. The methodology described here should allow genome-wide screening to identify mechanisms controlling the growth of S. Typhi and other intracellular pathogens in primary immune cells.
GATA4/5/6 family transcription factors are conserved determinants of cardiac versus pharyngeal mesoderm fate
Authors: Song Mengyi , Yuan Xuefei , Racioppi Claudia , Leslie Meaghan , Aleksandrova Anastasiia , Christiaen Lionel , Wilson Michael D. , Scott Ian C.
Published: December 2020

GATA4/5/6 transcription factors play essential, conserved roles in heart development. How these factors mediate the transition from multipotent mesoderm progenitors to a committed cardiac fate is unclear. To understand how GATA4/5/6 modulate cell fate decisions we labelled, isolated, and performed single-cell gene expression analysis on cells that expressgata5at pre-cardiac time points spanning gastrulation to somitogenesis. We found that most mesendoderm-derived lineages had dynamicgata5/6expression. In the absence of Gata5/6, the population structure of mesendoderm-derived cells was dramatically altered. In addition to the expected absence of cardiac mesoderm, we observed a concomitant expansion of cranial-pharyngeal mesoderm. Functional genetic analyses in zebrafish and the invertebrate chordateCiona, which possess a single GATA4/5/6 homolog, revealed an essential and cell-autonomous role for GATA4/5/6 in promoting cardiac and inhibiting pharyngeal mesoderm identity. Overall, the maintenance and repression of GATA4/5/6 activity plays a critical, evolutionarily conserved role in early development.
Identification of a novel cationic glycolipid inStreptococcus agalactiaethat contributes to brain entry and meningitis
Authors: Joyce Luke R. , Manzer Haider S. , Mendonça Jéssica da C. , Villarreal Ricardo , Nagao Prescilla E. , Doran Kelly S. , Palmer Kelli L. , Guan Ziqiang
Published: December 2020

Bacterial membrane lipids are critical for membrane bilayer formation, cell division, protein localization, stress responses, and pathogenesis. Despite their critical roles, membrane lipids have not been fully elucidated for many pathogens. Here, we report the discovery of a novel cationic glycolipid, Lysyl-Glucosyl-Diacylglycerol (Lys-Glc-DAG) that is synthesized in high abundance by the bacteriumStreptococcus agalactiae(Group BStreptococcus, GBS). To our knowledge, Lys-Glc-DAG is more positively charged than any other known lipids. Lys-Glc-DAG carries two positive net charges per molecule, distinct from the widely described lysylated phospholipid Lysyl-phosphatidylglycerol (Lys-PG) which carries one positive net charge due to the presence of a negatively charged phosphate moiety. We use normal phase liquid chromatography (NPLC) coupled with electrospray ionization (ESI) high-resolution tandem mass spectrometry (HRMS/MS) and genetic approaches to determine that Lys-Glc-DAG is synthesized by the enzyme MprF in GBS, which covalently modifies the neutral glycolipid Glc-DAG with the cationic amino acid lysine. GBS is a leading cause of neonatal meningitis, which requires traversal of the endothelial blood-brain barrier (BBB). We demonstrate that GBS strains lackingmprFexhibit a significant decrease in the ability to invade BBB endothelial cells. Further, mice challenged with a GBSΔmprFmutant developed bacteremia comparably to Wild-Type infected mice yet had less recovered bacteria from brain tissue and a lower incidence of meningitis. Thus, our data suggest that Lys-Glc-DAG may contribute to bacterial uptake into host cells and disease progression. Importantly, our discovery provides a platform for further study of cationic lipids at the host-pathogen interface.
Mobility shift-based electrophoresis coupled with fluorescent detection enables real-time enzyme analysis of carbohydrate sulfatase activity
Authors: Byrne Dominic P , London James A , Eyers Patrick A , Yates Edwin A , Cartmell Alan
Published: December 2020

Sulfated carbohydrate metabolism is a fundamental process, which occurs in all domains of life. Carbohydrate sulfatases are enzymes that remove sulfate groups from carbohydrates and are essential to the depolymerisation of complex polysaccharides. Despite their biological importance, carbohydrate sulfatases are poorly studied and challenges remain in accurately assessing the activity, specificity and kinetic parameters. Most notably, separation of desulfated products from sulfated substrates is currently a time-consuming process. In this paper, we describe the development of rapid capillary electrophoresis coupled to substrate fluorescence detection as a high-throughput and facile means of analysing carbohydrate sulfatase activity. The approach has utility for the determination of both kinetic and inhibition parameters and is based on existing microfluidic technology coupled to a new synthetic fluorescent 6S-GlcNAc carbohydrate substrate. Furthermore, we compare this technique in terms of both time and resources, to high performance anion exchange chromatography and NMR-based methods, which are the two current ‘gold standards’ for enzymatic carbohydrate sulfation analysis. Our study clearly demonstrates the advantages of mobility shift assays for the quantification of near real-time carbohydrate desulfation by purified sulfatases, and could support the search for small molecule inhibitors of these disease-associated enzymes.

One sentence summary

Sulfatases remove sulfate groups from biomolecules; in this study we report a rapid and robust capillary electrophoresis assay for the quantification of carbohydrate desulfation.
Versatile labeling and detection of endogenous proteins using tag-assisted split enzyme complementation
Authors: Makhija Suraj , Brown David , Bourke Struan , Wang Yina , Zhou Shuqin , Rudlaff Rachel , Cheloor-Kovilakam Rasmi , Huang Bo
Published: December 2020

Recent advances in genome engineering have expanded our capabilities to study proteins in their natural states. In particular, the ease and scalability of knocking-in small peptide tags has enabled high throughput tagging and analysis of endogenous proteins. To improve enrichment capacities and expand the functionality of knock-ins using short tags, we developed the tag-assisted split enzyme complementation (TASEC) approach, which uses two orthogonal small peptide tags and their cognate binders to conditionally drive complementation of a split enzyme upon labeled protein expression. Using this approach, we have engineered and optimized the tag-assisted split HaloTag complementation system (TA-splitHalo) and demonstrated its versatile applications in improving the efficiency of knock-in cell enrichment, detection of protein-protein interaction, and isolation of biallelic gene edited cells through multiplexing.