bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Ankle Fractures using Deep Learning Algorithms and Convolutional Neural Network
Authors: Ashkani-Esfahani Soheil , Mojahed Yazdi Reza , Bhimani Rohan , Kerkhoffs Gino M. , Maas Mario , Guss Daniel , DiGiovanni Christopher W. , Lubberts Bart
Published: July 2021

Early and accurate detection of ankle fractures is crucial for reducing future complications. Radiographs are the most abundant imaging techniques for assessing fractures. We believe deep learning (DL) methods, through adequately trained deep convolutional neural networks (DCNNs), can assess radiographic images fast and accurate without human intervention. Herein, we aimed to assess the performance of two different DCNNs in detecting ankle fractures using radiographs compared to the ground truth.

In this retrospective study, our DCNNs were trained using radiographs obtained from 1050 patients with ankle fracture and the same number of individuals with otherwise healthy ankles. Inception V3 and Renet50 pretrained models were used in our algorithms. Danis-Weber classification method was used. Out of 1050, 72 individuals were labeled as occult fractures as they were not detected in the primary radiographic assessment. Using single-view radiographs was compared with 3-views (anteroposterior, mortise, lateral) for training the DCNNs.

Our DCNNs showed a better performance using 3-views images versus single-view based on greater values for accuracy, F-score, and area under the curve (AUC). The sensitivity and specificity in detection of ankle fractures using 3-views were 97.5% and 93.9% using Resnet50 compared to 98.7% and 98.6 using inception V3, respectively. Resnet50 missed 3 occult fractures while Inception V3 missed only one case.

Clinical Significance

The performance of our DCNNs showed a promising potential that can be considered in developing the currently used image interpretation programs or as a separate assistant to the clinicians to detect ankle fractures faster and more precisely.

Level of evidence

III
Development of a federated learning approach to predict acute kidney injury in adult hospitalized patients with COVID-19 in New York City
Authors: Jaladanki Suraj K , Vaid Akhil , Sawant Ashwin S , Xu Jie , Shah Kush , Dellepiane Sergio , Paranjpe Ishan , Chan Lili , Kovatch Patricia , Charney Alexander W , Wang Fei , Glicksberg Benjamin S , Singh Karandeep , Nadkarni Girish N
Published: July 2021

Federated learning is a technique for training predictive models without sharing patient-level data, thus maintaining data security while allowing inter-institutional collaboration. We used federated learning to predict acute kidney injury within three and seven days of admission, using demographics, comorbidities, vital signs, and laboratory values, in 4029 adults hospitalized with COVID-19 at five sociodemographically diverse New York City hospitals, between March-October 2020. Prediction performance of federated models was generally higher than single-hospital models and was comparable to pooled-data models. In the first use-case in kidney disease, federated learning improved prediction of a common complication of COVID-19, while preserving data privacy.
The effective family size of immigrant founders predicts their long-term demographic outcome: from Québec settlers to their 20th-century descendants
Authors: Labuda Damian , Harding Tommy , Milot Emmanuel , Vézina Hélène
Published: July 2021

Human evolution involves population splits, size fluctuations, founder effects, and admixture. Population history reconstruction based on genetic diversity data routinely relies on simple demographic models while projecting the past. No specific demographic assumptions are needed to understand the genetic structure of the founder population of Québec. Because genealogy and genetics are intimately related, we used descending genealogies of this population to pursue the fate of its founder lineages. Maternal and paternal lines reflect the transmission of mtDNA and the Y-chromosome, respectively. We followed their transmission in real-time, from the 17thcentury down to its 20th-century population. We counted the number of married children of immigrants (i.e., their effective family size, EFS), estimated the proportion of successful immigrants in terms of their survival ratio, and assessed net growth rates and extinction. Likewise, we evaluated the same parameters for their Québec-born descendants. The survival ratio of the first immigrants was the highest and declined over time in association with the decreasing immigrants’ EFS. Parents with high EFS left plentiful married progeny, putting EFS as the most important variable determining the parental demographic success throughout time for generations ahead. The 17thand 18th-century immigrants bear the most remarkable demographic and genetic impact on the 20th-century population of Québec. Lessons learned from Québec genealogies can teach us about the consequences of founder effects and migrations through real people’s history. The effective family size of immigrant founders predicts their long-term demographic outcome.
Prospective validation of host transcriptomic biomarkers for pulmonary tuberculosis by real-time PCR
Authors: Mendelsohn Simon C. , Mbandi Stanley Kimbung , Fiore-Gartland Andrew , Penn-Nicholson Adam , Musvosvi Munyaradzi , Mulenga Humphrey , Fisher Michelle , Hadley Katie , Erasmus Mzwandile , Nombida Onke , Tameris Michèle , Walzl Gerhard , Naidoo Kogieleum , Churchyard Gavin , Hatherill Mark , Scriba Thomas J. ,   The Cross-sectional TB Cohort Study Team,   The CORTIS Study Team
Published: July 2021

We tested performance of host-blood transcriptomic tuberculosis (TB) signatures for active case-finding. Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2,923 and 861 were enrolled from five South African communities. Eight signatures were measured by microfluidic RT-qPCR and participants were microbiologically-investigated for pulmonary TB at baseline, and actively surveilled for incident disease through 15 months. Diagnostic AUCs for 61 HIV-uninfected (weighted-prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) prevalent TB cases for the 8 signatures were 0.63–0.79 and 0.65–0.88, respectively. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident TB (1.1 and 1.0 per 100 person-years, respectively). Prognostic AUCs through 15-months follow-up were 0.49–0.66 and 0.54–0.81, respectively. Prognostic performance for incident TB occurring within 6-12 months in HIV-negative participants was higher for all signatures. None of the signatures met WHO Target Product Profile criteria for a triage test to diagnose asymptomatic TB; most signatures met the criteria for symptomatic TB. Prognostic accuracy of most signatures for incident TB within six months of testing met the criteria for an incipient TB test.
COVID-19 Disease Severity among People with HIV Infection or Solid Organ Transplant in the United States: A Nationally-representative, Multicenter, Observational Cohort Study
Authors: Sun Jing , Patel Rena C. , Zheng Qulu , Madhira Vithal , Olex Amy L. , Islam Jessica Y. , French Evan , Chiang Teresa Po-Yu , Akselrod Hana , Moffitt Richard , Alexander G. Caleb , Andersen Kathleen M. , Vinson Amanda J. , Brown Todd T. , Chute Christopher G. , Crandall Keith A. , Franceschini Nora , Mannon Roslyn B. , Kirk Gregory D. ,   National COVID Cohort Collaborative (N3C) Consortium
Published: July 2021

Background

Individuals with immune dysfunction, including people with HIV (PWH) or solid organ transplant recipients (SOT), might have worse outcomes from COVID-19. We compared odds of COVID-19 outcomes between patients with and without immune dysfunction.

Methods

We evaluated data from the National COVID-19 Cohort Collaborative (N3C), a multicenter retrospective cohort of electronic medical record (EMR) data from across the United States, on. 1,446,913 adult patients with laboratory-confirmed SARS-CoV-2 infection. HIV, SOT, comorbidity, and HIV markers were identified from EMR data prior to SARS-CoV-2 infection. COVID-19 disease severity within 45 days of SARS-CoV-2 infection was classified into 5 categories: asymptomatic/mild disease with outpatient care; mild disease with emergency department (ED) visit; moderate disease requiring hospitalization; severe disease requiring ventilation or extracorporeal membrane oxygenation (ECMO); and death. We used multivariable, multinomial logistic regression models to compare odds of COVID-19 outcomes between patients with and without immune dysfunction.

Findings

Compared to patients without immune dysfunction, PWH and SOT had a greater likelihood of having ED visits (adjusted odds ratio [aOR]: 1.28, 95% confidence interval [CI] 1.27-1.29; aOR: 2.61, CI: 2.58-2.65, respectively), requiring ventilation or ECMO (aOR: 1.43, CI: 1.43-1.43; aOR: 4.82, CI: 4.78-4.86, respectively), and death (aOR: 1.20, CI: 1.19-1.20; aOR: 3.38, CI: 3.35-3.41, respectively). Associations were independent of sociodemographic and comorbidity burden. Compared to PWH with CD4>500 cells/mm3, PWH with CD4<350 cells/mm3 were independently at 4.4-, 5.4-, and 7.6-times higher odds for hospitalization, requiring ventilation, and death, respectively. Increased COVID-19 severity was associated with higher levels of HIV viremia.

Interpretation

Individuals with immune dysfunction have greater risk for severe COVID-19 outcomes. More advanced HIV disease (greater immunosuppression and HIV viremia) was associated with higher odds of severe COVID-19 outcomes. Appropriate prevention and treatment strategies should be investigated to reduce the higher morbidity and mortality associated with COVID-19 among PWH and SOT.
The Achilles’ heel of coronaviruses: targeting the 5’ Polyuridines tract of the antigenome to inhibit Mouse coronavirus-induced cell death
Authors: Ullah Hemayet , Averick Saadyah , Tang Qiyi
Published: July 2021

The current coronavirus pandemic situation is worsened by the rapidly-spreading SARS-CoV-2 virus variants. Identification of viral targets that are indispensable for the virus can be targeted to inhibit mutation-based new escape variant development. The 5’-polyU tract of the antigenome offers such a target. Host cells do not harbor 5’-polyU tracts on any of their transcripts, making the tract an attractive, virus-specific target. Inhibiting the 5’-polyU can limit the use of the tract as template to generate 3’ polyA tails of +RNAs of coronaviruses. Here, a modified DNA oligo with 3’ polyAs is used to target the 5-polyU tract in mouse coronavirus (MHV-A59). The oligo treatment in mouse 17CL-1 cells infected with MHV-A59 significantly prevented virus-induced cell deaths. This proof-of-concept result shows a unique mode of action against mouse coronavirus without affecting host cells, and can be used for the development of novel classes of drugs that inhibit coronavirus infection in host cells, specifically by the COVID-19-causing virus SARS-CoV-2. In addition, as the 5’-polyU tract is immediately generated upon infection, the tag can also be targeted for reliable early detection of viral infection.
Bacterial and metabolic factors of staphylococcal planktonic and biofilm environments differentially regulate macrophage immune activation
Authors: Seebach Elisabeth , Elschner Tabea , Kraus Franziska V. , Souto-Carneiro Margarida , Kubatzky Katharina F.
Published: July 2021

Biofilm formation is a leading cause for chronic implant-related bone infections as biofilms shield bacteria against the immune system and antibiotics. Additionally, biofilms generate a metabolic microenvironment that shifts the immune response towards tolerance. Here, we compared the impact of the metabolite profile of bacterial environments on macrophage immune activation usingStaphylococcus aureus(SA) andepidermidis(SE) conditioned media (CM) of planktonic and biofilm cultures. The biofilm environment had reduced glucose and increased lactate concentrations. Moreover, the expression of typical immune activation markers on macrophages was reduced in the biofilm environment compared to the respective planktonic CM. However, all CM caused a predominantly pro-inflammatory macrophage cytokine response with a comparable induction ofTnfaexpression. In biofilm CM this was accompanied by higher levels of anti-inflammatoryIl10. Planktonic CM on the other hand, induced an IRF-7 mediatedIfnbexpression which was absent in the biofilm environments. For SA but not for SE planktonic CM, this was accompanied by IRF3 activation. Stimulation of macrophages with TLR-2/-9 ligands under varying metabolic conditions revealed that, like in the biofilm setting, low glucose concentration reduced theTnfatoIl10mRNA ratio. However, addition of extracellular L-lactate but not D-lactate increased theTnfatoIl10mRNA ratio upon TLR-2/-9 stimulation. In summary, our data indicate that the mechanisms behind the activation of macrophages differs between planktonic and biofilm environments. These differences are independent of the metabolite profiles, suggesting that the production of different bacterial factors is ultimately more important than the concentrations of glucose and lactate in the environment.
Tolerability, safety and immunogenicity of intradermal delivery of a fractional dose mRNA-1273 SARS-CoV-2 vaccine in healthy adults as a dose sparing strategy
Authors: Roozen Geert V.T. , Prins Margaretha L.M. , van Binnendijk Rob , Hartog Gerco den , Kuiper Vincent P. , Prins Corine , Janse Jacqueline J. , Kruithof Annelieke C. , Feltkamp Mariet C.W. , Kuijer Marjan , Rosendaal Frits R. , Roestenberg Meta , Visser Leo G. , Roukens Anna H.E.
Published: July 2021

Background

There is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy.

Methods

We conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 µg mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 µg mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals.

Findings

Thirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 µg and the 20 µg group. In the higher dose group, systemic adverse reactions were more common, but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 µg intradermal group, 1,406 (953·5-2,074) BAU/mL for the 20 µg intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 µg intradermal group. Anti-S1 was 107·2 (63-182·2) BAU/mL for the convalescent plasma control group and 1,558 (547·8-4,433) BAU/mL for the individuals vaccinated with 100 µg mRNA-1273.

Interpretation

Intradermal administration of 10 µg and 20 µg mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing.

Funding

The trial was supported by crowdfunding (Wake Up to Corona).
Steady-state measures of visual suppression
Authors: Baker Daniel H. , Vilidaite Greta , Wade Alex R.
Published: July 2021

In the early visual system, suppression occurs between neurons representing different stimulus properties. This includes features such as orientation (cross-orientation suppression), eye-of-origin (interocular suppression) and spatial location (surround suppression), which are thought to involve distinct anatomical pathways. We asked if these separate routes to suppression can be differentiated by their pattern of gain control on the contrast response function measured in human participants using steady-state electroencephalography. Changes in contrast gain shift the contrast response function laterally, whereas changes in response gain scale the function vertically. We used a Bayesian hierarchical model to summarise the evidence for each type of gain control. A computational meta-analysis of 16 previous studies found the most evidence for contrast gain effects with overlaid masks, but no clear evidence favouring either response gain or contrast gain for other mask types. We then conducted two new experiments, comparing suppression from four mask types (monocular and dichoptic overlay masks, and aligned and orthogonal surround masks) on responses to sine wave grating patches flickering at 5Hz. At the occipital pole, there was strong evidence for contrast gain effects in all four mask types at the first harmonic frequency (5Hz). Suppression generally became stronger at more lateral electrode sites, but there was little evidence of response gain effects. At the second harmonic frequency (10Hz) suppression was stronger overall, and involved both contrast and response gain effects. Although suppression from different mask types involves distinct anatomical pathways, gain control processes appear to serve a common purpose, which we suggest might be to suppress less reliable inputs.
Short-term stimulation of collective cell migration in tissues reprograms long-term supracellular dynamics
Authors: Wolf Abraham E. , Heinrich Matthew A. , Breinyn Isaac B. , Zajdel Tom J. , Cohen Daniel J.
Published: July 2021

The ability to program collective cell migration can allow us to control critical multicellular processes in development, regenerative medicine, and invasive disease. However, while various technologies exist to make individual cells migrate, translating these tools to control myriad, collectively interacting cells within a single tissue poses many challenges. For instance, do cells within the same tissue interpret a global migration ‘command’ differently based on where they are in the tissue? Similarly, since no stimulus is permanent, what are the long-term effects of transient commands on collective cell dynamics? We investigate these questions by bioelectrically programming large epithelial tissues to globally migrate ‘rightward’ via electrotaxis. Tissues clearly developed distinct rear, middle, side, and front responses to a single global migration stimulus. Furthermore, at no point post-stimulation did tissues return to their pre-stimulation behavior, instead equilibrating to a third, new migratory state. These unique dynamics suggested that programmed migration resets tissue mechanical state, which was confirmed by transient chemical disruption of cell-cell junctions, analysis of strain wave propagation patterns, and quantification of cellular crowd dynamics. Overall, this work demonstrates how externally driving the collective migration of a tissue can reprogram baseline cell-cell interactions and collective dynamics, even well beyond the end of the global migratory cue, and emphasizes the importance of considering the supracellular context of tissues and other collectives when attempting to program crowd behaviors.
Substitution Rate Variation in a Robust Procellariiform Seabird Phylogeny is not Solely Explained by Body Mass, Flight Efficiency, Population Size or Life History Traits
Authors: Estandía Andrea , Chesser R. Terry , James Helen F. , Levy Max A. , Obiol Joan Ferrer , Bretagnolle Vincent , González-Solís Jacob , Welch Andreanna J.
Published: July 2021

Substitution rate variation among branches can lead to inaccurate reconstructions of evolutionary relationships and obscure the true phylogeny of affected clades. Body mass is often assumed to have a major influence on substitution rate, though other factors such as population size, life history traits, and flight demands are also thought to have an influence. Birds of the order Procellariiformes—which encompasses petrels, storm-petrels and albatrosses—show a striking 900-fold difference in body mass between the smallest and largest members, divergent life history traits, and substantial heterogeneity in mitochondrial substitution rates. Here, we used genome-scale nuclear DNA sequence data from 4365 ultraconserved element loci (UCEs) in 51 procellariiform species to examine whether phylogenetic reconstruction using genome-wide datasets is robust to the presence of rate heterogeneity, and to identify predictors of substitution rate variation. Our results provide a backbone phylogeny for procellariiform seabirds and resolve several controversies about the evolutionary history of the order, demonstrating that albatrosses are basal, storm-petrels are paraphyletic and diving petrels nestled within the Procellariidae. We find evidence of rate variation; however, all phylogenetic analyses using both concatenation and multispecies coalescent approaches recovered the same branching topology, including analyses implementing different clock models, and analyses of the most and least clock-like loci. Overall, we find that rate heterogeneity is little impacted by body mass, population size, age at first breeding, and longevity but moderately correlated with hand-wing index, a proxy for wing shape and flight efficiency. Given our results and the context of the broader literature perhaps it is time that we begin to question the prevailing paradigm that one or a few traits largely explain rate variation and accept instead that substitution rate may be the product of weak interactions among many, potentially taxon-specific, variables.
One year later: longitudinal effects of flexible school start times on teenage sleep and subjective psychological outcomes
Authors: Biller Anna M. , Molenda Carmen , Zerbini Giulia , Roenneberg Till , Winnebeck Eva C.
Published: July 2021

Early school times fundamentally clash with the late sleep of teenagers. This mismatch results in chronic sleep deprivation, which poses acute and long-term health risks and impairs students’ learning. Despite conclusive evidence that delaying school times has immediate benefits for sleep, the long-term effects on sleep are unresolved due to a shortage of longitudinal data. Here, we studied whether a flexible school start system, with the daily choice of an 8AM or 08:50AM-start, allowed secondary school students to improve their sleep and psychological functioning in a longitudinal pre-post design over exactly 1 year. Based on 2 waves, each with 6-9 weeks of daily sleep diary, we found that students maintained their 1-hour-sleep gain on days with later starts, both longitudinally (n=28) and cross-sectionally (n=79). This sleep gain was independent of chronotype and frequency of later starts but differed between genders. Girls were more successful in keeping early sleep onsets despite later sleep offsets, whereas boys delayed their onsets and thus had reduced sleep gains after 1 year. Students also reported psychological benefits (n=93), increased sleep quality and reduced alarm-driven waking on later school days. Despite these benefits on later schooldays, overall sleep duration was not extended in the flexible system. This was likely due to the persistently low uptake of the late-start option. If uptake can be further promoted, the flexible system is an appealing alternative to a fixed delay of school starts owing to possible circadian advantages (speculatively through prevention of phase-delays) and psychological mechanisms (e.g. sense of control).

Significance statement

Teenage sleep becomes progressively later during adolescence but school starts do not accommodate this shifted sleep window. This mismatch results in chronic sleep deprivation in teenagers worldwide, which is a pervasive public health concern. Delaying school starts could counteract this misalignment if students keep sleep onsets stable. However, few studies have investigated long-term effects of delayed starts on sleep. We observed here that students slept persistently longer and better when school started later in a flexible start system. Girls were especially successful in keeping stable onsets. Students also benefitted psychologically and liked the flexible system despite only a modest uptake of later starts. The flexible system is an interesting alternative to a fixed delay and should receive more scientific attention.
A Novel, Improved, Application for the Normalization of RNA-seq Expression Data in Complex Polyploids
Authors: Evans Dyfed Lloyd
Published: July 2021

Much of the work on the normalization of RNA-seq data has been performed on human, notably cancer tissue. Little work has been done in plants, particularly polyploids and those species with incomplete or no genomes. We present a novel implementation of GeTMM (Gene Length Corrected TMM) that accounts for GC bias and works at the transcript level. The algorithm also employs transcript length as a factor, allowing for incomplete transcripts and alternate transcripts. This significantly improves overall normalization. The GCGeTMM methodology also allows for simultaneous determination of differentially expressed transcripts (and by extension genes) and stably expressed genes to act as references for qRT-PCR and microarray analyses.
Structural basis of Ty3 retrotransposon integration at RNA Polymerase III-transcribed genes
Authors: Abascal-Palacios Guillermo , Jochem Laura , Pla-Prats Carlos , Beuron Fabienne , Vannini Alessandro
Published: July 2021

Retrotransposons are endogenous elements that have the ability to mobilise their DNA and integrate at different locations in the host genome. In budding yeast, the Ty3 retrotransposon integrates with an exquisite specificity in a narrow window upstream of RNA Polymerase III-transcribed genes, such as the genes of transfer RNAs, representing a paradigm for specific targeted integration.

Here we present the cryo-EM reconstruction at 4.0 Å-resolution of an active Ty3 strand-transfer complex (Ty3 intasome) caught in the act of integrating onto a specific tRNA gene bound to the RNA Polymerase III general transcription factor TFIIIB, which is required for Ty3 specific targeting.

The structure unravels the molecular mechanisms underlying Ty3 integration specificity at RNA Polymerase III-transcribed genes and sheds light into the architecture of a retrotransposon integration machinery during the process of strand transfer at a genomic locus. The Ty3 intasome establishes contacts with a region of the TATA-binding protein (TBP), a subunit of TFIIIB, which is blocked by the ubiquitous transcription regulator negative cofactor 2 (NC2) in RNA Pol II-transcribed genes.

A previously unrecognised chromodomain of the Ty3 integrase mediates non- canonical interactions with TFIIIB and the tRNA gene itself, defining with extreme precision the position of the integration site. Surprisingly, Ty3 retrotransposon tethering to TFIIIB topologically resembles LEDGF/p75 transcription factor targeting by HIV retrovirus, highlighting mechanisms of convergent evolution by unrelated mobile elements and host organisms.

The Ty3 intasome-TFIIIB-tRNA promoter complex presented here represents a detailed molecular snapshot of a general transcription factor’s co-option by a mobile element, resulting in harmless integration into the host genome.
Can fMRI functional connectivity index dynamic neural communication?
Authors: Martínez Sonsoles Alonso , Llera Alberto , Horst Gert ter , Vidaurre Diego
Published: July 2021

In order to continuously respond to a changing environment and support self-generating cognition and behaviour, neural communication must be highly flexible and dynamic at the same time than hierarchically organized. While whole-brain fMRI measures have revealed robust yet changing patterns of statistical dependencies between regions, it is not clear whether these statistical patterns —referred to as functional connectivity— can reflect dynamic large-scale communication in a way that is relevant to human cognition. For functional connectivity to reflect cognition, and therefore actual communication, we propose three necessary conditions: it must span sufficient temporal complexity to support the needs of cognition while still being highly organized so that the system behaves reliably; it must be able to adapt to the current behavioural context; it must exhibit fluctuations at timescales that are compatible with the timescales of cognition. To obtain reliable estimations of time-varying functional connectivity, we developed principal components of connectivity analysis (PCCA), an approach based on applying principal component analysis on multiple runs of a time-varying functional connectivity model. We use PCCA to show that functional connectivity follows low-yet multi-dimensional trajectories that can be reliably measured, and that these trajectories meet the aforementioned criteria. These analyses suggest that these trajectories might index certain aspects of communication between neural populations and support moment-to-moment cognition.

Significance Statement

fMRI functional connectivity is one of the most widely used metrics in neuroimaging research in both theoretical research and clinical applications. However, this work suffers from a lack of context because we still do not fully understand what fMRI functional connectivity can or cannot reflect biologically and behaviourally. In particular, can it reflect between-region neuronal communication? We develop methods to reliably quantify temporal trajectories of functional connectivity and investigate the nature of these trajectories across different experimental conditions. Using these methods, we demonstrate that functional connectivity exhibits reliable changes that are context-dependent, reflect cognitive complexity, and bear a relationship with cognitive abilities. These conditions show that fMRI functional connectivity could reflect changes in between-region communication above and beyond non-neural factors.
Orthogonal but linked neural codes for value
Authors: Maisson David J-N. , Fine Justin M. , Yoo Seng Bum Michael , Cash-Padgett Tyler V. , Wang Maya Zhe , Sleezer Brianna J. , Zimmermann Jan , Hayden Benjamin Y.
Published: July 2021

Our ability to effectively choose between dissimilar options implies that information regarding the options’ values must be available, either explicitly or implicitly, in the brain. Explicit realizations of value involve single neurons whose responses depend on value and not on the specific features that determine it. Implicit realizations, by contrast, come from the coordinated action of neurons that encode specific features. One signature of implicit value coding is that population responses to offers with the same value but different features should occupy semi- or fully orthogonal neural subspaces that are nonetheless linked. Here, we examined responses of neurons in six core value-coding areas in a choice task with risky and safe options. Using stricter criteria than some past studies have used, we find, surprisingly, no evidence for abstract value neurons (i.e., neurons with the response to equally valued risky and safe options) in any of these regions. Moreover, population codes for value resided in orthogonal subspaces; these subspaces were linked through a linear transform of each of their constituent subspaces. These results suggest that in all six regions, populations of neurons embed value implicitly in a distributed population.
Executable Network of SARS-CoV-2-Host Interaction Predicts Drug Combination Treatments
Authors: Howell Rowan , Clarke Matthew A. , Reuschl Ann-Kathrin , Chen Tianyi , Abbott-Imboden Sean , Singer Mervyn , Lowe David M. , Bennett Clare L. , Chain Benjamin , Jolly Clare , Fisher Jasmin
Published: July 2021

The COVID-19 pandemic has pushed healthcare systems globally to a breaking point. The urgent need for effective and affordable COVID-19 treatments calls for repurposing combinations of approved drugs. The challenge is to identify which combinations are likely to be most effective and at what stages of the disease. Here, we present the first disease-stage executable signalling network model of SARS-CoV-2-host interactions used to predict effective repurposed drug combinations for treating early- and late-stage severe disease. Using our executable model, we performed in silico screening of 9870 pairs of 140 potential targets and have identified 12 new drug combinations. Camostat and Apilimod were predicted to be the most promising combination in effectively supressing viral replication in the early stages of severe disease and were validated experimentally in human Caco-2 cells. Our study further demonstrates the power of executable mechanistic modelling to enable rapid pre-clinical evaluation of combination therapies tailored to disease progression. It also presents a novel resource and expandable model system that can respond to further needs in the pandemic.
A phospho-switch at Acinus-Serine437 controls autophagic responses to Cadmium exposure and neurodegenerative stress
Authors: Nandi Nilay , Zaidi Zuhair , Tracy Charles , Krämer Helmut
Published: July 2021

Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by Acinus and the Cdk5-dependent phosphorylation of its serine437 (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of Acinus-S437 phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an Acinus gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-Acinus levels. Cdk5-dependent phosphorylation of Acinus serine437 in nil1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington’s disease model. Consistent with previous findings that Cd2+ inhibits PPM-type phosphatases, Cd2+-exposure elevated Acinus-serine437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the Acinus- S437 phospho-switch as critical integrator of multiple stress signals regulating neuronal autophagy.
Endorsement and Phylogenetic Analysis of some Fabaceae Plants based on DNA Barcoding gene MatK
Authors: Abdelsalam Nader R. , Hasan Mohamed E. , Rabie Samar M.A. , El-wakeel Houssam El-Din M.F. , Zaitoun Amera F. , Ghareeb Rehab Y. , Abdelsalam Aly Z. , Aly Hesham M. , Ibrahim Amira A. , Hemeida Alaa A.
Published: July 2021

DNA barcodes have been considered as a tool to facilitate species identification based on their simplicity and high-level accuracy compression to the complexity and subjective biases linked to morphological identification of taxa. MaturaseK gene “MatK” of the chloroplast is very crucial in the plant system which is involved in the group II intron splicing. The main objective of this current study is determining the relative utility of the “MatK” chloroplast gene for barcoding in fifteen legume trees by both single region and multiregional approaches. The chloroplast “MatK” gene sequences were submitted to GenBank and accession numbers (GenBank: LC602060, LC602154, LC602263, LC603347, LC603655, LC603845, LC603846, LC603847, LC604717, LC604718, LC605994, LC604799, LC605995, LC606468, LC606469) were obtained with sequence length ranging from 730 to 1545 nucleotides. These DNA sequences were aligned with database sequence using PROMALS server, Clustal Omega server and Bioedit program. Also, the maximum likelihood and neighbor-joining algorithms for phylogenetic reconstruction using the MEGA-X program were employed. Overall, these results indicated that the phylogenetic tree analysis and the evolutionary distances of an individual dataset of each species were agreed with a phylogenetic tree of all each other consisting of two clades, the first clade comprising (Enterolobium contortisiliquum, Albizia lebbek), Acacia saligna, Leucaena leucocephala, Dichrostachys Cinerea, (Delonix regia, Parkinsonia aculeata), (Senna surattensis, Cassia fistula, Cassia javanica) and Schotia brachypetala were more closely to each other, respectively. The remaining four species of Erythrina humeana, (Sophora secundiflora, Dalbergia Sissoo, Tipuana Tipu) constituted the second clade. Therefore, MatK gene is considered promising a candidate for DNA barcoding in plant family Fabaceae and providing a clear relationship between the families. Moreover, their sequences could be successfully utilized in single nucleotide polymorphism (SNP) or part of the sequence as DNA fragment analysis utilizing polymerase chain reaction (PCR) in plant systematic.
Targeted Protein Acetylation in Cells Using Heterobifunctional Molecules
Authors: Wang Wesley W. , Chen Li-Yun , Wozniak Jacob M. , Jadhav Appaso M. , Anderson Hayden , Malone Taylor E. , Parker Christopher G.
Published: July 2021

Protein acetylation is a central event in orchestrating diverse cellular processes. However, current strategies to investigate protein acetylation in cells are often non-specific or lack temporal and magnitude control. Here, we developed an acetylation tagging system, AceTAG, to induce acetylation of targeted proteins. The AceTAG system utilizes bifunctional molecules to direct the lysine acetyltransferase p300/CBP to proteins fused with the small protein tag FKBP12F36V, resulting in their induced acetylation. Using AceTAG, we induced targeted acetylation of a diverse array of proteins in cells, specifically histone H3.3, the NF-κB subunit p65/RelA, and the tumor suppressor p53. We demonstrate that targeted acetylation with the AceTAG system is rapid, selective, reversible, and can be controlled in a dose-dependent fashion. AceTAG represents a useful strategy to modulate protein acetylation and will enable the exploration of targeted acetylation in basic biological and therapeutic contexts.

Abstract Figure
Automated slice-specific z-shimming for fMRI of the human spinal cord
Authors: Kaptan Merve , Vannesjo S. Johanna , Mildner Toralf , Horn Ulrike , Hartley-Davies Ronald , Oliva Valeria , Brooks Jonathan C.W. , Weiskopf Nikolaus , Finsterbusch Jürgen , Eippert Falk
Published: July 2021

Functional magnetic resonance imaging (fMRI) of the human spinal cord faces many challenges, such as signal loss due to local magnetic field inhomogeneities. This issue can be addressed with slice-specific z-shimming, which compensates for the dephasing effect of the inhomogeneities using a slice-specific gradient pulse. Here, we aim to address outstanding issues regarding this technique by evaluating its effects on several aspects that are directly relevant for spinal fMRI and by developing two automated procedures in order to improve upon the time-consuming and subjective nature of manual selection of z-shims: one procedure finds the z-shim that maximizes signal intensity in each slice of an EPI reference-scan and the other finds the through-slice field inhomogeneity for each EPI-slice in field map data and calculates the required compensation gradient moment. We demonstrate that the beneficial effects of z-shimming are apparent across different echo times, hold true for both the dorsal and ventral horn, and are also apparent in the temporal signal-to-noise ratio (tSNR) of EPI time-series data. Both of our automated approaches were faster than the manual approach, lead to significant improvements in gray matter tSNR compared to no z-shimming and resulted in beneficial effects that were stable across time. While the field-map-based approach performed slightly worse than the manual approach, the EPI-based approach performed as well as the manual one and was furthermore validated on an external corticospinal data-set (N>100). Together, automated z-shimming may improve the data quality of future spinal fMRI studies and lead to increased reproducibility in longitudinal studies.
DectiSomes: Glycan Targeting of Liposomal Drugs Improves the Treatment of Disseminated Candidiasis
Authors: Ambati Suresh , Phan Tuyetnhu , Lewis Zachary A. , Lin Xiaorong , Meagher Richard B.
Published: July 2021

Candida albicans causes life-threatening disseminated candidiasis. Individuals at greatest risk have weakened immune systems. An outer cell wall, exopolysaccharide matrix, and biofilm rich in oligoglucans and oligomannans help Candida spp. evade host defenses. Even after antifungal drug treatment the one-year mortality rate exceeds 25%. Undoubtedly there is room to improve antifungal drug performance. The mammalian C-type lectin pathogen receptors Dectin-1 and Dectin-2 bind to fungal oligoglucans and oligomannans, respectively. We previously coated amphotericin B-loaded liposomes, AmB-LLs, pegylated analogs of AmBisome, with the ligand binding domains of these two Dectins. DectiSomes, DEC1-AmB-LLs and DEC2-AmB-LLs, showed two distinct patterns of binding to the exopolysaccharide matrix surrounding C. albicans hyphae grown in vitro, while untargeted AmB-LLs did not bind. DectiSomes were preferentially associated with fungal colonies in the kidneys. In a neutropenic mouse model of candidiasis, DEC1-AmB-LLs and DEC2-AmB-LLs delivering only one dose of 0.2 mg/kg AmB significantly reduced the kidney fungal burden several fold relative to AmB-LLs, based on either colony forming units (P= 0.013 to 8.8 × 10-5) or quantitative PCR of fungal rRNA ITS (P= 5.5×10-5 to 3.0×10-10). DEC1-AmB-LLs and DEC2-AmB-LLs significantly increased the percent of surviving mice relative to AmB-LLs. Dectin-2 targeted anidulafungin loaded liposomes and AmBisomes, DEC2-AFG-LLs and DEC2-AmBisome reduced fungal burden in the kidneys several fold over their untargeted counterparts (P=7.8×10-5 and 0.0020, respectively). The data herein suggest that targeting of a variety of antifungal drugs to fungal glycans may achieve lower safer effective doses and improve drug efficacy against a variety of invasive fungal infections.
Characterization of a Novel Plasmid in Serratia marcescens Harboring blaGES-5 Isolated from a Nosocomial Outbreak in Japan
Authors: Nakanishi Noriko , Komatsu Shoko , Iwamoto Tomotada , Nomoto Ryohei
Published: July 2021

Serratia marcescens is a nosocomial pathogen with carbapenem resistance, limiting the availability of effective treatment options. In this study, we performed molecular characterization of GES-5 carbapenemase-producing S. marcescens isolated from an outbreak in Japan. Comparative genetic analysis revealed that the blaGES-5–encoding plasmid p2020-O-9 is a unique plasmid contributing towards carbapenem resistance. Furthermore, this study highlights the necessity of surveillance programs for monitoring novel, along with commonly occurring carbapenemases in clinical settings.
Gds1 interacts with NuA4 to promote H4 acetylation at ribosomal protein genes
Authors: Joo Yoo Jin , Buratowski Stephen
Published: July 2021

In our previously published studies, RNA polymerase II transcription initiation complexes were assembled from yeast nuclear extracts onto immobilized transcription templates and analyzed by quantitative mass spectrometry. In addition to the expected basal factors and coactivators, we discovered that the uncharacterized protein Gds1 showed activator-stimulated association with promoter DNA. Gds1 co-precipitated with the histone H4 acetyltransferase NuA4, and its levels often tracked with NuA4 in immobilized template experiments. GDS1 deletion led to reduction in H4 acetylation in vivo and other phenotypes consistent with partial loss of NuA4 activity. Genome-wide chromatin immunoprecipitation revealed that the reduction in H4 acetylation was strongest at ribosomal protein gene promoters and other genes with high NuA4 occupancy. Therefore, while Gds1 is not a stoichiometric subunit of NuA4, we propose that it interacts with and modulates NuA4 in specific promoter contexts. Gds1 has no obvious metazoan homolog, but structural predictions suggest it may be distantly related to the DEK protein.
Data-driven multiscale dynamical framework to control a pandemic evolution with non-pharmaceutical interventions
Authors: Reingruber Jürgen , Papale Andrea , Ruckly Stéphane , Timsit Jean-Francois , Holcman David
Published: July 2021

Before the availability of vaccines, many countries have resorted multiple times to drastic social restrictions to prevent saturation of their health care system, and to regain control over an otherwise exponentially increasing COVID-19 pandemic. With the advent of data-sharing, computational approaches are key to efficiently control a pandemic with non-pharmaceutical interventions (NPIs). Here we develop a data-driven computational framework based on a time discrete and age-stratified compartmental model to control a pandemic evolution inside and outside hospitals in a constantly changing environment with NPIs. Besides the calendrical time, we introduce a second time-scale for the infection history, which allows for non-exponential transition probabilities. We develop inference methods and feedback procedures to successively recalibrate model parameters as new data becomes available. As a showcase, we calibrate the framework to study the pandemic evolution inside and outside hospitals in France until February 2021. We combine national hospitalization statistics from governmental websites with clinical data from a single hospital to calibrate hospitalization parameters. We infer changes in social contact matrices as a function of NPIs from positive testing and new hospitalization data. We use simulations to infer hidden pandemic properties such as the fraction of infected population, the hospitalisation probability, or the infection fatality ratio. We show how reproduction numbers and herd immunity levels depend on the underlying social dynamics.
An efficient method of evaluating multiple concurrent management actions on invasive populations
Authors: Davis Amy J. , Farrar Randy , Jump Brad , Hall Parker , Guerrant Travis , Pepin Kim M.
Published: July 2021

Evaluation of the efficacy of management actions to control invasive species is crucial for maintaining funding and to provide feedback for the continual improvement of management efficiency. However, it is often difficult to assess the efficacy of control methods due to limited resources for monitoring. Many managers view effort on monitoring as effort taken away from performing management actions. We developed a method to estimate invasive species abundance, evaluate management effectiveness, and evaluate population growth overtime from a combination of removal activities (e.g., aerial gunning, trapping, ground shooting) using only data collected during removal efforts (the method of removal, the date, location, number of animals removed, and the effort). This dynamic approach allows for estimating abundance at discrete time points and the estimation of population growth between removal periods. We applied this method to removal data from Mingo National Wildlife Refuge in Missouri from December 2015 to September 2019, where the management objective is elimination. Populations of feral swine on Mingo NWR have fluctuated over time but showed more marked declines in the last 3-6 months of the time series. More dramatic declines were observed in the center of the refuge likely aided by reducing potential immigration from the rest of the refuge. To counteract population growth (from both births and immigration) the percent of the population of feral swine removed monthly must be greater than the growth rate. On average, we found that removing 10% of the population monthly had only a 50% chance of causing a population decline, whereas removing 15% of the population monthly had a 95% chance of causing a population decline. Our method provides advancement over traditional removal modeling approaches because it can be applied to evaluate management programs that use a broad range of removal techniques concurrently and whose management effort and spatial coverage vary across time.