bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and Risk Factors for Metabolic Syndrome Among Childhood Acute Lymphoblastic Leukemia Survivors: Experience From South India
Authors: Nirmal Garima , Thankamony Priyakumari , Chellapam Sojamani Guruprasad , Nair Manjusha , Rajeswari Binitha , Varikkattu Rajendran Prasanth , Krishna K.M. Jagathnath
Published: June 2020

Background and Objectives:

Improved survival of childhood acute lymphoblastic leukemia (ALL) has diverted attention to the long-term consequences of the treatment; metabolic abnormalities being one of the most important issues.

Methods:

Children diagnosed with ALL at age 14 years and younger at Regional Cancer Centre in South India who completed treatment and who were on follow-up for >2 years were enrolled in the study between April 1, 2018 and March 31, 2019. They were prospectively evaluated for the presence of metabolic syndrome (MS) and associated risk factors.

Results and Discussion:

A total of 277 survivors of pediatric ALL were recruited during the study period. MS was present in 8.3% (n=23) and 6% (n=13) survivors by National Cholesterol Education Programme Adult Treatment Panel III (NCEPATP III) and International Diabetes Federation (IDF) criteria, respectively. The prevalence of overweight and obesity in the survivors was 9% and 13%. The prevalence of increased waist circumference, low high-density lipoprotein cholesterol, elevated triglycerides, elevated fasting glucose, and increased blood pressure were 10.5%, 28.9%, 24.9%, 2.5%, and 9%, respectively. Overweight/obese survivors were at an increased risk for developing MS (odds ratio=17.66; 95% confidence interval=6.2-50.16, P=0.001). Survivors who received cranial radiotherapy were at an elevated risk for having low high-density lipoprotein cholesterol (P=0.001).

Conclusions:

In our study, the prevalence of MS was higher in childhood ALL survivors, as compared with the general population. The study points to the need for regular screening of pediatric ALL survivors for early detection of MS, along with lifestyle modification in those with metabolic abnormalities, to curb the growing incidence of coronary artery disease.
Front-Line Human Resource Time-Use for Early Infant HIV Diagnosis: A Comparative Time-Motion Study at Centralized and Point-of-Care Health Facilities in Zimbabwe
Authors: Adetunji Oluwarantimi , Mukherjee Sushant , Sacks Emma , Ciaranello Andrea , Chadambuka Addmore , Mafaune Haurovi , McCann Nicole , Cohn Jennifer
Published: June 2020

Background:

Point-of-care (POC) assays for early infant diagnosis of HIV (EID) increase access to testing, shorten time to results, and expedite initiation of antiretroviral therapy when compared with laboratory-based assays. However, there is a significant gap in our understanding of its human resource impact at the facility level. This study evaluates front-line health workers' (HWs') time associated with EID.

Setting:

Using time-motion methodology, we collected time-use data on EID tasks performed by HWs at 3 EID facility types in Zimbabwe—5 POC hubs, 9 POC spokes, and 11 facilities that used centralized laboratories.

Methods:

Data collectors observed 30 EID processes and 30 HWs' provided self-reported time. Comparisons of mean differences of HWs' time-use between centralized and POC EID were performed with a 2-samplettest with unequal variances.

Results:

Observed average total labor time per EID test at POC facilities was 28 minutes, 22 seconds [95% confidence interval (CI): 22:51 to 35:48], which was equivalent to the average preresult time at facilities using centralized EID. HWs performed other tasks while the machine processed samples. Observed average preresult time (counseling to sample preparation) was 18 minutes, 6 Supported by seconds (95% CI: 13:00 to 23:42) for POC compared with 27 minutes, 48 seconds (95% CI: 23:48 to 32:50) for facilities using centralized laboratories. The mean difference of 9 minutes, 42 seconds (95% CI: 03:04 to 16:18) was statistically significant. The differences in self-reported average total labor time per EID test between HWs at facilities using centralized laboratories or POC were not statistically significant.

Conclusion:

Use of POC assays did not incur additional human resource time compared with sending dried blood spots to a centralized laboratory for EID.
HIV Mother-to-Child Transmission in Cameroon: EID Positivity Yields and Key Risk Factors by Health Service Points After Usage of POC EID Systems
Authors: Tchendjou Patrice , Nzima Valery , Lekeumo Simplice , Sacks Emma , Bianchi Flavia , Lemaire Jean-Francois , Zoung Kanyi Bissek Anne-Cecile , Binde Thierry , Ngoh Elvis Akwo , Tchounga Boris , Tiam Appolinaire , Cohn Jennifer ,   for Cameroon POC EID Study group
Published: June 2020

Background:

Most HIV-exposed infants access early infant diagnosis (EID) through the prevention of mother-to-child transmission (PMTCT) service points. However, there are limited data on HIV positivity in non-PMTCT health care settings (pediatric wards, emergency departments, outpatient departments, tuberculosis clinics, etc.). The introduction of point-of-care testing provided an opportunity to describe HIV positivity at alternative health service points and associated risk factors.

Methods:

We performed a cross-sectional subanalysis with data from 58 health facilities in Cameroon. The risk of a child being HIV positive at a health service point was considered as a dependent variable, and exploratory variables were assessed using multivariate models with a significance level of 0.05.

Results:

Overall, 2254 HIV-exposed infants identified by clinical or biological screening were tested by polymerase chain reaction using point-of-care EID. Approximately 74.3% of the infants were tested at a PMTCT entry point, whereas 25.7% were tested at non-PMTCT service points. The positivity yield was 5.7% (95 of the 1674) at the PMTCT service point and 17.6% (102 of the 580) at non-PMTCT service points. Non-PMTCT service points [adjusted odds ratio (aOR): 1.95; 95% confidence interval (CI): 1.36 to 2.80] and vaginal delivery (aOR: 2.56; 95% CI: 1.25 to 5.25) were independently associated with HIV positivity. In a separate analysis (infants aged 0–6 months), mixed feeding mode (aOR: 3.68; 95% CI: 2.00 to 6.77) was also associated with HIV positivity.

Conclusions:

More than half of children newly identified as HIV-positive were tested at non-PMTCT service points. The highest EID positivity yields were found in non-PMTCT service points. Strengthening HIV testing in non-PMTCT service points may help to identify additional infected children and improve timely initiation of treatment and care.
Strengthening Existing Laboratory-Based Systems vs. Investing in Point-of-Care Assays for Early Infant Diagnosis of HIV: A Model-Based Cost-Effectiveness Analysis
Authors: McCann Nicole C. , Cohn Jennifer , Flanagan Clare , Sacks Emma , Mukherjee Sushant , Walensky Rochelle P. , Adetunji Oluwarantimi , Maeka Kenneth K. , Panella Christopher , Chadambuka Addmore , Mafaune Haurovi , Odhiambo Collins , Freedberg Kenneth A. , Ciaranello Andrea L.
Published: June 2020

Background:

To improve early infant HIV diagnosis (EID) programs, options include replacing laboratory-based tests with point-of-care (POC) assays or investing in strengthened systems for sample transport and result return.

Setting:

We used the CEPAC-Pediatric model to examine clinical benefits and costs of 3 EID strategies in Zimbabwe for infants 6 weeks of age.

Methods:

We examined (1) laboratory-based EID (LAB), (2) strengthened laboratory-based EID (S-LAB), and (3) POC EID (POC). LAB/S-LAB and POC assays differed in sensitivity (LAB/S-LAB 100%, POC 96.9%) and specificity (LAB/S-LAB 99.6%, POC 99.9%). LAB/S-LAB/POC algorithms also differed in: probability of result return (79%/91%/98%), time until result return (61/53/1 days), probability of initiating antiretroviral therapy (ART) after positive result (52%/71%/86%), and total cost/test ($18.10/$30.47/$30.71). We projected life expectancy (LE) and average lifetime per-person cost for all HIV-exposed infants. We calculated incremental cost-effectiveness ratios (ICERs) from discounted (3%/year) LE and costs in $/year-of-life saved (YLS), defining cost effective as an ICER <$580/YLS (reflecting programs providing 2 vs. 1 ART regimens). In sensitivity analyses, we varied differences between S-LAB and POC in result return probability, result return time, ART initiation probability, and cost.

Results:

For infants who acquired HIV, LAB/S-LAB/POC led to projected one-year survival of 67.3%/69.9%/75.6% and undiscounted LE of 21.74/22.71/24.49 years. For all HIV-exposed infants, undiscounted LE was 63.35/63.38/63.43 years, at discounted lifetime costs of $200/220/240 per infant. In cost-effectiveness analysis, S-LAB was an inefficient use of resources; the ICER of POC vs. LAB was $830/YLS.

Conclusions:

Current EID programs will attain greater benefit from investing in POC EID rather than strengthening laboratory-based systems.
John Frederick Nye. 26 February 1923—8 January 2019
Authors: Berry Michael
Published: June 2020

John Nye was an internationally renowned physicist who made fundamental contributions to the understanding of crystals, ice and light. He explored defects in crystal structures, in particular continuous distributions of dislocations. He explained the mechanics of the flow of glaciers: their advance and retreat, and how this depends on the underlying topography; and how water flows beneath and within them. He was a pioneer in the study of optical singularities on three levels: stable caustics in geometrical optics; phase singularities (wavefront dislocations) in scalar waves; and lines of circular and linear polarization in electromagnetic fields.
Validation of a Self-administrable, Saliva-based RT-qPCR Test Detecting SARS-CoV-2
Authors: Miller Meghan , Jansen Michael , Bisignano Alexander , Mahoney Shannon , Wechsberg Christine , Albanese Nikita , Castillo Louise , Farinas Pia , Lazarin Gabriel A. , Jaremko Malgorzata
Published: June 2020

Background

Rapid and easy COVID-19 diagnostic testing is essential to controlling the pandemic and facilitating safe resumption of clinical care, employment and other social activities.

Methods

This study was conducted to validate an self-administrable saliva-based RT-qPCR test for the SARS-CoV2 virus under controlled laboratory conditions (analytical validation) according to federal guidance. An additional clinical study assessed positive (n = 34) and negative (n = 57) nasopharyngeal swab samples collected contemporaneously with saliva samples. Assessments for analytical specificity, sensitivity, cross reactivity and sample stability to simulate shipping conditions were conducted.

Results

Positive and negative agreement with third-party laboratory results were reported as 97.1% and 96.5–98.2%, respectively. Limit of detection was established at 5 copies/µL. Stability through simulated shipping conditions found 100% concordance up to 56 hours after collection. Discussion: These data validate a self-collected saliva-based COVID-19 RT-qPCR assay that performs comparably well to an assay of health care-provider administered nasopharyngeal swab samples. Accordingly, the United States Food and Drug Administration granted emergency use authorization in June 2020. Use of the saliva-based assay overcomes barriers to the necessary widespread testing, including strained health care resources, supply chain disruptions of laboratory materials, testing and protective equipment and exposure risks due to close interpersonal contact.
Scrutinizing the heterogeneous spreading of COVID-19 outbreak in Brazilian territory
Authors: Silva Rafael M. da , Mendes Carlos F.O. , Manchein Cesar
Published: June 2020

After the spread of COVID-19 out of China, the evolution of the pandemic shows remarkable similarities and differences among countries across the world. Eventually, such characteristics are also observed between different regions of the same country. Herewith, we study the heterogeneous spreading of the confirmed infected cases and deaths by the COVID-19 until May 30th, 2020, in the Brazilian territory, which has been seen as the current epicenter of the pandemic in South America. Our first set of results is related to the similarities and it shows that: (i) a power-law growth of the cumulative number of infected people is observed for federative units of the five regions of Brazil; and (ii) the Distance Correlation (DC) calculated between the time series of the most affected federative units and the curve that describes the evolution of the pandemic in Brazil remains about 1 in most of the time, while such quantity calculated for the federative units with a low incidence of newly infected people remains about 0.95. In the second set of results, we focus on the heterogeneous distribution of the confirmed cases and deaths, which is demonstrated by the fact that only three regions concentrate 92% of the cases. By applying the epidemiological SIRD model we estimated the effective reproduction number ℛe during the pandemic evolution and found that: (i) the mean value of ℛe for the eight most affected federative units in Brazil is about 2; (ii) the current value of ℛe for Brazil is greater than 1, which indicates that the epidemic peak is far; and (iii) Ceará was the only federative unit for which the current ℛe < 1. Based on these findings, we projected the effects of increase or decrease the effective reproduction number and concluded that if the value of ℛe increases 20%, not only the peak might grow at least 40% but also its occurrence might be anticipated, which hastens the collapse of the public health care system. In all cases, to keep the effective reproduction number 20% below the current one can save thousands of people in the long term.
Heliconiini butterflies can learn time-dependent reward associations
Authors: Toure M. Wyatt , Young Fletcher J. , McMillan W. Owen , Montgomery Stephen H.
Published: June 2020

For many pollinators, flowers provide predictable temporal schedules of resource availability, meaning an ability to learn time-dependent information could be widely beneficial. However, this ability has only been demonstrated in a handful of species. Observational studies ofHeliconiusbutterflies suggest that they may have an ability to form time-dependent foraging preferences.Heliconiusare unique among butterflies in actively collecting and digesting pollen, a dietary behaviour linked to spatiotemporally faithful ‘trap-line’ foraging. Time-dependency of foraging preferences is hypothesised to allowHeliconiusto exploit temporal predictability in alternative pollen resources, as well as contributing to optimal use of learnt foraging routes. Here, we provide the first experimental evidence in support of this hypothesis, demonstrating thatHeliconius hecalecan learn opposing colour preferences in two time periods. This shift in preference is robust to the order of presentation, suggesting that preference is tied to the time of day and not due to ordinal learning. However, we also show that this ability is not limited toHeliconius, as previously hypothesised, but is also present in a related genus of non-pollen feeding butterflies. This demonstrates that time learning pre-dates the origin of pollen-feeding and may be prevalent across butterflies with less specialized foraging behaviours.
Functional and molecular early enteric biomarkers for Parkinson’s disease in mice and men
Authors: Gries Manuela , Christmann Anne , Schulte Steven , Weyland Maximilian , Rommel Stephanie , Martin Monika , Baller Marko , Röth Ralph , Schmitteckert Stefanie , Unger Marcus , Liu Yang , Sommer Frederik , Mühlhaus Timo , Schroda Michael , Timmermans Jean-Pierre , Pintelon Isabel , Rappold Gudrun A. , Britschgi Markus , Lashuel Hilal , Menger Michael D. , Laschke Matthias W. , Niesler Beate , Schäfer Karl-Herbert
Published: June 2020

Parkinson’s disease (PD) usually has a late clinical onset. The lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use an α-synuclein-overexpressing transgenic (Th-1-SNCA-A30P) mouse model of PD to identify appropriate candidate markers in the gut for early stages of PD before hallmark symptoms begin to manifest. A30P mice did not show alterations in gait parameters at 2 months of age, and these mice were therefore defined as pre-symptomatic A30P mice (psA30P). We discovered early functional motility changes in the gut and early molecular dysregulations in the myenteric plexus of psA30P mice by comparative protein and miRNA profiling and cell culture experiments. We found that the proteins neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are potential biomarkers of early PD that may facilitate timely treatment and/or prevention of PD in men.
A single-cell RNA-seq Training and Analysis Suite using the Galaxy Framework
Authors: Tekman Mehmet , Batut Bérénice , Ostrovsky Alexander , Antoniewski Christophe , Clements Dave , Ramirez Fidel , Etherington Graham J , Hotz Hans-Rudolf , Scholtalbers Jelle , Manning Jonathan R , Bellenger Lea , Doyle Maria A , Heydarian Mohammad , Huang Ni , Soranzo Nicola , Moreno Pablo , Mautner Stefan , Papatheodorou Irene , Nekrutenko Anton , Taylor James , Blankenberg Daniel , Backofen Rolf , Grüning Björn
Published: June 2020

Background

The vast ecosystem of single-cell RNA-seq tools has until recently been plagued by an excess of diverging analysis strategies, inconsistent file formats, and compatibility issues between different software suites. The uptake of 10x Genomics datasets has begun to calm this diversity, and the bioinformatics community leans once more towards the large computing requirements and the statistically-driven methods needed to process and understand these ever-growing datasets.

Results

Here we outline several Galaxy workflows and learning resources for scRNA-seq, with the aim of providing a comprehensive analysis environment paired with a thorough user learning experience that bridges the knowledge gap between the computational methods and the underlying cell biology. The Galaxy reproducible bioinformatics framework provides tools, workflows and trainings that not only enable users to perform one-click 10x preprocessing, but also empowers them to demultiplex raw sequencing from custom tagged and full-length sequencing protocols. The downstream analysis supports a wide range of high-quality interoperable suites separated into common stages of analysis: inspection, filtering, normalization, confounder removal and clustering. The teaching resources cover an assortment of different concepts from computer science to cell biology. Access to all resources is provided at thesinglecell.usegalaxy.euportal.

Conclusions

The reproducible and training-oriented Galaxy framework provides a sustainable HPC environment for users to run flexible analyses on both 10x and alternative platforms. The tutorials from the Galaxy Training Network along with the frequent training workshops hosted by the Galaxy Community provide a means for users to learn, publish and teach scRNA-seq analysis.

Key Points

Single-cell RNA-seq has stabilised towards 10x Genomics datasets.

Galaxy provides rich and reproducible scRNA-seq workflows with a wide range of robust tools.

The Galaxy Training Network provides tutorials for the processing of both 10x and non-10x datasets.
The Impact of Restriction-Modification Systems on Mating inHaloferax volcanii
Authors: Ouellette Matthew , Makkay Andrea M. , Louyakis Artemis S. , Gophna Uri , Gogarten J. Peter , Papke R. Thane
Published: June 2020

Halobacteria have been observed to be highly recombinogenic, frequently exchanging genetic material. Several barriers to mating in the Halobacteria have been examined, such as CRISPR-Cas, glycosylation, and archaeosortases, but these are low barriers that do not drastically reduce the recombination frequency. Another potential barrier could be restriction-modification (RM) systems, which cleave DNA that is not properly methylated, thus limiting the exchange of genetic material between cells which do not have compatible RM systems. In order to examine the role of RM systems on limiting recombination in the Halobacteria, the impact of RM systems on cell-to-cell mating inHaloferax volcanii, a well-characterized method of genetic exchange and recombination in a halobacterial species, was examined. Strains which possessed all naturally-occurring RM system genes inH. volcanii(RM+) and strains without these RM systems (ΔRM) were mated together to compare the efficiency of gene transfer between RM-compatible strains and RM-incompatible strains. The results indicated that mating RM-incompatible strains together resulted in a decrease in gene transfer efficiency compared to mating RM-compatible strains together, suggesting that RM systems limit mating inH. volcanii, but do not act as absolute barriers to recombination. Therefore, RM systems are low barriers to recombination in the Halobacteria, with RM-incompatible strains exchanging genetic material at a lower frequency than those with compatible RM systems, similar to other low recombination barriers in the Halobacteria.
Unique molecular characteristics of visceral afferents arising from different levels of the neuraxis: location of afferent somata predicts function and stimulus detection modalities
Authors: Meerschaert Kimberly A. , Adelman Peter C. , Friedman Robert L. , Albers Kathryn M. , Koerber H. R. , Davis Brian M.
Published: June 2020

Visceral organs receive neural innervation from sensory ganglia located adjacent to multiple levels of the brainstem and spinal cord. Here we examined whether molecular profiling could be used to identify functional clusters of colon afferents from thoracolumbar (TL), lumbosacral (LS), and nodose ganglia (NG) in the mouse. Profiling of TL and LS bladder afferents was also done. Visceral afferents were back-labeled using retrograde tracers injected into proximal and distal regions of colon or bladder, followed by single cell RT-qPCR and analysis via an automated hierarchical clustering method. Genes were chosen for assay (32 for bladder; 48 for colon) based on their established role in stimulus detection, regulation of sensitivity/function or neuroimmune interaction. A total of 132 colon afferents (from NG, TL and LS) and 128 bladder afferents (from TL and LS) were analyzed. Retrograde labeling from the colon showed NG and TL afferents innervate proximal and distal regions of the colon whereas 98% of LS afferents only project to distal regions. There were clusters of colon and bladder afferents, defined by mRNA profiling, that localized to either TL or LS ganglia. Mixed TL/LS clustering also was found. In addition, transcriptionally, NG colon afferents were almost completely segregated from colon DRG (TL or LS) neurons. These results indicate that populations of primary visceral afferents are functionally “tuned” to detect and interact with the internal environment and that information from all levels is integrated at higher (CNS) levels, not only for regulation of homeostatic functions, but for conscious visceral sensations including pain.

Significance Statement

Visceral organs are innervated by sensory neurons whose cell bodies are located in multiple ganglia associated with the brainstem and spinal cord. For the colon, this overlapping innervation is proposed to facilitate visceral sensation and homeostasis, where sensation and pain is mediated by spinal afferents and fear and anxiety (the affective aspects of visceral pain) are the domain of nodose afferents. Transcriptomic analysis performed here reveals that genes implicated in both homeostatic regulation and pain are found in afferents across all ganglia types, suggesting that conscious sensation and homeostatic regulation is the result of convergence, and not segregation, of sensory input.
Spontaneous variability predicts adaptive motor response in vocal pitch control
Authors: Tachibana Ryosuke O. , Xu Mingdi , Hashimoto Ryu-ichiro , Homae Fumitaka , Okanoya Kazuo
Published: June 2020

Our motor system uses sensory feedback to keep behavioral performance in desired status. From this view, motor fluctuation is not simply ‘noise’ inevitably caused in the nervous system, but should provide a role in generating variations to explore better outcomes via their sensory feedback. Vocal control system offers a good model to investigate such adaptive sensory-motor interactions. The pitch, or fundamental frequency (FF), of voice is adaptively regulated by hearing its auditory feedback to compensate FF deviations. Animal studies, particularly for songbirds, have demonstrated that the variability in vocal features contributes to the adaptive control, although the same issue in human vocalizations has remained unclear. Here, we tested whether and how the motor variability contributes to adaptive control of vocal FF in humans. We measured the amount of compensatory vocal responses against FF shifts in the auditory feedback, and quantified the motor variability as amplitudes of spontaneous FF fluctuations during no shift vocalizations. The result showed a positive correlation between the ratio of compensation and the spontaneous vocal variability. Further analysis indicated that this correlation was due to slowly fluctuating components (<5 Hz) of the variability, but not fast fluctuations (6-30 Hz), which is likely to reflect controllability from the central nervous system. Moreover, the compensatory responses consisted of the same frequency range with the slow component in the spontaneous variability. These findings consistently demonstrated that the spontaneous motor variability predicts the adaptive control in vocal FF, supporting the motor exploration hypothesis.

Significance statement

We regulate our own vocalization by hearing own voice. This fact is typically observed as canceling-out (compensatory) responses in vocalized pitch when artificial pitch shifts were induced in the auditory feedback of own voice. Interestingly, the amount of such compensation widely ranges among talkers from perfect cancellation to almost nothing. Here we demonstrated that participants who spontaneously exhibited larger fluctuations showed greater amounts of the compensation against feedbacked pitch shifts. Our in-depth analyses showed that slowly fluctuating components in spontaneous pitch variability are specifically correlated with the compensation ratios, and was shared in the compensatory response as a dominant component. These findings support the idea that such variability contributes to generating motor explorations to find better outcomes in motor controls.
Female and male plumage colour is linked to parental quality, pairing and extra-pair mating in a tropical passerine
Authors: Leitão Ana V. , Hall Michelle L. , Mulder Raoul A.
Published: June 2020

Sexual selection has been proposed to drive the evolution of elaborate phenotypic traits in males, which often confer success in competition or mating. However, in many species both males and females display such traits, although studies reporting selection acting in both sexes are scarce. In this study, we investigated whether plumage ornamentation is sexually selected in female and male lovely fairy-wrensMalurus amabilis,a cooperatively breeding songbird. We found that female and male plumage colour was correlated with parental quality but did not incur survival costs. We also found evidence of positive assortative mating based on plumage colour. Microsatellite analyses of paternity indicated that the lovely fairywren has high levels of extra-pair paternity, with 53% of offspring resulting from extra-pair mating. Female and male plumage colour did not predict reproductive success and female proportion of extra-pair offspring in its own nest, but less colourful males obtained higher extra-pair paternity. We argue that plumage colour may be under sex-specific selection, highlighting the importance of looking at both sexes in studies of sexual selection and ornament evolution. The current findings together with previous study, suggest that plumage colour in female and male lovely fairy-wrens appears to be an honest signal relevant in both intra and inter-sexual competition contexts.
ORN: Extracting Latent Pathway Activities in Cancer with OR-gate Network
Authors: Liang Lifan , Zhu Kunju , Lu Songjian
Published: June 2020

Pathway level understanding of cancer plays a key role in precision oncology. In this study, we developed a novel data-driven model, called the OR-gate Network (ORN), to simultaneously infer functional relationships among mutations, patient-specific pathway activities, and gene co-expression. In principle, logical OR gates agree with mutual exclusivity patterns in somatic mutations and bicluster patterns in transcriptomic profiles. In a trained ORN, the differential expression profiles of tumours can be explained by somatic mutations perturbing signalling pathways. We applied ORN to lower grade glioma (LLG) samples in TCGA and breast cancer samples from METABRIC. Both datasets have shown pathway patterns related to immune response and cell cycles. In LLG samples, ORN identified multiple metabolic pathways closely related to glioma development and revealed two pathways closely related to patient survival. Additional results from the METABRIC datasets showed that ORN could characterize key mechanisms of cancer and connect them to less studied somatic mutations (e.g., BAP1, MIR604, MICAL3, and telomere activities), which may generate novel hypothesis for targeted therapy.
Drug2ways: Reasoning over causal paths in biological networks for drug discovery
Authors: Rivas-Barragan Daniel , Mubeen Sarah , Bernat Francesc Guim , Hofmann-Apitius Martin , Domingo-Fernández Daniel
Published: June 2020

Elucidating the causal mechanisms responsible for disease can reveal potential therapeutic targets for pharmacological intervention and, accordingly, guide drug repositioning and discovery. In essence, the topology of a network can reveal the impact a drug candidate may have on a given biological state, leading the way for enhanced disease characterization and the design of advanced therapies. Network-based approaches, in particular, are highly suited for these purposes as they hold the capacity to identify the molecular mechanisms underlying disease. Here, we present drug2ways, a novel methodology that leverages multimodal causal networks for predicting drug candidates. Drug2ways implements an efficient algorithm which reasons over causal paths in large-scale biological networks to propose drug candidates for a given disease. We validate our approach using clinical trial information and demonstrate how drug2ways can be used for multiple applications to identify: i) single-target drug candidates, ii) candidates with polypharmacological properties that can optimize multiple targets, and iii) candidates for combination therapy. Finally, we make drug2ways available to the scientific community as a Python package that enables conducting these applications on multiple standard network formats.
Norepinephrine as a Spatial Memory Reset Signal
Authors: Grella Stephanie L. , Gomes Sarah M. , Lackie Rachel E. , Renda Briana , Marrone Diano F.
Published: June 2020

Contextual information is represented in the hippocampus (HPC) partially through the recruitment of distinct neuronal ensembles. It is believed that reactivation of these ensembles underlies memory retrieval processes. Recently, we showed that norepinephrine (NE) input from phasic locus coeruleus (LC) activation induces hippocampal plasticity resulting in the recruitment of new neurons and a disengagement from previously established representations. We hypothesize that NE may provide a neuromodulatory, mnemonic switch signaling the HPC to move from a state of retrieval to encoding in the presence of novelty, and therefore, plays a role in memory updating. Here, we tested whether bilateral dorsal dentate gyrus (DG) infusions of the β-adrenergic receptor (BAR) agonist isoproterenol (ISO), administered prior to encoding or retrieval, would impair spatial working and reference memory by reverting the system to encoding (thereby recruiting new neurons) potentially interfering with retrieval of the previously established spatial ensemble. We also investigated whether dDG infusions of ISO could promote cognitive flexibility by switching the system to encoding when it is adaptive (i.e. when new information is presented e.g. reversal learning). We found that intra-dDG infusions of ISO given prior to retrieval caused deficits in working and reference memory which was blocked by pre-treatment with the BAR-antagonist, propranolol (PRO). In contrast, ISO administered prior to reversal learning led to improved performance. These data support our hypothesis that NE serves as a novelty signal to update HPC contextual representations via BAR activation-facilitated recruitment of new neurons. This can be both maladaptive and adaptive depending on the situation.

SIGNIFICANCE STATEMENT

The current work highlights the involvement of hippocampal BARs in determining the flexibility of contextual representations to promote new learning in a way that supports adaptive behavior. This work builds upon previous work showing that noradrenergic input to the hippocampus is involved in recruiting new neurons resulting in new contextual representations and may be involved in the underlying neural mechanisms that support memory updating. These data suggest targets for anxiety disorders such as PTSD, which are characterized by noradrenergic dysregulation, and may also involve impairments in memory updating mechanisms where the incorporation of new information is not effectively encoded. The further understanding of the neurobiological mechanisms involved in updating memories may provide insight into novel treatment strategies.
Temporal transcriptome profiling ofMicrochloropsis gaditanaCCMP526 under hyper-saline conditions
Authors: Karthikaichamy Anbarasu , Beardall John , Coppel Ross , Noronha Santosh , Srivastava Sanjeeva , Bulach Dieter
Published: June 2020

Microalgae can tolerate a wide range of environmental conditions and have been exploited for their lipid and carbohydrate accumulating properties. The utility of this process could be further enhanced through understanding the critical gene regulatory networks that govern the acclimatization process. Advancements in systems biology and sequencing tools now enable us to obtain a genome-wide overview of gene expression under particular conditions of interest. Under salinity stress,Microchloropsis gaditanaCCMP526, a commercially important alga has been previously reported to accumulate carbohydrate and lipid. To understand the mechanism of acclimatization, here we report a temporal transcriptomic analysis ofM. gaditanaunder two different salinity levels (55 and 100 PSU). The short term (0, 1 and 6 h) and long term (24 and 72 h) responses of the salt-induced transcript pool were used to identify salinity-inducible genes using correspondence analysis. The transcript abundance of genes involved in triacylglycerol biosynthesis, membrane lipid modification, carbon assimilation and shunting, and osmolyte biosynthesis indicated thatM. gaditanaemploys a two-stage acclimatization strategy during hypersaline conditions.
Double Emulsion Picoreactors for High-Throughput Single-Cell Encapsulation and Phenotyping via FACS
Authors: Brower Kara K. , Khariton Margarita , Suzuki Peter H. , Still Chris , Kim Gaeun , Calhoun Suzanne G. K. , Qi Lei S. , Wang Bo , Fordyce Polly M.
Published: June 2020

In the past five years, droplet microfluidic techniques have unlocked new opportunities for the high-throughput genome-wide analysis of single cells, transforming our understanding of cellular diversity and function. However, the field lacks an accessible method to screen and sort droplets based on cellular phenotype upstream of genetic analysis, particularly for large and complex cells. To meet this need, we developed Dropception, a robust, easy-to-use workflow for precise single-cell encapsulation into picoliter-scale double emulsion droplets compatible with high-throughput phenotyping via fluorescence-activated cell sorting (FACS). We demonstrate the capabilities of this method by encapsulating five standardized mammalian cell lines of varying size and morphology as well as a heterogeneous cell mixture of a whole dissociated flatworm (5 - 25 μm in diameter) within highly monodisperse double emulsions (35 μm in diameter). We optimize for preferential encapsulation of single cells with extremely low multiple-cell loading events (<2% of cell-containing droplets), thereby allowing direct linkage of cellular phenotype to genotype. Across all cell lines, cell loading efficiency approaches the theoretical limit with no observable bias by cell size. FACS measurements reveal the ability to discriminate empty droplets from those containing cells with good agreement to single-cell occupancies quantified via microscopy, establishing robust droplet screening at single-cell resolution. High-throughput FACS phenotyping of cellular picoreactors has the potential to shift the landscape of single-cell droplet microfluidics by expanding the repertoire of current nucleic acid droplet assays to include functional screening.

ABSTRACT FIGURE
Functional and cognitive outcomes after COVID-19 delirium
Authors: Mcloughlin Benjamin C , Miles Amy , Webb Thomas , Knopp Paul , Eyres Clodagh , Fabbri Ambra , Humphries Fiona , Davis Daniel
Published: June 2020

Purpose

To ascertain delirium prevalence and outcomes in COVID-19.

Methods

We conducted a point-prevalence study in a cohort of COVID-19 inpatients at University College Hospital. Delirium was defined by DSM-IV criteria. The primary outcome was all-cause mortality at 4 weeks; secondary outcomes were physical and cognitive function.

Results

In 71 patients, 31 (42%) had delirium, of which only 19 had been recognised by the clinical team. At 4 weeks, 20 (28%) had died, 26 (36%) were interviewed by telephone and 21 (30%) remained as inpatients. Physical function was substantially worse in people after delirium (−39 points on functional scale/166, 95% CI −92 to −21, p=0.01) (Table 2). Mean cognitive scores at follow-up were similar and delirium was not associated with mortality in this sample.

Conclusions

Our findings indicate that delirium is common, yet under-recognised. Delirium is associated with functional impairments in the medium-term.

Key summary points

Aim

To investigate functional and cognitive outcomes among patients with delirium in COVID-19.

Findings

Delirium in COVID-19 was prevalent (42%) but only a minority had been recognised by the clinical team. At 4-week follow-up, delirium was significantly associated with worse functional outcomes, independent of pre-morbid frailty. Cognitive outcomes were not appreciably worse.

Message

The presence of delirium is a significant factor in predicting worse functional outcomes in patients with COVID-19.
Who dies from COVID-19? Post-hoc explanations of mortality prediction models using coalitional game theory, surrogate trees, and partial dependence plots
Authors: Yang Russell
Published: June 2020

As of early June, 2020, approximately 7 million COVID-19 cases and 400,000 deaths have been reported. This paper examines four demographic and clinical factors (age, time to hospital, presence of chronic disease, and sex) and utilizes Shapley values from coalitional game theory and machine learning to evaluate their relative importance in predicting COVID-19 mortality. The analyses suggest that out of the 4 factors studied, age is the most important in predicting COVID-19 mortality, followed by time to hospital. Sex and presence of chronic disease were both found to be relatively unimportant, and the two global interpretation techniques differed in ranking them. Additionally, this paper creates partial dependence plots to determine and visualize the marginal effect of each factor on COVID-19 mortality and demonstrates how local interpretation of COVID-19 mortality prediction can be applicable in a clinical setting. Lastly, this paper derives clinically applicable decision rules about mortality probabilities through a parsimonious 3-split surrogate tree, demonstrating that high-accuracy COVID-19 mortality prediction can be achieved with simple, interpretable models.
Topography of speech-related acoustic and phonological feature encoding throughout the human core and parabelt auditory cortex
Authors: Hamilton Liberty S. , Oganian Yulia , Chang Edward F.
Published: June 2020

Speech perception involves the extraction of acoustic and phonological features from the speech signal. How those features map out across the human auditory cortex is unknown. Complementary to noninvasive imaging, the high spatial and temporal resolution of intracranial recordings has greatly contributed to recent advances in our understanding. However, these approaches are typically limited by piecemeal sampling of the expansive human temporal lobe auditory cortex. Here, we present a functional characterization of local cortical encoding throughout all major regions of the primary and non-primary human auditory cortex. We overcame previous limitations by using rare direct recordings from the surface of the temporal plane after surgical microdissection of the deep Sylvian fissure between the frontal and temporal lobes. We recorded neural responses using simultaneous high-density direct recordings over the left temporal plane and the lateral superior temporal gyrus, while participants listened to natural speech sentences and pure tone stimuli. We found an anatomical separation of simple spectral feature tuning, including tuning for pure tones and absolute pitch, on the superior surface of the temporal plane, and complex tuning for phonological features, relative pitch and speech amplitude modulations on lateral STG. Broadband onset responses are unique to posterior STG and not found elsewhere in auditory cortices. This onset region is functionally distinct from the rest of STG, with latencies similar to primary auditory areas. These findings reveal a new, detailed functional organization of response selectivity to acoustic and phonological features in speech throughout the human auditory cortex.
Population density modeling of mixed polymorphic phenotypes: an application of spatial mark-resight models
Authors: Harihar Abishek , Lahkar Dipankar , Singh Aparajita , Das Sunit Kumar , Ahmed M Firoz , Begum Ramie H
Published: June 2020

Melanism is a form of pigmentation polymorphism where individuals have darker colouration than what is considered the “wild” phenotype. In the case of leopards,Panthera pardus, melanism occurs at higher frequencies amongst populations in tropical and subtropical moist forests of south and southeast Asia, presenting a unique challenge in estimating and monitoring these populations. Unlike the wild phenotype that is readily recognizable by its rosette patterns, melanism results in individuals being unidentifiable or ‘unmarked’ through photographic captures obtained using white flash cameras. Spatial mark-resight (SMR) models that require only a subset of the population to be ‘marked’ offer the opportunity to estimate population density. In this study, we present an application of SMR models to estimate leopard densities using camera trap survey data from three sampling years at Manas National Park (MNP), India. By using an SMR model that allowed us to include captures of unidentified sightings of marked individuals, we were also able to incorporate captures where identity was either not confirmed or only known from a single flank. Following 18,674 trap-days of sampling across three years, we obtained 728 leopard photo-captures, of which 22.6% (165) were melanistic. We estimated leopard densities of 4.33, 2.61 and 3.37 individuals/100km2across the three years. To our best knowledge, these represent the first known estimates of leopard densities from populations comprising both melanistic and wild phenotypes. Finally, we highlight that SMR models present an opportunity to revisit past camera trap survey data for leopards and other species such as Jaguars,P. onca, that exhibit phenotypic polymorphism towards generating valuable information on populations.
Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia
Authors: Pasetto Laura , Grassano Maurizio , Pozzi Silvia , Luotti Silvia , Sammali Eliana , Migazzi Alice , Basso Manuela , Spagnolli Giovanni , Biasini Emiliano , Micotti Edoardo , Cerovic Milica , Carli Mirjana , Forloni Gianluigi , Marco Giovanni De , Manera Umberto , Moglia Cristina , Mora Gabriele , Traynor Bryan J. , Chiò Adriano , Calvo Andrea , Bonetto Valentina
Published: June 2020

Aggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. However, the molecular mechanism by which TDP-43 aggregates form and cause neurodegeneration remains poorly understood. Cyclophilin A, also known as peptidyl-prolylcis-transisomerase A (PPIA), is a foldase and molecular chaperone. We previously found that PPIA interacts with TDP-43 and governs some of its functions, and its deficiency accelerates disease in a mouse model of ALS. Here we characterizedPPIAknock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of FTD, marked TDP-43 pathology and late-onset motor dysfunction. In the mouse brain, deficient PPIA induces aggregation of the GTP-binding nuclear protein Ran, a PPIA substrate required for TDP-43 nucleocytoplasmic trafficking. Moreover, in absence of PPIA, TDP-43 autoregulation is perturbed and TDP-43 and proteins involved in synaptic function are downregulated, leading to impairment of synaptic plasticity. Finally, we found that PPIA was downregulated in several ALS and ALS-FTD patients and identified a PPIA loss-of-function mutation in a sporadic ALS patient. The mutant PPIA has low stability, altered structure and impaired interaction with TDP-43. These findings strongly implicate that defective PPIA function causes TDP-43 mislocalization and dysfunction and should be considered in future therapeutic approaches.
PKA drives an increase in AMPA receptor unitary conductance during LTP in the hippocampus
Authors: Park Pojeong , Georgiou John , Sanderson Thomas M. , Ko Kwang-Hee , Kang Heather , Kim Ji-il , Bradley Clarrisa A. , Bortolotto Zuner A. , Zhuo Min , Kaang Bong-Kiun , Collingridge Graham L.
Published: June 2020

Long-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance (γ). Here we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10 s inter-episode interval, involved purely an increase in N (LTPN). In contrast, either a spaced TBS, with a 10 min inter-episode interval, or a single TBS, delivered when PKA was activated, resulted in LTP that was associated with a transient increase in γ (LTPγ). This γ increase was due to the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII was necessary and sufficient for LTPNwhilst PKA was additionally required for LTPγ. Thus, two mechanistically distinct forms of LTP co-exist at these synapses.