bluuebunny/crossref_metadata_2025 huggingface dataset:
Drone versus ground delivery of simulated blood products to an urban trauma center: The Montreal Medi-Drone pilot study
Authors: Homier Valerie , Brouard Danny , Nolan Michael , Roy Marie-Andrée , Pelletier Patricia , McDonald Melissa , de Champlain François , Khalil Elene , Grou-Boileau Frederic , Fleet Richard
Published: October 2020

BACKGROUND

Timely and safe distribution of quality blood products is a major challenge faced by blood banks around the world. Our primary objective was to determine if simulated blood product delivery to an urban trauma center would be more rapidly achieved by unmanned aerial vehicle (UAV) than by ground transportation. A secondary objective was to determine the feasibility of maintaining simulated blood product temperatures within a targeted range.

METHODS

In this prospective pilot study, we used two distinct methods to compare UAV flight duration and ground transport times. Simulated blood products included packed red blood cells, platelet concentrate, and fresh frozen plasma. For each blood product type, three UAV flights were conducted. Temperature was monitored during transport using a probe coupled to a data logger inside each simulated blood product unit.

RESULTS

All flights were conducted successfully without any adverse events or safety concerns reported. The heaviest payload transported was 6.4 kg, and the drone speed throughout all nine flights was 10 m/s. The mean UAV transportation time was significantly faster than ground delivery (17:06 ± 00:04 minutes vs. 28:54 ± 01:12 minutes, p < 0.0001). The mean ± SD initial temperature for packed red blood cells was 4.4°C ± 0.1°C with a maximum 5% mean temperature variability from departure to landing. For platelet concentrates, the mean ± SD initial temperature was 21.6°C ± 0.5°C, and the maximum variability observed was 0.3%. The mean ± SD initial fresh frozen plasma temperature was −19°C ± 2°C, and the greatest temperature variability was from −17°C ± 2°C to −16°C ± 2°C.

CONCLUSIONS

Unmanned aerial vehicle transportation of simulated blood products was significantly faster than ground delivery. Simulated blood product temperatures remained within their respective acceptable ranges throughout transport. Further studies assessing UAV transport of real blood products in populated areas are warranted.

LEVEL OF EVIDENCE

Therapeutic/care management, level IV.
Hypercoagulable viscoelastic blood clot characteristics in critically ill coronavirus disease 2019 patients and associations with thrombotic complications
Authors: Roh David J. , Eiseman Katherine , Kirsch Hannah , Yoh Nina , Boehme Amelia , Agarwal Sachin , Park Soojin , Connolly E. Sander , Claassen Jan , Wagener Gebhard
Published: October 2020

BACKGROUND

Critically ill coronavirus disease 2019 (COVID-19) patients have frequent thrombotic complications and laboratory evidence of hypercoagulability. The relationship of coagulation tests and thrombosis requires investigation to identify best diagnostic and treatment approaches. We assessed for hypercoagulable characteristics in critically ill COVID-19 patients using rotational thromboelastometry (ROTEM) and explored relationships of D-dimer and ROTEM measurements with thrombotic complications.

METHODS

Critically ill adult COVID-19 patients receiving ROTEM testing between March and April 2020 were analyzed. Patients receiving therapeutic anticoagulation before ROTEM were excluded. Rotational thromboelastometry measurements from COVID-19 patients were compared with non–COVID-19 patients matched by age, sex, and body mass index. Intergroup differences in ROTEM measurements were assessed using t tests. Correlations of D-dimer levels to ROTEM measurements were assessed in COVID-19 patients who had available concurrent testing. Intergroup differences of D-dimer and ROTEM measurements were explored in COVID-19 patients with and without thrombosis.

RESULTS

Of 30 COVID-19 patients receiving ROTEM, we identified hypercoagulability from elevated fibrinogen compared with non–COVID-19 patients (fibrinogen assay maximum clot firmness [MCF], 47 ± 13 mm vs. 20 ± 7 mm; mean intergroup difference, 27.4 mm; 95% confidence interval [CI], 22.1–32.7 mm; p < 0.0001). In our COVID-19 cohort, thrombotic complications were identified in 33%. In COVID-19 patients developing thrombotic complications, we identified higher D-dimer levels (17.5 ± 4.3 μg/mL vs. 8.0 ± 6.3 μg/mL; mean difference, 9.5 μg/mL; 95% CI, 13.9–5.1; p < 0.0001) but lower fibrinogen assay MCF (39.7 ± 10.8 mm vs. 50.1 ± 12.0 mm; mean difference, −11.2 mm; 95% CI, −2.1 to −20.2; p = 0.02) compared with patients without thrombosis. We identified negative correlations of D-dimer levels and ROTEM MCF in these patients (r = −0.61; p = 0.001).

CONCLUSION

We identified elevated D-dimer levels and hypercoagulable blood clot characteristics from increased fibrinogen on ROTEM testing in critically ill COVID-19 patients. However, we identified lower, albeit still hypercoagulable, ROTEM measurements of fibrinogen in COVID-19 patients with thrombotic complications compared with those without. Further work is required to externally validate these findings and to investigate the mechanistic drivers for these relationships to identify best diagnostic and treatment approaches for these patients.

LEVEL OF EVIDENCE

Epidemiologic, level IV.
Does routine repeat imaging for blunt high-grade renal trauma lead to unnecessary interventions?
Authors: Loftus Christopher J. , Hagedorn Judith C. , Johnsen Niels V.
Published: October 2020

BACKGROUND

Most high-grade renal injuries with urinary extravasation (UE) may be managed conservatively without intervention. For such patients, the American Urological Association Urotrauma guidelines recommend repeat imaging within 48 to 72 hours of injury. We sought to examine whether routine, proactive follow-up renal imaging was associated with need for urologic intervention or risk of complications.

METHODS

Patients treated to an urban level 1 trauma center for a five-state region, between 2005 and 2017 were identified by International Classification of Diseases, Ninth Revision and Tenth Revision, codes from a prospectively collected institutional trauma registry. Individual patient charts and imaging were reviewed to identify all patients with American Association for the Surgery of Trauma grade IV renal injuries. Those with UE were included, and patients with penetrating trauma, immediate urologic surgery, or in-hospital mortality were excluded.

RESULTS

Of 342 patients with grade IV injuries, 108 (32%) met the inclusion criteria. Urologic intervention was performed in 23% (25 of 108 patients) including endoscopic procedure (24 of 108 patients) and nephrectomy (1 of 108 patients). Repeat imaging was performed within 48 to 72 hours after initial imaging in 65% (70 to 108 patients). Patients who underwent routine reimaging had a higher rate of undergoing subsequent urologic procedure (31.4% vs. 7.1%, p = 0.008). For patients with reimaging who underwent a procedure, 18% (4 of 22 patients) were symptomatic, while all nonroutinely reimaged patients who underwent a procedure were symptomatic (3 of 3 patients). Patients who received routine repeat imaging had a higher mean number of abdominal computed tomography scans during their admission (2.5 vs. 1.7, p < 0.001), while the complication rate was similar between groups.

CONCLUSIONS

Patients with grade IV renal lacerations with UE from blunt trauma who received routine repeat imaging were more likely to undergo an operation in the absence of symptoms and received more radiation during their hospital stay. Forgoing repeat imaging was not associated with an increase in urological complications. These data suggest that, in the absence of signs/symptoms, repeat imaging may be avoidable.

LEVEL OF EVIDENCE

Therapeutic/care management, level IV.
American Association for the Surgery of Trauma–World Society of Emergency Surgery guidelines on diagnosis and management of peripheral vascular injuries
Authors: Kobayashi Leslie , Coimbra Raul , Goes Adenauer M. O. , Reva Viktor , Santorelli Jarrett , Moore Ernest E. , Galante Joseph , Abu-Zidan Fikri , Peitzman Andrew B. , Ordonez Carlos , Maier Ronald V. , Di Saverio Salomone , Ivatury Rao , De Angelis Nicola , Scalea Thomas , Catena Fausto , Kirkpatrick Andrew , Khokha Vladimir , Parry Neil , Civil Ian , Leppaniemi Ari , Chirica Mircea , Pikoulis Emmanouil , Fraga Gustavo P. , Chiarugi Massimo , Damaskos Dimitrios , Cicuttin Enrico , Ceresoli Marco , De Simone Belinda , Vega-Rivera Felipe , Sartelli Massimo , Biffl Walt , Ansaloni Luca , Weber Dieter G. , Coccolini Federico
Published: October 2020

The peripheral arteries and veins of the extremities are among the most commonly injured vessels in both civilian and military vascular trauma. Blunt causes are more frequent than penetrating except during military conflicts and in certain geographic areas. Physical examination and simple bedside investigations of pulse pressures are key in early identification of these injuries. In stable patients with equivocal physical examinations, computed tomography angiograms have become the mainstay of screening and diagnosis. Immediate open surgical repair remains the first-line therapy in most patients. However, advances in endovascular therapies and more widespread availability of this technology have resulted in an increase in the range of injuries and frequency of utilization of minimally invasive treatments for vascular injuries in stable patients. Prevention of and early detection and treatment of compartment syndrome remain essential in the recovery of patients with significant peripheral vascular injuries. The decision to perform amputation in patients with mangled extremities remains difficult with few clear indicators. The American Association for the Surgery of Trauma in conjunction with the World Society of Emergency Surgery seeks to summarize the literature to date and provide guidelines on the presentation, diagnosis, and treatment of peripheral vascular injuries.

LEVEL OF EVIDENCE

Review study, level IV.
American Association for the Surgery of Trauma–World Society of Emergency Surgery guidelines on diagnosis and management of abdominal vascular injuries
Authors: Kobayashi Leslie , Coimbra Raul , Goes Adenauer M.O. , Reva Viktor , Santorelli Jarrett , Moore Ernest E. , Galante Joseph M. , Abu-Zidan Fikri , Peitzman Andrew B. , Ordonez Carlos A. , Maier Ronald V. , Di Saverio Salomone , Ivatury Rao , De Angelis Nicola , Scalea Thomas , Catena Fausto , Kirkpatrick Andrew , Khokha Vladimir , Parry Neil , Civil Ian , Leppaniemi Ari , Chirica Mircea , Pikoulis Emmanouil , Fraga Gustavo P. , Chiarugi Massimo , Damaskos Dimitrios , Cicuttin Enrico , Ceresoli Marco , De Simone Belinda , Vega-Rivera Felipe , Sartelli Massimo , Biffl Walt , Ansaloni Luca , Weber Dieter G. , Coccolini Federico
Published: October 2020

Abdominal vascular trauma accounts for a small percentage of military and a moderate percentage of civilian trauma, affecting all age ranges and impacting young adult men most frequently. Penetrating causes are more frequent than blunt in adults, while blunt mechanisms are more common among pediatric populations. High rates of associated injuries, bleeding, and hemorrhagic shock ensure that, despite advances in both diagnostic and therapeutic technologies, immediate open surgical repair remains the mainstay of treatment for traumatic abdominal vascular injuries. Because of their devastating nature, abdominal vascular injuries remain a significant source of morbidity and mortality among trauma patients. The American Association for the Surgery of Trauma in conjunction with the World Society of Emergency Surgery seek to summarize the literature to date and provide guidelines on the presentation, diagnosis, and treatment of abdominal vascular injuries.

LEVEL OF EVIDENCE

Review study, level IV.
Confluent White Matter in Progression to Alzheimer Dementia
Authors: Heng Li Cheng , Lim Shu Han , Foo Heidi , Kandiah Nagaendran
Published: October 2020

Background:

Alongside Alzheimer disease pathology, cerebral small vessel disease (CSVD) contributes to the differential progression rates from mild cognitive impairment (MCI) to dementia. Hence, identification of specific type of CSVD lesions that influence progression is needed.

Objective:

The objective of this study was to evaluate the role of silent CSVD in the progression from MCI to dementia and if confluent white matter hyperintensities (WMHs) pose a higher risk for progression in the clinical setting.

Methods:

Patients with MCI with baseline magnetic resonance imaging and longitudinal follow-up were evaluated. WMH were quantified using visual scoring at baseline (all subjects) and at end of study period (subgroup). Influences of baseline total WMH, baseline confluent WMH, and increase of WMH on progression from MCI to dementia were analyzed.

Results:

A total of 200 patients with a mean age of 67.9 (SD 8.7) years were evaluated. Progression to dementia was significantly higher among patients with MCI with confluent WMH (55.7% vs. 32.3%; P<0.001). The odds ratio of a patient with confluent WMH progressing to dementia was 2.66. The annual decline in Mini Mental State Examination was significantly higher in those with confluent WMH lesions (−1.60 vs. −1.20; P=0.010). In the subgroup with follow-up magnetic resonance imaging (n=70), patients who demonstrated an increase in WMH had greater decline in annual Mini Mental State Examination scores (−1.79 vs. −0.59; P=0.054).

Conclusion:

Confluent WMH lesions in MCI are associated with higher rates of progression to dementia.
Impaired neurocognitive function in glioma patients: from pathophysiology to novel intervention strategies
Authors: Noll Kyle R. , Walbert Tobias , Wefel Jeffrey S.
Published: October 2020

Purpose of review

This review succinctly summarizes the recent literature regarding etiological contributors to impaired neurocognitive function (NCF) in adult patients with glioma. A brief overview of intervention and prevention strategies is also provided.

Recent findings

A majority of patients with glioma exhibit NCF deficits, most frequently in memory and executive functioning. Impairments are often disabling and associated with reduced quality of life and survival. Cause is multifactorial and includes the tumour itself, treatments received and associated comorbidities. Although modern techniques such as brain mapping, dosing modifications and prophylactic medication aim to improve the NCF outcomes following neurosurgical resection and radiation therapy, a sizeable proportion of patients continue to evidence treatment-related NCF declines related to adverse effects to both local and distributed cerebral networks. Numerous patient and tumour characteristics, including genetic markers and sociodemographic factors, influence the pattern and severity of NCF impairment. Some rehabilitative and pharmacologic approaches show promise in mitigating NCF impairment in this population, though benefits are somewhat modest and larger scale intervention studies are needed.

Research regarding NCF in patients with glioma has dramatically proliferated, providing insights into the mechanisms underlying impaired NCF and pointing to potential interventions, though further work is needed.
Neddylation of M1 negatively regulates the replication of influenza A virus
Authors: Li Yucen , Chai Wenjia , Min Jie , Ye Zhen , Tong Xiaomei , Qi Dandan , Liu Wenjun , Luo Enjie , Li Jing , Ye Xin
Published: October 2020

Post-translational modification plays a critical role in viral replication. Previously we reported that neddylation of PB2 of influenza A virus (IAV) can inhibit viral replication. However, we found that NEDD8 overexpression can still inhibit the replication of PB2 K699R mutant viruses, implying that other viral protein(s) can be neddylated. In this study, we revealed that M1 of IAV can also be modified by NEDD8. We found that the E3 ligase HDM2 significantly promotes M1 neddylation. Furthermore, we identified M1 K187 as the major neddylation site. We generated an IAV M1 K187R mutant (WSN-M1 K187R) and compared the growth of wild-type and mutant viruses in Madin–Darby canine kidney (MDCK) cells. The data showed that the replication of WSN-M1 K187R was more efficient than that of wild-type WSN. More importantly, we observed that overexpression of NEDD8 inhibited the replication of the wild-type WSN more effectively than that of WSN-M1 K187R. In addition, we found that the neddylation-deficient M1 mutant (M1 K187R) had a longer half-life than that of wild-type M1, indicating that the neddylation of M1 reduces stability. Then we performed a viral infection assay and found that WSN-M1 K187R exhibited greater virulence in mice than wild-type WSN, suggesting that the neddylation of M1 reduced IAV replication in vivo. In conclusion, we uncovered that neddylation of M1 by HDM2 negatively regulates the stability of M1, which in turn inhibits viral replication.
COVID-19 era, Preventive effect of no going out against co-infection of the seasonal influenza virus and SARS-CoV-2
Authors: Hayashi Takuma , Yaegashi Nobuo , Konishi Ikuo
Published: October 2020

In the situation where expansion of coronavirus infectious disease-2019 (COVID-19) does not stop, there is concern about co-infection of people with the seasonal influenza infections from late autumn to winter 2020. Therefore, the importance of supplying vaccines against the seasonal influenza has been pointed out all over the world. As an example in Japan, the number of people infected with the seasonal influenza, hand-foot-and-mouth disease (HFMD), epidemic keratoconjunctivitis, and pharyngoconjunctival fever (PCF), which are the seasonal infectious diseases in the 2020 season, has decreased remarkably compared to the number of people infected each year. It is believed that the significant reduction in the number of people infected with these seasonal infectious diseases is a result of the pervasive hand washing, wearing masks and maintaining social distance in COVID-19 rea. To examine the correlation between the three factors of the number of people with each seasonal infectious disease, the mask wearing rate, and the outing rate, we created a three-dimensional scatter plot based on these three factors using principal component analysis. Our research findings demonstrated preventive effect of no going out against co-infection with the seasonal influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Oil Immersed Lossless Total Analysis System (OIL-TAS): Integrated RNA Extraction and Detection for SARS-CoV-2 Testing
Authors: Juang Duane S. , Juang Terry D. , Dudley Dawn M. , Newman Christina M. , Friedrich Thomas C. , O’Connor David H. , Beebe David J.
Published: October 2020

The coronavirus disease 2019 (COVID-19) pandemic exposed difficulties in scaling current quantitative PCR (qPCR)-based diagnostic methodologies for large-scale infectious disease testing. Bottlenecks include the lengthy multi-step process of nucleic acid extraction followed by qPCR readouts, which require costly instrumentation and infrastructure, as well as reagent and plastic consumable shortages stemming from supply chain constraints. Here we report a novel Oil Immersed Lossless Total Analysis System (OIL-TAS), which integrates RNA extraction and detection onto a single device that is simple, rapid, cost effective, uses minimal supplies and requires reduced infrastructure to perform. We validated the performance of OIL-TAS using contrived samples containing inactivated SARS-CoV-2 viral particles, which show that the assay can reliably detect an input concentration of 10 copies/μL and sporadically detect down to 1 copy/μL. The OIL-TAS method can serve as a faster, cheaper, and easier-to-deploy alternative to current qPCR-based methods for infectious disease testing.
Characterizing the genetic diversity of the Andean blueberry (Vaccinium floribundumKunth.) across the Ecuadorian Highlands
Authors: Vega-Polo Pamela , Cobo Maria M. , Argudo Andrea , Gutierrez Bernardo , Rowntree Jennifer , de Lourdes Torres Maria
Published: October 2020

The Ecuadorianpáramo, a high altitude tundra-like ecosystem, is a unique source of various ecosystem services and distinct biodiversity. Anthropogenic activities are associated with its fragmentation, which alters ecological factors and directly threatens resident species.Vaccinium floribundumKunth., commonly known as Andean blueberry ormortiño, is a wild shrub endemic to the Andean region and highly valued in Ecuador for its berries, which are widely used in food preparations and hold an important cultural value. Since it is a wild species,mortiñocould be vulnerable to environmental changes, resulting in a reduction of the size and distribution of its populations. To evaluate the extent of these effects on themortiñopopulations, we assessed the genetic diversity and population structure of the species along the Ecuadorian highlands. We designed and developed a set of 30 homologous SSR markers and used 16 of these to characterize 100mortiñoindividuals from 27 collection sites. Our results revealed a high degree of genetic diversity (HE=0.73) for the Ecuadorianmortiño, and a population structure analyses suggested the existence of distinct genetic clusters present in the northern, central and southern highlands. A fourth, clearly differentiated cluster was also found and included individuals from locations at higher elevations. We suggest that the population structure of the species could be explained by an isolation-by-distance model and can be associated to the geological history of the Andean region. Our results suggest that elevation could also be a key factor in the differentiation ofmortiñopopulations. This study provides an extensive overview of the species across its distribution range in Ecuador, contributing to a better understanding of its conservation status. These results can assist the development of conservation programs for this valuable biological and cultural resource and for thepáramoecosystems as a whole.
ezGeno: An Automatic Model Selection Package for Genomic Data Analysis
Authors: Lin Jun-Liang , Hsieh Tsung-Ting , Tung Yi-An , Chen Xuan-Jun , Hsiao Yu-Chun , Yang Chia-Lin , Liu Tyng-Luh , Chen Chien-Yu
Published: October 2020

To facilitate the process of tailor-making a deep neural network for exploring the dynamics of genomic DNA, we have developed a hands-on package called ezGeno that automates the search process of various parameters and network structure. ezGeno considers three different sets of search spaces, namely, the number of filters, dilation factors, and the connectivity between different layers. ezGeno can be applied to any kind of 1D genomic input such as genomic sequences, histone modifications, DNase feature data and so on. Combinations of multiple abovementioned 1D features are also applicable. Specifically, for the task of predicting TF binding using genomic sequences as the input, ezGeno can consistently return the best performing set of parameters and network structure, as well as highlight the important segments within the original sequences. For the task of predicting tissue-specific enhancer activity using both sequence and DNase feature data as the input, ezGeno also regularly outperforms the hand-designed models. In this study, we demonstrate that ezGeno is superior in efficiency and accuracy when compared to AutoKeras, a general open-source AutoML package. The average AUC of ezGeno is also consistently higher than the result of using a one-layer DeepBind model. With the flexibility of ezGeno, we expect that this package can provide future researchers not only support of model design in their analysis of genomic studies but also more insights into the regulatory landscape.

Availability

The ezGeno package can be freely accessed athttps://github.com/ailabstw/ezGeno.

Contact

Dr. Chien-Yu Chen,chienyuchen@ntu.edu.tw
Scene context impairs perception of semantically congruent objects
Authors: Spaak Eelke , Peelen Marius V. , de Lange Floris P.
Published: October 2020

Visual scene context is well-known to facilitate the recognition of scene-congruent objects. Interestingly, however, according to the influential theory of predictive coding, scene congruency should lead to reduced (rather than enhanced) processing of congruent objects, compared to incongruent ones, since congruent objects elicit reduced prediction error responses. We tested this counterintuitive hypothesis in two online behavioural experiments with human participants (N = 300). We found clear evidence for impaired perception of congruent objects, both in a change detection task measuring response times as well as in a bias-free object discrimination task measuring accuracy. Congruency costs were related to independent subjective congruency ratings. Finally, we show that the reported effects cannot be explained by low-level stimulus confounds, response biases, or top-down strategy. These results provide convincing evidence for perceptual congruency costs during scene viewing, in line with predictive coding theory.

Statement of Relevance

The theory of the ‘Bayesian brain’, the idea that our brain is a hypothesis-testing machine, has become very influential over the past decades. A particularly influential formulation is the theory of predictive coding. This theory entails that stimuli that are expected, for instance because of the context in which they appear, generate a weaker neural response than unexpected stimuli. Scene context correctly ‘predicts’ congruent scene elements, which should result in lower prediction error. Our study tests this important, counterintuitive, and hitherto not fully tested, hypothesis. We find clear evidence in favour of it, and demonstrate that these ‘congruency costs’ are indeed evident in perception, and not limited to one particular task setting or stimulus set. Since perception in the real world is never of isolated objects, but always of entire scenes, these findings are important not just for the Bayesian brain hypothesis, but for our understanding of real-world visual perception in general.
Negative controls of chemical probes can be misleading
Authors: Lee Jinyoung , Schapira Matthieu
Published: October 2020

Chemical probes are selective modulators that are used in cell assays to link a phenotype to a gene and have become indispensable tools to explore gene function and discover therapeutic targets. While binding to off-targets can be acceptable or beneficial for drugs, it is a confounding factor for chemical probes, as the observed phenotype may be driven by inhibition of an unknown off-target instead of the targeted protein. A negative control – a close chemical analog of the chemical probe that is inactive against the intended target – is typically used to verify that the phenotype is indeed driven by targeted protein. Here, we compare the selectivity profiles of four unrelated chemical probes and their respective negative controls and find that the control is sometimes inactive against up to 80% of known off-targets, suggesting that a lost phenotype upon treatment with the negative control may be driven by loss of inhibition of the off-target. To extend this analysis, we inspect the crystal structures of 90 pairs of unrelated proteins, where both proteins within each pair is in complex with the same drug-like ligand, and estimate that in 50% of cases, methylation (a simple chemical modification often used to generate negative controls) of the ligand at a position that will preclude binding to one protein (intended target) will also preclude binding to the other (off-target). These results uncover a risk associated with the use of negative controls to confirm gene-phenotype associations. We propose that a best practice should rather be to verify that two chemically unrelated chemical probes targeting the same protein lead to the same phenotype.

Abstract Figure
Towards understanding the regulation of histone H1 somatic subtypes with OMICs
Authors: Ponte Inma , Andrés Marta , Jordan Albert , Roque Alicia
Published: October 2020

Background

Histone H1 is involved in the regulation of chromatin higher-order structure and compaction. In humans, histone H1 is a multigene family with seven subtypes differentially expressed in somatic cells. Which are the regulatory mechanisms that determine the variability of the H1 complement is a long-standing biological question regarding histone H1. We have used a new approach based on the integration of OMICs data to address this question.

Results

We have examined the 3D-chromatin structure, the binding of transcription factors (TFs), and the expression of somatic H1 genes in human cell lines, using data from public repositories, such as ENCODE. Analysis of Hi-C, ChIP-seq, and RNA-seq data, have shown that transcriptional control has a greater impact on H1 regulation than previously thought. Somatic H1 genes located in TADs show higher expression than in boundaries. H1 genes are targeted by a variable number of transcription factors including cell cycle-related TFs, and tissue-specific TFs, suggesting a finetuned, subtype-specific transcriptional control. We describe, for the first time, that all H1 somatic subtypes are under transcriptional co-regulation. The replication-independent subtypes, which are encoded in different chromosomes, isolated from other histone genes are also co-regulated with the rest of the somatic H1 genes, indicating that transcriptional co-regulation extends beyond the histone cluster.

Conclusions

Transcriptional control and transcriptional co-regulation explain, at least in part, the variability of H1 complement, the fluctuations of H1 subtypes during development, and also the compensatory effects observed, in model systems, after perturbation of one or more H1 subtypes.
Retroactivity induced operating regime transition in a phosphorylation-dephosphorylation cycle
Authors: Parundekar Akshay , Viswanathan Ganesh A
Published: October 2020

Operating regimes characterizing the input-output behaviour of an activated phosphorylation-dephosphorylation reaction cycle (PdPC) such as a single MAPK cascade are dictated by the saturated/unsaturated state of the two underlying enzymatic reactions. Four combinations of the states of these two enzymatic reactions led to identification of distinct operating regimes,viz., Hyperbolic (H), Signal transducing (ST), Threshold-hyperbolic (TH) and Ultrasensitive (U). A single PdPC without an explicit feedback have been classically viewed as a module offering signal flow from upstream to downstream, that is, one-way communication. Recently it has been shown that load due to sequestration of the phosphorylated or unphosphorylated form of the substrate by corresponding downstream targets permits retroactive signalling that offers two-way communication. We systematically characterize the operating regimes of a single PdPC subject to retroactivity in either of the substrate forms. We identify five possible regime transitions that could be achieved by increasing the retroactivity strength on either of the two substrate forms. Remarkably, a retroactivity strength of 0.30 in the unphosphorylated form of the substrate is sufficient to induce a transition from ST to H regime indicating that the input-output behaviour of a PdPC is highly sensitive to the presence of a downstream load. Using sensitivity and rate-balance analysis, we show that modulation of the saturation levels of the two enzymatic reactions by increasing retroactivity is the fundamental mechanism governing operating regime transition.

Highlights

Characterization of operating regimes in the presence of retroactivity.

Retroactivity can induce a transition between different operating regimes.

Saturation levels of the two enzymatic reactions govern the regime transition.

Sensitivity of the protein levels to retroactivity is dictated by saturation levels.
Extreme suction attachment performance from specialised insects living in mountain streams (Diptera: Blephariceridae)
Authors: Kang Victor , White Robin T. , Chen Simon , Federle Walter
Published: October 2020

Suction is widely used by animals for strong controllable underwater adhesion but is less well understood than adhesion of terrestrial climbing animals. Here we investigate the attachment of an aquatic insect larva (Blephariceridae), which clings to rocks in torrential streams using the only known muscle-actuated suction organs in insects. We measured their attachment forces on well-defined rough substrates and found their adhesion was much less reduced by micro-roughness than terrestrial climbing insects.In vivovisualisation of the suction organs in contact with microstructured substrates revealed that they can mould around large asperities to form a seal. Moreover, we showed that spine-like microtrichia on the organ are stiff cuticular structures that only make tip contact on smooth and microstructured substrates. Our results highlight the performance and versatility of blepharicerid suction organs and introduce a new study system to explore biological suction.
Inference of high-resolution trajectories in single cell RNA-Seq data from RNA velocity
Authors: Zhang Ziqi , Zhang Xiuwei
Published: October 2020

Trajectory inference methods are used to infer cell developmental trajectories in a continuous biological process, for example, stem cell differentiation. Most of the current trajectory inference methods infer the developmental trajectories based on transcriptome similarity between cells, using single cell RNA-Sequencing (scRNA-Seq) data. These methods are often restricted to certain trajectory structures like linear structure or tree structure, and the directions of the trajectory can only be determined when the root cell is provided. On the other hand, RNA velocity inference method is shown to be a promising alternative in predicting short term cell developmental direction from the sequencing data. Here by we presentCellPath, a single cell trajectory inference method that infers developmental trajectories by integrating RNA velocity information.CellPathis able to find multiple high-resolution cell developmental paths instead of a single backbone trajectory obtained from traditional trajectory inference methods, and it no longer constrains the trajectory structure to be of any specific topology. The direction information provided by RNA-velocity also allowsCellPathto automatically detect the root cell and the direction of the dynamic process. We evaluateCellPathon both real and synthetic datasets, and show thatCellPathfinds more accurate and detailed trajectories compared to the state-of-the-art trajectory inference methods.
Nabo – a framework to define leukemia-initiating cells and differentiation in single-cell RNA-sequencing data
Authors: Dhapola Parashar , Eldeeb Mohamed , Ugale Amol , Olofzon Rasmus , Erlandsson Eva , Soneji Shamit , Bryder David , Göran Karlsson
Published: October 2020

Single-cell transcriptomics facilitates innovative approaches to define and identify cell types within tissues and cell populations. An emerging interest in the cancer field is to assess the heterogeneity of transformed cells, including the identification of tumor-initiating cells based on similarities to their normal counterparts. However, such cell mapping is often confounded by the large effects on total gene expression programs introduced by strong perturbations such as an oncogenic event. Here, we present Nabo, a novel computational method that allows mapping of cells from one population to the most similar cells in a reference population, independently of confounding changes to gene expression programs initiated by perturbation. We validated this method on multiple datasets from different sources and platforms and show that Nabo achieves higher rates of accuracy than conventional classification methods. Nabo is available as an integrated toolkit for preprocessing, cell mapping, differential gene expression identification, and visualization of single-cell RNA-Seq data. For exploratory studies, Nabo includes methods to help evaluate the reliability of cell mapping results. We applied Nabo on droplet-based single-cell RNA-Seq data of healthy and oncogene-induced (MLL-ENL) hematopoietic progenitor cells (GMLPs) differentiating in vitro. Despite a substantial cellular heterogeneity resulting from differentiation of GMLPs and the large transcriptional effects induced by the fusion oncogene, Nabo could pinpoint the specific cell stage where differentiation arrest occurs, which included an immunophenotypic definition of the tumor-initiating population. Thus, Nabo allows for relevant comparison between target and control cells, without being confounded by differences in population heterogeneity.
Constructing and analysing dynamic models with modelbase v1.0 - a software update
Authors: van Aalst Marvin , Ebenhöh Oliver , Matuszyńska Anna
Published: October 2020

Background

Computational mathematical models of biological and biomedical systems have been successfully applied to advance our understanding of various regulatory processes, metabolic fluxes, effects of drug therapies and disease evolution or transmission. Unfortunately, despite community efforts leading to the development of SBML or the BioModels database, many published models have not been fully exploited, largely due to lack of proper documentation or the dependence on proprietary software. To facilitate synergies within the emerging research fields of systems biology and medicine by reusing and further developing existing models, an open-source toolbox that makes the overall process of model construction more consistent, understandable, transparent and reproducible is desired.

Results and Discussion

We provide here the update on the development ofmodelbase, a free expandable Python package for constructing and analysing ordinary differential equation-based mathematical models of dynamic systems. It provides intuitive and unified methods to construct and solve these systems. Significantly expanded visualisation methods allow convenient analyses of structural and dynamic properties of the models. Specifying reaction stoichiometries and rate equations, the system of differential equations is assembled automatically. A newly provided library of common kinetic rate laws highly reduces the repetitiveness of the computer programming code, and provides full SBML compatibility. Previous versions provided functions for automatic construction of networks for isotope labelling studies. Using user-provided label maps,modelbasev1.0 streamlines the expansion of classic models to their isotope-specific versions. Finally, the library of previously published models implemented inmodelbaseis continuously growing. Ranging from photosynthesis over tumour cell growth to viral infection evolution, all models are available now in a transparent, reusable and unified format usingmodelbase.

Conclusion

With the small price of learning a new software package, which is written in Python, currently one of the most popular programming languages, the user can develop new models and actively profit from the work of others, repeating and reproducing models in a consistent, tractable and expandable manner. Moreover, the expansion of models to their label specific versions enables simulating label propagation, thus providing quantitative information regarding network topology and metabolic fluxes.
Effects of Malaise trap spacing on species richness and composition of terrestrial arthropod bulk samples
Authors: Steinke D , Braukmann TWA , Manerus L , Woodhouse A , Elbrecht V
Published: October 2020

The Malaise trap has gained popularity for assessing diverse terrestrial arthropod communities because it collects large samples with modest effort. A number of factors that influence collection efficiency, placement being one of them. For instance, when designing larger biotic surveys using arrays of Malaise traps we need to know the optimal distance between individual traps that maximises observable species richness and community composition. We examined the influence of spacing between Malaise traps by metabarcoding samples from two field experiments at a site in Waterloo, Ontario, Canada. For one experiment, we used two trap pairs deployed at weekly increasing distance (3m increments from 3 to 27 m). The second experiment involved a total of 10 traps set up in a row at 3m distance intervals for three consecutive weeks.

Results show that community similarity of samples decreases over distance between traps. The amount of species shared between trap pairs shows drops considerably at about 15m trap-to-trap distance. This change can be observed across all major taxonomic groups and for two different habitat types (grassland and forest). Large numbers of OTUs found only once within samples cause rather large dissimilarity between distance pairs even at close proximity. This could be caused by a large number of transient species from adjacent habitat which arrive at the trap through passive transport, as well as capture of rare taxa, which end up in different traps by chance.
REC protein family expansion by the emergence of a new signaling pathway
Authors: Garber Megan E. , Frank Vered , Kazakov Alexey E. , Incha Matthew R. , Nava Alberto A. , Zhang Hanqiao , Keasling Jay D. , Rajeev Lara , Mukhopadhyay Aindrila
Published: October 2020

This report presents multi-genomes and experimental evidence that REC protein family expansion occurs when the emergence of new pathways give rise to functional discordance. Specificity between REC-domain containing response regulators with paired histidine kinases are under negative purifying selection, constrained by the presence of other bacterial two-component systems signaling cascades that share sequence and structural identity. Presuming that the two-component systems can evolve by neutral drift when these constraints are relaxed, how might the REC protein family expand when constraints remain intact? Using an unsupervised machine learning approach to observe the sequence landscape of REC domains across long phylogenetic distances, we find that within-gene-recombination, a subcategory of gene conversion, switched the effector domain, and consequently the regulatory context of a duplicated response regulator from transcriptional regulation by σ54 to σ70. We determined that the recombined response regulator diverged from its parent by positive episodic diversifying selection, giving rise to two new residues. Functional experiments of the parent of recombined response regulators in our model system,Pseudomonas putidaKT2440, revealed that the parent and recombined response regulators sense and respond to carboxylic acids and that the two new residues in the recombined regulator form a new interaction interface and prevent crosstalk. Overall, our study finds genetic perturbations can create conditions of functional discordance, whereby the REC protein family can evolve by positive diversifying selection.
Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer’s disease neuropathology and atypical effects of the cholinergic antagonist atropine
Authors: Alcantara-Gonzalez David , Chartampila Elissavet , Scharfman Helen E
Published: October 2020

It has been reported that hyperexcitability occurs in a subset of patients with Alzheimer’s disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2-3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitabilityin vivothat was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward glutamatergic current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Although not usually measured, intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG and cholinergic system contribute to hyperexcitability early in life in AD mouse models.

HIGHLIGHTS

Granule cells (GCs) in young Tg2576 mice had abnormal synaptic activity.

Young Tg2576 GCs had increased excitatory and reduced inhibitory synaptic activity.

GC intrinsic properties were altered in young Tg2576 mice.

Muscarinic cholinergic regulation of GCs was altered in young Tg2576 mice.

Atropine led to a novel spontaneous inward current that was very strong in Tg2576 GCs.
Improved protein model quality assessment by integrating sequential and pairwise features using deep learning
Authors: Jing Xiaoyang , Xu Jinbo
Published: October 2020

Motivation

Accurately estimating protein model quality in the absence of experimental structure is not only important for model evaluation and selection, but also useful for model refinement. Progress has been steadily made by introducing new features and algorithms (especially deep neural networks), but accuracy of quality assessment (QA) is still not very satisfactory, especially local QA on hard protein targets.

Results

We propose a new single-model-based QA method ResNetQA for both local and global quality assessment. Our method predicts model quality by integrating sequential and pairwise features using a deep neural network composed of both 1D and 2D convolutional residual neural networks (ResNet). The 2D ResNet module extracts useful information from pairwise features such as model-derived distance maps, co-evolution information and predicted distance potential. The 1D ResNet is used to predict local (global) model quality from sequential features and pooled pairwise information generated by 2D ResNet. Tested on the CASP12 and CASP13 datasets, our experimental results show that our method greatly outperforms existing state-of-the-art methods. Our ablation studies indicate that the 2D ResNet module and pairwise features play an important role in improving model quality assessment.

Availability and Implementation

https://github.com/AndersJing/ResNetQA

Contact

jinboxu@gmail.com