bluuebunny/crossref_metadata_2025 huggingface dataset:
Can dorzolamide/timolol-fixed combination effectively treat primary open-angle glaucoma?
Authors: Qi Yan-Xiu , Liu Hong-wei , Sun Quan , Su Xing-jie , Han Lin
Published: November 2020

Background:

Primary open-angle glaucoma (POAG) is a very common disorder, and it is the second leading cause that results in blindness worldwide after cataracts. Previous studies have reported that dorzolamide/timolol-fixed combination (DTFC) can be used in treating POAG. However, there are still inconsistent results. Thus, this study will systematically investigate the efficacy and safety of DTFC on POAG.

Methods:

A comprehensive search will be carried out in Cochrane Library, MEDLINE, EMBASE, CINAHI, ACMD, China National Knowledge Infrastructure, and WANGFANG database from origin to the present. There are no limitations related to the language and publication status. Only randomized controlled trials that assessed the efficacy and safety of DTFC for the treatment of POAG will be included. Two researchers will independently undertake record selection, data extraction, and study quality assessment. Any divisions will be solved by discussion with a third researcher. We will perform statistical analysis using RevMan 5.3 software

Results:

This study will summarize the present evidence to identify the efficacy and safety of DTFC in treating POAG through mean intraocular pressure, best corrected visual acuity, contrast sensitivity, bioelectric activity of the retina, rate of progression of glaucoma, quality of life, and adverse events.

Conclusions:

The results of this study will provide evidence of DTFC for the treatment of POAG.

Systematic review registration:

INPLASY202040120.
Venetoclax + hypomethylating agents combined with dose-adjusted HAG for relapsed/refractory acute myeloid leukemia
Authors: Wang Hongxia , Bai Junjun , Pei Zhixin , Zhang Bei , Wang Junjie , Lian Xingli , Song Qinglin
Published: November 2020

Rationale:

Some acute myeloid leukemia (AML) patients are unresponsive to treatment or have remission followed by worsening of disease (known as relapsed/refractory AML [R/RAML]) after standardized treatment. The CAG/HAG regimen is not often used clinically because heterogenous patient responses, resistance, and hematopoietic bone marrow dysfunction have been reported with its use. We present 2 cases of R/RAML treated with a new combined therapy (venetoclax+ hypomethylating agents [HMAs]) in which the HAG dose was adjusted and effective in the first course of treatment.

Patient characteristics:

Case 1 involved a 23-year-old man who had suffered from AML for >4 years, and his FLT3 mutation status was positive at the initial diagnosis. After the first course of treatment with the standard-dose “Da” plan, the patient experienced complete remission. During the subsequent courses of treatment, the patient experienced 6 recurrences and was treated with the “ID Ara-C + MIT + sidaaniline” and “CAG + sidaaniline” regimens. However, the disease did not respond. Case 2 involved a 26-year-old man who received chemotherapy with the “Da,” “ID Ara-C,” “decitabine + half-dose CAG,” and “HAE” regimens. In this patients, remission could not be achieved. Reintroduction of the “ia” scheme also failed after treatment in our hospital.

Diagnosis:

Two patients were diagnosed with R/RAML.

Interventions:

The patient in case 2 received chemotherapy interventions, whereas the patient in case 1 refused to receive medical services at our hospital.

Outcomes:

The patient in case 1 was discharged after complete response treatment due to economic reasons and relapsed 2 months later. The patient ultimately died of infection and heart failure. The patient in case 2 is receiving a second cycle of chemotherapy.

Lessons:

We recommend the “venetoclax + HMAs combined with dose-adjusted CAH/HAG” regimen as an effective treatment for adult R/RAML.
Photonic hybrid state entanglement swapping using cat state superpositions
Authors: Parker Ryan C. , Joo Jaewoo , Spiller Timothy P.
Published: November 2020

We propose the use of hybrid entanglement in an entanglement swapping protocol, as means of distributing a Bell state with high fidelity to two parties. The hybrid entanglement used in this work is described as a discrete variable (Fock state) and a continuous variable (cat state super- position) entangled state. We model equal and unequal levels of photonic loss between the two propagating continuous variable modes, before detecting these states via a projective vacuum-one-photon measurement, and the other mode via balanced homodyne detection. We investigate homodyne measurement imperfections, and the associated success probability of the measurement schemes chosen in this protocol. We show that our entanglement swapping scheme is resilient to low levels of photonic losses, as well as low levels of averaged unequal losses between the two propagating modes, and show an improvement in this loss resilience over other hybrid entanglement schemes using coherent state superpositions as the propagating modes. Finally, we conclude that our protocol is suitable for potential quantum networking applications which require two nodes to share entanglement separated over a distance of

5
--
10
 

km

, when used with a suitable entanglement purification scheme.
Addressing the curse of dimensionality in stochastic dynamics: a Wiener path integral variational formulation with free boundaries
Authors: Petromichelakis Ioannis , Kougioumtzoglou Ioannis A.
Published: November 2020

A Wiener path integral variational formulation with free boundaries is developed for determining the stochastic response of high-dimensional nonlinear dynamical systems in a computationally efficient manner. Specifically, a Wiener path integral representation of a marginal or lower-dimensional joint response probability density function is derived. Due to this
a priori
marginalization, the associated computational cost of the technique becomes independent of the degrees of freedom (d.f.) or stochastic dimensions of the system, and thus, the ‘curse of dimensionality’ in stochastic dynamics is circumvented. Two indicative numerical examples are considered for highlighting the capabilities of the technique. The first relates to marine engineering and pertains to a structure exposed to nonlinear flow-induced forces and subjected to non-white stochastic excitation. The second relates to nano-engineering and pertains to a 100-d.f. stochastically excited nonlinear dynamical system modelling the behaviour of large arrays of coupled nano-mechanical oscillators. Comparisons with pertinent Monte Carlo simulation data demonstrate the computational efficiency and accuracy of the developed technique.
Contactless acoustic micro/nano manipulation: a paradigm for next generation applications in life sciences
Authors: Mohanty Sumit , Khalil Islam S. M. , Misra Sarthak
Published: November 2020

Acoustic actuation techniques offer a promising tool for contactless manipulation of both synthetic and biological micro/nano agents that encompass different length scales. The traditional usage of sound waves has steadily progressed from mid-air manipulation of salt grains to sophisticated techniques that employ nanoparticle flow in microfluidic networks. State-of-the-art in microfabrication and instrumentation have further expanded the outreach of these actuation techniques to autonomous propulsion of micro-agents. In this review article, we provide a universal perspective of the known acoustic micromanipulation technologies in terms of their applications and governing physics. Hereby, we survey these technologies and classify them with regards to passive and active manipulation of agents. These manipulation methods account for both intelligent devices adept at dexterous non-contact handling of micro-agents, and acoustically induced mechanisms for self-propulsion of micro-robots. Moreover, owing to the clinical compliance of ultrasound, we provide future considerations of acoustic manipulation techniques to be fruitfully employed in biological applications that range from label-free drug testing to minimally invasive clinical interventions.
What would it take to describe the global diversity of parasites?
Authors: Carlson Colin J. , Dallas Tad A. , Alexander Laura W. , Phelan Alexandra L. , Phillips Anna J.
Published: November 2020

How many parasites are there on Earth? Here, we use helminth parasites to highlight how little is known about parasite diversity, and how insufficient our current approach will be to describe the full scope of life on Earth. Using the largest database of host–parasite associations and one of the world’s largest parasite collections, we estimate a global total of roughly 100 000–350 000 species of helminth endoparasites of vertebrates, of which 85–95% are unknown to science. The parasites of amphibians and reptiles remain the most poorly described, but the majority of undescribed species are probably parasites of birds and bony fish. Missing species are disproportionately likely to be smaller parasites of smaller hosts in undersampled countries. At current rates, it would take centuries to comprehensively sample, collect and name vertebrate helminths. While some have suggested that macroecology can work around existing data limitations, we argue that patterns described from a small, biased sample of diversity aren’t necessarily reliable, especially as host–parasite networks are increasingly altered by global change. In the spirit of moonshots like the Human Genome Project and the Global Virome Project, we consider the idea of a Global Parasite Project: a global effort to transform parasitology and inventory parasite diversity at an unprecedented pace.
Pathogenicity and immune response against porcine circovirus type 3 infection in caesarean-derived, colostrum-deprived pigs
Authors: Temeeyasen Gun , Lierman Shay , Arruda Bailey L. , Main Rodger , Vannucci Fabio , Gimenez-Lirola Luis G. , Piñeyro Pablo E.
Published: November 2020

Recently, a novel PCV species (PCV3) has been detected in cases associated with sow mortality, lesions consistent with porcine dermatitis and nephropathy syndrome, reproductive failure and multisystemic inflammation. The pathogenesis and clinical significance of PCV3 is still unclear. In this study, we investigated the immunopathogenesis of PCV3 in CD/CD pigs. Four treatment groups, PCV3 (n=6), PCV3-KLH (n=6), control (n=3) and control-KLH (n=3), were included with PCV3-positive tissue homogenate (gc=3.38×1012 ml−1 and gc=1.04×1011 ml−1), confirmed by quantitative PCR (qPCR) and next-generation sequencing. Clinical signs, viremia, viral shedding, systemic cytokines, humoral (IgG) and T-cellular response were evaluated for 42 days. At necropsy, tissues were collected for histological evaluation and PCV3 detection by qPCR and in situ hybridization. No significant clinical signs were observed through the study. Viremia was detected in both PCV3-inoculated groups from 3 days post-inoculation (p.i.) until the end of the study. Nasal shedding was detected from 3 to 28 days p.i. and faecal shedding was transient. PCV3 induced an early (7 days p.i.) and sustained (42 days p.i.) IgG response. No significant T-cell response was observed. Histological evaluation demonstrated lesions consistent with multisystemic inflammation and perivasculitis. All tissues evaluated were positive by qPCR and virus replication was confirmed by positive in situ hybridization. This study demonstrated the potential role of PCV3 in subclinical infection, producing a mild, multisystemic inflammatory response, prolonged viremia detectable for 42 days p.i., presence of IgG humoral response and viral shedding in nasal secretions. More research is required to understand and elucidate potential co-factors necessary in the manifestation and severity of clinical disease.
Low Dose Radiation Therapy for COVID-19 Pneumonia: A Pilot Study
Authors: Sharma Daya Nand , Guleria Randeep , Wig Naveet , Mohan Anant , Rath Goura Kisor , Subramani Vellaiyan , Bhatnagar Sushma , Mallick Supriya , Sharma Aman , Patil Pritee , Madan Karan , Soneja Manish , Thulkar Sanjay , Singh Angel Rajan , Singh Sheetal
Published: November 2020

Background

The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19) as pandemic in March 2020. Currently there is no vaccine or specific effective treatment for COVID-19. The major cause of death in COVID-19 is severe pneumonia leading to respiratory failure. Radiation in low doses (<100 cGy) has been known for its anti-inflammatory effect and therefore, low dose radiation therapy (LDRT) to lungs can potentially mitigate the severity of pneumonia and reduce mortality. We conducted a pilot trial to study the feasibility and clinical efficacy of LDRT to lungs in the management of patients with COVID-19.

Methods

From June to Aug 2020, we enrolled 10 patients with COVID-19 having moderate to severe risk disease [National Early Warning Score (NEWS) of ≥5]. Patients were treated as per the standard COVID-19 management guidelines along with LDRT to both lungs with a dose of 70cGy in single fraction. Response assessment was done based on the clinical parameters using the NEWS.

Results

All patients completed the prescribed treatment. Nine patients had complete clinical recovery mostly within a period ranging from 3-7 days. One patient, who was a known hypertensive, showed clinical deterioration and died 24 days after LDRT. No patients showed the signs of acute radiation toxicity.

Conclusion

Results of our study (90% response rate) suggest the feasibility and clinical effectiveness of LDRT in COVID-19 patients having moderate to severe risk disease. This mandates a randomized controlled trial to establish the clinical efficacy of LDRT in COVID-19 pneumonia.
Declining Trend in the Initial SARS-CoV-2 Viral Load During the Pandemic: Preliminary Observations from Detroit, Michigan
Authors: Zein Said El , El-Hor Nivine , Chehab Omar , Alkassis Samer , Mishra Tushar , Trivedi Vichar , Salimnia Hossein , Chandrasekar Pranatharthi
Published: November 2020

We report a downward trend in the initial SARS-CoV-2 viral load in nasopharyngeal swab samples of hospitalized patients with COVID-19 in Detroit, Michigan, coinciding with a decrease in the number of deaths during April-June 2020. A gradual decrease in the initial viral load reflected the downward progression of the pandemic.
Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation
Authors: Chioh Florence WJ , Fong Siew-Wai , Young Barnaby E. , Wu Kan-Xing , Siau Anthony , Krishnan Shuba , Chan Yi-Hao , Teo Louis LY , Gao Fei , Tan Ru San , Zhong Liang , Koh Angela S. , Tan Seow-Yen , Tambyah Paul A. , Renia Laurent , Ng Lisa FP , Lye David C , Cheung Christine
Published: November 2020

The rapid rise of coronavirus disease 2019 patients who suffer from vascular events after their initial recovery is expected to lead to a worldwide shift in disease burden. We aim to investigate the impact of COVID-19 on the pathophysiological state of blood vessels in convalescent patients. Here, convalescent COVID-19 patients with or without preexisting conditions (i.e. hypertension, diabetes, hyperlipidemia) were compared to non-COVID-19 patients with matched cardiovascular risk factors or healthy participants. Convalescent patients had elevated circulating endothelial cells (CECs), and those with underlying cardiovascular risk had more pronounced endothelial activation hallmarks (ICAM1, P-selectin or CX3CL1) expressed by CECs. Multiplex microbead-based immunoassays revealed some levels of cytokine production sustained from acute infection to recovery phase. Several proinflammatory and activated T lymphocyte-associated cytokines correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Finally, the activation markers detected on CECs mapped to the counter receptors (i.e.ITGAL, SELPLG, andCX3CR1) found primarily on CD8+ T cells and natural killer cells, suggesting that activated endothelial cells could be targeted by cytotoxic effector cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.

Graphical abstract
Amphipathic Fluorescent Dyes for Sensitive and Long-Term Monitoring of Plasma Membranes
Authors: Takahashi Masataka , Seino Ryo , Ezoe Takatoshi , Ishiyama Munetaka , Ueno Yuichiro
Published: November 2020

The plasma membrane (PM) plays a critical role in many cellular processes, and PM dysfunction is a key biomarker related to the cell status and several diseases. Imaging techniques using small fluorescent probes have become increasingly important tools for visualizing living cells, particularly their PMs. Among the commercially available PM-specific probes, PKH dyes are widely used; however, the utility of these dyes is limited by their short membrane retention times and high cytotoxicity. Herein, PlasMem Bright Green and Red are implemented as new PM-specific fluorescent probes, which employ a polycyclic aromatic fluorophore to improve their retention ability and a strong acid moiety to reduce their transmembrane diffusion and cytotoxicity. We demonstrate that the long retention and low cytotoxicity of the PlasMem Bright dyes enable them to be applied for observing neuronal PMs and monitoring PM dynamics involving the endocytic pathway. Furthermore, we successfully detected mitochondria in nerve axons over long periods using PlasMem Bright dyes. Finally, the combined use of exosome staining probes and PlasMem Bright dyes allowed clear visualization of the endocytic pathway.

TOC graphic
Impact of COVID-19: Decrease in the Number of Fledging Barn Swallow Chicks in Tokyo
Authors: Hayashi Takuma , Yaegashi Nobuo , Konishi Ikuo
Published: November 2020

Barn swallows that have crossed the sea from Southeast Asia usually appear in the Kyushu Region of Japan around March after passing through Okinawa Prefecture. When the climate becomes warmer, these birds then move further north, nesting and raising their chicks in various parts of Japan. It is worth noting that barn swallows typically nest on man-made objects, for example, the roofs of houses and barns. It is believed that this is because barn swallows protect their eggs and chicks from foreign enemies such as sparrows and crows so they build their nests in populated areas. The barn swallow’s behavior of using the presence of people to keep foreign enemies away shows that barn swallows are quite wise. However, it has been reported that from the spring to summer of 2020, barn swallows, nesting and raising their chicks, which were seen every year, were not found in various parts of Japan. Therefore, we investigated the relationship between people’s self-restraint from going out and the fledging of barn swallow chicks in Tokyo metropolitan during the corona virus disease 2019 (COVID-19) era. The results of the survey showed a link between people’s refraining from going out and the fledging of barn swallow chicks. Next spring of 2021, the termination of COVID-19 is an important environment for swallow chick fledging.
Longitudinal characterization of phenotypic profile of T cells in chronic hepatitis B identifies immune markers predicting HBsAg loss
Authors: Xiong Shue , Zhu Dan , Liang Boyun , Li Mingyue , Pan Wen , He Junyi , Wang Hua , Sutter Kathrin , Dittmer Ulf , Lu Mengji , Liu Di , Yang Dongliang , Liu Jia , Zheng Xin
Published: November 2020

The current desirable endpoint of treatment against chronic hepatitis B virus infection (cHBV) is to achieve a functional cure, which is defined as HBsAg loss (sAg-L) with or without anti-HBs seroconversion. However, the immunological features that are associated with functional cure have not been studied in detail. Here, a total of 172 cHBV patients including 31 sAg-L patients, and 24 healthy individuals were examined for their T cell phenotypic profile and HBV-specific T cell responses by flow cytometry. sAg-L patients showed distinct CD4 and CD8 T cell phenotype fingerprints compared to those of HBsAg-positive patients, as indicated by the upregulation of CD25, CD40L and CTLA-4 expression on CD4 T cells; HLA-DR, CD95 and PD-1 on both CD4 and CD8 T cells; as well as a potent HBcAg-specific CD8 T cell response. The changes in the T cell phenotype in sAg-L patients began during rapid HBsAg decrease upon treatment onset, were maintained after sAg-L. HLA-DR expression on T cells was positively correlated with the level of HBsAg reduction and the magnitude of the HBcAg-specific T cell responses in cHBV patients. Importantly, increased HLA-DR and CTLA-4 expression on CD4, as well as HLA-DR and TIM-3 expression on CD8 T cells were identified as predictive factors for HBsAg loss within 48 weeks of therapy in cHBV patients. The onset of HBsAg decrease and subsequent loss in cHBV patients on treatment is associated with significant alterations of both CD4 and CD8 T cell phenotypes. Characterization of the T cell phenotype in cHBV patients possessed greater predicative value for sAg-L.
Cellular and molecular mechanisms of frontal bone development in spotted gar (Lepisosteus oculatus)
Authors: Enny Alyssa , Thompson Andrew W. , Racicot Brett , Braasch Ingo , Nakamura Tetsuya
Published: November 2020

Background

The molecular mechanisms initiating vertebrate cranial dermal bone formation is a conundrum in evolutionary and developmental biology. Decades of studies have determined the developmental processes of cranial dermal bones in various vertebrate species, finding possible inducers of dermal bone. However, the evolutionarily derived characters of current experimental model organisms hinder investigations of the ancestral and conserved mechanisms of vertebrate cranial dermal bone induction. Thus, investigating such mechanisms with animals diverging at evolutionarily crucial phylogenetic nodes is imperative.

Results

We investigated the cellular and molecular foundations of skull frontal bone formation in the spotted garLepisosteus oculatus, a basally branching actinopterygian. Whole-mount bone and cartilage stainings and hematoxylin-eosin section stainings revealed that mesenchymal cell condensations in the frontal bone of spotted gar develop in close association with the underlying cartilage. We also identified novel aspects of frontal bone formation: Upregulation of F-actin and plasma membrane in condensing cells, and extension of podia from osteoblasts to the frontal bone, which may be responsible for bone mineral transport.

Conclusion

This study highlights the process of frontal bone formation with dynamic architectural changes of mesenchymal cells in spotted gar, illuminating supposedly ancestral and likely conserved developmental mechanisms of skull bone formation among vertebrates.
Antagonistic activities of Fmn2 and ADF regulate axonal F-actin patch dynamics and the initiation of collateral branching
Authors: Kundu Tanushree , Das Sooraj S , Kumar Divya Sthanu , Sewatkar Lisas K , Ghose Aurnab
Published: November 2020

Interstitial collateral branching of axons is a critical component in the development of functional neural circuits. Axon collateral branches are established through a series of cellular processes initiated by the development of a specialized, focal F-actin network in axons. The formation, maintenance and remodelling of this F-actin patch is critical for the initiation of axonal protrusions that are subsequently consolidated to form a collateral branch. However, the mechanisms regulating F-actin patch dynamics are poorly understood.

Fmn2 is a formin family member implicated in multiple neurodevelopmental disorders. We find that Fmn2 regulates the initiation of axon collateral protrusions. Fmn2 localises to the protrusion-initiating axonal F-actin patches and regulates the lifetime and size of these F-actin networks. The F-actin nucleation activity of Fmn2 is necessary for F-actin patch stability but not for initiating patch formation. We show that Fmn2 insulates the F-actin patches from disassembly by the actin-depolymerizing factor, ADF, and promotes long-lived, larger patches that are competent to initiate axonal protrusions.

The regulation of axonal branching can contribute to the neurodevelopmental pathologies associated with Fmn2 and the dynamic antagonism between Fmn2 and ADF may represent a general mechanism of formin-dependent protection of Arp2/3-initiated F-actin networks from disassembly.
Plant PhysioSpace: a robust tool to compare stress response across plant species
Authors: Esfahani Ali Hadizadeh , Maß Janina , Hallab Asis , Schuldt Bernhard M. , Nevarez David , Usadel Björn , Ott Mark-Christoph , Buer Benjamin , Schuppert Andreas
Published: November 2020

Generalization of transcriptomics results can be achieved by comparison across experiments, which is based on integration of interrelated transcriptomics studies into a compendium. Both characterization of the fate of the organism as well as distinguishing between generic and specific responses can be gained in such a broader context. There are numerous methods for analyzing such data sets, most focusing on gene-wise dimension reduction to obtain marker genes and gene sets, e.g. for pathway analysis. Relying only on isolated biological modules might lead to missing of important confounders and relevant context.

We have developed a novel method called Plant PhysioSpace, which provides the ability to compute experimental conditions across species and platforms without a priori reducing the reference information to specific gene-sets. It extracts physiologically relevant signatures from a reference data set, a collection of public data sets, by integrating and transforming heterogeneous reference gene expression data into a set of physiology-specific patterns. New experimental data can be mapped to these patterns, resulting in similarity scores which provide quantitative likeness of the new experiment to the a priori compendium.

Because of its robustness against noise and platform bias, Plant PhysioSpace can be used as an inter-species or cross-platform similarity measure. We have demonstrated its success in translating stress responses between different species and platforms (including single-cell technologies).

We also report the implementation of two R packages, one software and one data package, and a shiny web application, which provides plant biologists convenient ways to access our method and precomputed models from four different species.
Identification of Covalent Modifications Regulating Immune Signaling Complex Composition and Phenotype
Authors: Frauenstein Annika , Ebner Stefan , Sinha Ankit , Phulphagar Kshiti , Swatek Kirby , Hornburg Daniel , Mann Matthias , Meissner Felix
Published: November 2020

Cells signal through rearrangements of protein communities governed by covalent modifications and reversible interactions of distinct sets of proteins. A method that identifies those post-transcriptional modifications regulating signaling complex composition and functional phenotypes in one experimental setup would facilitate an efficient identification of novel molecular signaling checkpoints. Here we devisedModifications,Interactions andPhenotypesbyAffinityPurificationMassSpectrometry (MIP-APMS), comprising the streamlined cloning and transduction of tagged proteins into functionalized reporter cells as well as affinity chromatography, followed by MS-based quantification. We report the time-resolved interplay of more than 50 previously undescribed modification and hundreds of protein-protein interactions of 19 immune protein complexes in monocytes. Validation of interdependecies between covalent, reversible and functional protein complex regulations by knock-out or site-specific mutation, revealed isgylation and phosphorylation of TRAF2 as well as ARHGEF18 interaction in Toll-like receptor 2 signaling. Moreover, we identify distinct mechanisms of action for small molecule inhibitors of p-38 (MAPK14). Our method provides a fast and cost-effective pipeline for the molecular interrogation of protein communities in diverse biological systems and primary cells.

Highlights

Experimental framework to reveal dynamic signaling checkpoints in primary cells

Identification of crosstalk between protein modifications and interactions in signaling complexes

Discovery of TRAF2 isgylation, phosphorylation and ARHGEF18 interaction in monocytes

Differential drug mode of action for p-38 (MAPK14) kinase inhibitors

Graphical abstract
Network based multifactorial modelling of miRNA-target interactions
Authors: Yuka Selcen Ari , Yilmaz Alper
Published: November 2020

Competing endogenous RNA (ceRNA) regulations and crosstalk between various types of non-coding RNA in human is an important and under-explored subject. Several studies have pointed out that an alteration in miRNA:target interaction can result in unexpected changes due to indirect and complex interactions. In this paper, we defined a new network-based model that incorporates miRNA:ceRNA interactions with expression values and then calculates network-wide effects after perturbation in expression level of element(s) while utilizing miRNA interaction factors such as seed type, binding energy. We have carried out analysis of large scale miRNA:target networks from breast cancer patients. Highly perturbing genes identified by our approach coincide with breast cancer associated genes and miRNAs. Our network-based approach helps unveiling the crosstalk between node elements in miRNA:target network where abundance of targets leading to sponge effect is taken into account. The model has potential to reveal unforeseen and unpredicted regulations which are only evident when considered in network context. Our tool is scalable and can be plugged in with emerging miRNA effectors such as circRNAs, lncRNAs and available as R package ceRNAnet-simhttps://www.bioconductor.org/packages/release/bioc/html/ceRNAnetsim.html.
Effect of cholesterol on permeability of carbon dioxide across lipid membranes
Authors: Blosser M.C. , So J. , Madani M.S. , Malmstadt N.
Published: November 2020

Determining the permeability of lipid membranes to gases is important for understanding the biological mechanisms of gas transport. Experiments on model membranes have been used to determine the permeability of lipid bilayers in the absence of proteins. Previous measurements have used a number of different methods and obtained widely varying results. We have developed a microfluidic based microscopy assay that measures the rate of CO2permeation in Giant Unilamellar Vesicles (GUVs), and we report permeability data for the POPC-cholesterol system. We find that cholesterol has a strong effect on permeability; bilayers containing high levels of cholesterol are an order of magnitude less permeable than bilayers without cholesterol, 9.9 ± 1.0 x 10−4cm/s vs. 9.6 ± 1.4 x 10−3cm/s.

Statement of Significance

Diffusion of dissolved gasses such as carbon dioxide through cell membranes is an important step in physiological processes. Key to understanding the behavior in cells is the measurement of gas diffusion through model lipid membranes, which isolates the effect of the lipids from other membrane components and allows for control of the composition. Previous measurements have yielded different results for the magnitude of gas transport, and have disagreed on the amount that cholesterol affects transport. The present study presents new data on gas transport across lipid mixtures containing cholesterol, and develops a microfluidic assay for gas transport that will enable further work.
Adding software to package management systems can increase their citation by 280%
Authors: Jalili Vahid , Clements Dave , Grüning Björn , Blankenberg Daniel , Goecks Jeremy
Published: November 2020

A growing number of biomedical methods and protocols are being disseminated as open-source software packages. When put in concert with other packages, they can execute in-depth and comprehensive computational pipelines. Therefore, their integration with other software packages plays a prominent role in their adoption in addition to their availability. Accordingly, package management systems are developed to standardize the discovery and integration of software packages. Here we study the impact of package management systems on software dissemination and their scholarly recognition. We study the citation pattern of more than 18,000 scholarly papers referenced by more than 23,000 software packages hosted by Bioconda, Bioconductor, BioTools, and ToolShed—the package management systems primarily used by the Bioinformatics community. Our results suggest that there is significant evidence that the scholarly papers’ citation count increases after their respective software was published to package management systems. Additionally, our results show that the impact of different package management systems on the scholarly papers’ recognition is of the same magnitude. These results may motivate scientists to distribute their software via package management systems, facilitating the composition of computational pipelines and helping reduce redundancy in package development.

Significance Statement

Software packages are the building blocks of computational pipelines. A myriad of packages are developed; however, the lack of integration and discovery standards hinders their adoption, leaving most scientists’ scholarly contributions unrecognized. Package management systems are developed to facilitate software dissemination and integration. However, developing software to meet their code and packaging standards is an involved process. Therefore, our study results on the significant impact of the package management systems on scholarly paper’s recognition can motivate scientists to invest in disseminating their software via package management systems. Dissemination of more software via package management systems will lead to a more straightforward composition of computational pipelines and less redundancy in software packages.
Track-To-Learn: A general framework for tractography with deep reinforcement learning
Authors: Théberge Antoine , Desrosiers Christian , Descoteaux Maxime , Jodoin Pierre-Marc
Published: November 2020

Abstract

Diffusion MRI tractography is currently the only non-invasive tool able to assess the white-matter structural connectivity of a brain. Since its inception, it has been widely documented that tractography is prone to producing erroneous tracks while missing true positive connections. Anatomical priors have been conceived and implemented in classical algorithms to try and tackle these issues, yet problems still remain and the conception and validation of these priors is very challenging. Recently, supervised learning algorithms have been proposed to learn the tracking procedure implicitly from data, without relying on anatomical priors. However, these methods rely on labelled data that is very hard to obtain. To remove the need for such data but still leverage the expressiveness of neural networks, we introduceTrack-To-Learn: A general framework to pose tractography as a deep reinforcement learning problem. Deep reinforcement learning is a type of machine learning that does not depend on ground-truth data but rather on the concept of “reward”. We implement and train algorithms to maximize returns from a reward function based on the alignment of streamlines with principal directions extracted from diffusion data. We show that competitive results can be obtained on known data and that the algorithms are able to generalize far better to new, unseen data, than prior machine learning-based tractography algorithms. To the best of our knowledge, this is the first successful use of deep reinforcement learning for tractography.
Comprehensive generation, visualization, and reporting of quality control metrics for single-cell RNA sequencing data
Authors: Hong Rui , Koga Yusuke , Bandyadka Shruthi , Leshchyk Anastasia , Wang Yichen , Akavoor Vidya , Cao Xinyun , Sarfraz Irzam , Wang Zhe , Alabdullatif Salam , Jansen Frederick , Yajima Masanao , Johnson W. Evan , Campbell Joshua D.
Published: November 2020

Single-cell RNA sequencing (scRNA-seq) can be used to gain insights into cellular heterogeneity within complex tissues. However, a variety of technical artifacts can be present in scRNA-seq data and need to be assessed before downstream analyses can be performed. While several algorithms and tools have been developed to perform individual quality control (QC) tasks, they are scattered in different packages across several programming environments. Comprehensive pipelines to streamline the process of generating and visualizing QC metrics are lacking. To address this need, we built the SCTK-QC pipeline within thesingleCellTKR package (https://github.com/compbiomed/singleCellTK). Features in this pipeline include the ability to import data from 11 different preprocessing tools or file formats, perform empty droplet detection with 2 different algorithms, generate standard quality control metrics such as number of UMIs per cell or the percentage of mitochondrial counts, predict doublets using 6 different algorithms, and estimate ambient RNA. QC data can be exported to R and/or Python objects used in popular down-stream workflows. Results are visualized in an easy-to-read HTML report. This pipeline can also be used by non-computational users with an interactive graphical user interface developed with R/Shiny. Overall, the SCTK-QC pipeline will streamline and standardize QC analysis for scRNA-seq data across a variety of different single-cell transcriptomic platforms and preprocessing tools.
Engineering self-organized criticality in living cells
Authors: Vidiella Blai , Guillamon Antoni , Sardanyés Josep , Maull Victor , Conde-Pueyo Nuria , Solé Ricard
Published: November 2020

Complex dynamical fluctuations, from molecular noise within cells, collective intelligence, brain dynamics or computer traffic have been shown to display noisy behaviour consistent with a critical state between order and disorder. Living close to the critical point can have a number of adaptive advantages and it has been conjectured that evolution could select (and even tend to) these critical states. One way of approaching such state is by means of so called self-organized criticality (SOC) where the system poises itself close to the critical point. Is this the case of living cells? It is difficult to test this idea given the enormous dimensionality associated with gene and metabolic webs. In this paper we present an alternative approach: to engineer synthetic gene networks displaying SOC behaviour. This is achieved by exploiting the presence of a saturation (congestion) phenomenon of the ClpXP protein degradation machinery inE. colicells. Using a feedback design that detects and then reduces ClpXP congestion, acritical motifis built from a two-gene network system, where SOC can be successfully implemented. Both deterministic and stochastic models are used, consistently supporting the presence of criticality in intracellular traffic. The potential implications for both cellular dynamics and designed intracellular noise are discussed.
Characterization of the microbiome of Down syndrome mouse model (Ts65Dn) in standard and high-fat diet
Authors: Grabowicz Ilona E. , Fructuoso Marta , DeToma Ilario , Dierssen Mara , Wilczyński Bartek
Published: November 2020

The intestinal microbiota is known to affect its host in numerous ways and can be altered by many factors including the host genotype and high-calorie diets. Down syndrome (DS) is a genetic neurodevelopmental disorder caused by the total or partial triplication of chromosome 21. Recently, a human study reported microbiota differences between DS and euploid humans. To further explore the differences due to the genotype, we here investigated the microbiome of trisomic mice (Ts65Dn). In trisomic mice we found a significant enrichment in abundances of bacteria:Bacteroides ovatus, B. thetaiotaomicron, andAkkermansia muciniphila- the mucus-degrading and gut-health promoting species. Since diet composition has an effect on microbiota species, we studied the effect of a high-fat diet on the observed genotypic differences. Our study provides evidence that microbiomes of trisomic mice on the control diet present more inter-individual differences than WT mice. Moreover, we observed that the high-fat diet led to increased differences between individuals and this effect was even more pronounced in the trisomic than in WT mice. We validated the results obtained with widely used 16rRNA gene sequencing with the sequencing of the total RNA.

Highlights

Down syndrome (DS) model mice faecal microbiomes are characterized by an overrepresentation ofBacteroides ovatus, Bacteroides thetaiotaomicron, andAkkermansia muciniphilaspecies.

DS mice are characterized by higher heterogeneity of their microbiome communities than WT mice.

High-fat diet leads to more diverse microbiome communities between mice, especially in trisomic genotype.
Secondary transmission of COVID-19 in preschool and school settings after their reopening in northern Italy: a population-based study
Authors: Larosa Elisabetta , Djuric Olivera , Cassinadri Mariateresa , Cilloni Silvia , Bisaccia Eufemia , Vicentini Massimo , Venturelli Francesco , Rossi Paolo Giorgi , Pezzotti Patrizio , Bedeschi Emanuela ,   the Reggio Emilia Covid-19 Working Group
Published: November 2020

Background

School closures was one of the main measures undertaken to reduce the number of social contacts during the first wave of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We aimed to describe the data on secondary transmission of SARS-CoV-2 among students and teachers/personnel after the reopening of preschools and schools in Reggio Emilia, Italy.

Methods

This prospective population-based study included all consecutive cases leading to an investigation in 41 classes of 36 educational institutions (8 infant-toddler centres and preschools, 10 primary and 18 secondary schools) in the period September 1 – October 15, 2020, in Reggio Emilia province, Italy. We report the characteristics of the school, of the index case, including the possible source of infection, the number of contacts (students and teachers/personnel) that were identified and tested and the characteristics of secondary cases.

Results

In the study period, 994 students and 204 teachers were tested during related investigations due to notification of 43 primary cases (38 among students and 5 among teachers). Of these, 10 students and two teachers created 39 secondary cases, resulting in an attack rate of 3.9%. There were no secondary cases among teachers/stuff. Secondary transmission occurred in one primary school and 8 secondary schools. Except for two students and one teacher, the possible source of infection for all index cases was identified as they had all had previous contact with a positive case; the majority of secondary cases did not report any previous close contact with a positive case. The clusters ranged from one to 22 secondary cases.

Conclusions

Transmission at school occurred in a non-negligible number of cases, particularly in secondary schools. Prompt testing and isolation of classmates could probably reduce the risk of transmission in school settings.
SARS-CoV-2 epidemic after social and economic reopening in three US states reveals shifts in age structure and clinical characteristics
Authors: Wikle Nathan , Tran Thu Nguyen-Anh , Gentilesco Bethany , Leighow Scott M , Albert Joseph , Strong Emily R , Břinda Karel , Inam Haider , Yang Fuhan , Hossain Sajid , Chan Philip , Hanage William P , Messick Maria , Pritchard Justin R , Hanks Ephraim M , Boni Maciej F
Published: November 2020

In the United States, state-level re-openings in spring 2020 presented an opportunity for the resurgence of SARS-CoV-2 transmission. One important question during this time was whether human contact and mixing patterns could increase gradually without increasing viral transmission, the rationale being that new mixing patterns would likely be associated with improved distancing, masking, and hygiene practices. A second key question to follow during this time was whether clinical characteristics of the epidemic would improve after the initial surge of cases. Here, we analyze age-structured case, hospitalization, and death time series from three states – Rhode Island, Massachusetts, and Pennsylvania – that had successful re-openings in May 2020 without summer waves of infection. Using a Bayesian inference framework on eleven daily data streams and flexible daily population contact parameters, we show that population-average mixing rates dropped by >50% during the lockdown period in March/April, and that the correlation between overall population mobility and transmission-capable mobility was broken in May as these states partially re-opened. We estimate the reporting rates (fraction of symptomatic cases reporting to health system) at 96.0% (RI), 72.1% (MA), and 75.5% (PA); in Rhode Island, when accounting for cases caught through general-population screening programs, the reporting rate estimate is 94.5%. We show that elderly individuals were less able to reduce contacts during the lockdown period when compared to younger individuals. Attack rate estimates through August 31 2020 are 6.4% (95% CI: 5.8% – 7.3%) of the total population infected for Rhode Island, 5.7% (95% CI: 5.0% – 6.8%) in Massachusetts, and 3.7% (95% CI: 3.1% – 4.5%) in Pennsylvania, with some validation available through published seroprevalence studies. Infection fatality rates (IFR) estimates for the spring epidemic are higher in our analysis (>2%) than previously reported values, likely resulting from the epidemics in these three states affecting the most vulnerable sub-populations, especially the most vulnerable of the ≥80 age group.
Fully Convolutional Networks for pathophysiological Intracranial Pressure waveform classification
Authors: Vrabie O. , Faltermeier R. , Schmidt N.O. , Brawanski A. , Lang E. W.
Published: November 2020

It is generally assumed that the analysis of intracranial pressure (ICP) waveforms could be used for the detection of multiple cerebral pathophysiologies. A main obstacle for the analysis of ICP waveforms is given by the large variation of their generating signal, the arterial blood pressure (ABP). Using extended principal component analysis (PCA) we show that it is possible to distinguish between ICP waveforms generated by pathological ABP waveforms, e.g. in the case of a heart failure, without loosing information about the state of the cerebral compliance. We also create a dataset for ICP pulse classification that can be used to train models to distinguish between an intact and diminished cerebral compliance, as a function of the ICP-generating ABP pulse. As a baseline for classification we build a fully convolutional network (FCN) that reaches high performance with relatively few data.
Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein and improves immune response
Authors: Chen Wenshu , Saxton Bryanna , Belinsky Steven A.
Published: November 2020

Immunotherapy using checkpoint blockers (antibodies) has been a major advance in recent years in the management of various types of solid cancers including lung cancer. One target of checkpoint blockers is programmed death ligand 1 (PD-L1) expressed by cancer cells, which engages programmed death 1 (PD-1) on T cells and Natural Killer (NK) cells resulting in suppression of their activation and cancer-killing function, respectively. Apart from antibodies, other clinically relevant agents that can inhibit PD-L1 are limited. PD-L1 protein stability depends on its glycosylation. Here we show that L-glutamine:D-fructose amidotransferase 1 (GFAT1) a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP) which produces uridine diphosphate-N-acetyl-β-glucosamine (UDP-GlcNAc), a precursor for glycosylation, is required for the stability of PD-L1 protein. Inhibition of GFAT1 activity markedly reduced interferon γ (IFNγ)-induced PD-L1 levels in various lung cancer cell lines. GFAT1 inhibition suppressed glycosylation of PD-L1 and accelerated its proteasomal degradation. Importantly, inhibition of GFAT1 in IFNγ-treated cancer cells enhanced the activation of T cells and the cancer-killing activity of NK cells. These findings support using GFAT1 inhibitors to manipulate PD-L1 protein level that could augment the efficacy of immunotherapy for lung cancer.