bluuebunny/crossref_metadata_2025 huggingface dataset:
Early outcomes with utilization of tissue plasminogen activator in COVID-19–associated respiratory distress: A series of five cases
Authors: Christie D. Benjamin , Nemec Hannah M. , Scott Anthony M. , Buchanan John T. , Franklin Christopher M. , Ahmed Aftab , Khan Muhammad S. , Callender Charles W. , James Erskine A. , Christie Amy B. , Ashley Dennis W.
Published: May 2020

BACKGROUND

Coronavirus patients demonstrate varying degrees of respiratory insufficiency; many will progress to respiratory failure with a severe version of acute respiratory distress syndrome refractory to traditional supportive strategies. Providers must consider alternative therapies to deter or prevent the cascade of decompensation to fulminant respiratory failure.

METHODS

This is a case-series of five COVID-19 positive patients who demonstrated severe hypoxemia, declining respiratory performance, and escalating oxygen requirements. Patients met the following criteria: COVID-19 positivity, worsening respiratory performance, severe hypoxemia (Pao
2 ≤ 80) despite traditional supportive measures, escalating supplemental oxygen requirements, and D-dimer greater than 1.5 μg/mL. All patients received protocol directed thrombolytic therapy with tissue plasminogen activator (tPA).

RESULTS

All five patients improved without deleterious effects of thrombolytic therapy. Patient one was on maximum ventilator support, paralytics, and prone positioning without improvement. During tPA administration his Pao
2/FIO2 ratio improved from 69 to 127. Ventilator support was weaned immediately on posttreatment day 1, and he was extubated on posttreatment day 12. Our second through fifth patients were not intubated at time of initiation of tPA therapy. These patients each required significant oxygen supplementation trending toward intubation. After tPA therapy, all patients demonstrated a noticeable increase in Pao
2 values overtime. Three of these patients avoided intubation due to COVID-19–associated respiratory failure.

CONCLUSION

Administration of thrombolytics was followed by overall improvement in patients' oxygen requirements, and in three cases, prevented progression to mechanical ventilation, without deleterious effects. Clinical trials of thrombolytic therapy would further serve to underscore the efficacy and utility of this therapy.

LEVEL OF EVIDENCE

Case series of therapeutic effect, Level V.
Inhibition of phosphatidylinositol kinase-III alpha induces or facilitates lysosome exocytosis from microglia.
Authors: Mu Shujing , Lim Nastasia K.-H. , Huang Fude
Published: May 2020

Besides degradation, lysosomes can also carry molecules for secretion out of the cell, such as ATP and cytokines, during unconventional secretion. Phosphatidylinositols and their metabolizing enzymes play important roles in the sorting and trafficking of lysosomal materials through the trans-Golgi network. The present study reveals a new function of phosphatidylinositol kinase-III alpha in the ‘kiss-and-run’ fusion of lysosomes at the plasma membrane to release ATP from microglia.
Effect of repetitive transcranial magnetic stimulation on the kynurenine pathway in stroke patients
Authors: Niimi Masachika , Ishima Tamaki , Hashimoto Kenji , Hara Takatoshi , Yamada Naoki , Abo Masahiro
Published: May 2020

Objective

Repetitive transcranial magnetic stimulation (rTMS) improves depressive symptoms and motor function in stroke patients. While metabolic derangement of the kynurenine pathway has been reported in stroke patients, the effect of rTMS on this pathway remains unknown. This study was performed to investigate the effect of rTMS on serum levels of kynurenine and tryptophan in stroke patients.

Methods

Sixty-two stroke patients received rTMS in addition to intensive rehabilitation and 33 stroke patients received intensive rehabilitation alone for 14 days. The rTMS involved low-frequency stimulation (at 1 Hz) of the primary motor cortex on the unaffected side of the cerebrum. The depressive state of the patients was evaluated with the Beck Depression Inventory (BDI) before and after treatment. Motor function of the patients was evaluated with Fugl-Meyer Assessment (FMA). Serum levels of kynurenine and tryptophan levels were also measured before and after treatment.

Results

The serum tryptophan level decreased in the group receiving rTMS to the right brain and increased in the group receiving rTMS to the left brain. The serum kynurenine/tryptophan ratio was elevated in the group receiving rTMS to the right brain. The BDI indicated improvement of depressive symptoms in the rehabilitation alone group and the group receiving rTMS to the right brain plus rehabilitation. The FMA improved in all groups.

Conclusions

The effect of low-frequency rTMS on the kynurenine pathway may differ depending on whether it is applied to the right or left cerebral hemisphere.
Mechanisms of cross-modal selective attentional bias for negative faces of anger and disgust in high-trait anxiety individuals
Authors: Mao Ningning , Xia Luyao , Zhang Qin , Li Chieh , Cui Lixia
Published: May 2020

Research reveals that selective attentional bias to socially negative information is a reliable characteristic of individuals with high-trait anxiety (HTA). However, for selective attentional bias across sensory channels (visual and auditory), the interaction between attentional bias type and negative face type remains unclear. In this study, we recruited 30 individuals with high- and low-trait anxiety (LTA) (15 in each group), and measured their engagement and disengagement bias indices using the cross-modal attentional-probe paradigm, and measured the occipital P1 component using a 64-channel electroencephalography system. The results showed that under the engagement condition in the HTA group, the occipital P1 amplitude of an angry face was smaller than that of a neutral face, and there also exhibited smaller attentional bias indices of angry faces in the HTA group than that of the LTA group. For the presence of disgusted faces, the attentional bias indices of the HTA group were smaller than that of the LTA group under the disengagement condition. These findings demonstrate that the selective attentional bias occurs both in the engagement and the disengagement facets within the cross modal. There is a feature of facilitated attentional engagement bias for an angry face, and a feature of promoted attentional disengagement bias for a disgusted face in HTA individuals.
T2-sequence with contrast inversion: diagnostic value in the investigation of gray matter heterotopias
Authors: Rösch Julie , Mennecke Angelika , Knott Michael , Hamer Hajo M. , Doerfler Arnd , Engelhorn Tobias
Published: May 2020

To compare the diagnostic value of T1-inversion recovery sequence (T1 IR) to that of a T2-sequence with contrast inversion (T2 CI) in the investigation of heterotopias. In this study, we processed a contrast-inverted copy of our coronal T2-sequence of 21 patients with subependymal and subcortical heterotopias on an online picture archiving and communication system workstation. The diagnostic performance of these images was compared with the T1 IR of the same patients by quantitative and qualitative assessments regarding signal-to-noise ratio (SNR), lesion-to-white matter contrast-to-noise ratio (CNR), lesion conspicuity, level of artifacts, overall image quality as well as diagnostic content. SNR values of the T2 CI were significantly higher than those of the T1 IR. CNR values of both sequences were similar. No relevant difference was found for lesion conspicuity and level of artifacts. Overall image quality of the T2 CI was rated slightly better by one reader. Both readers voted the images to have the same diagnostic content. Beside the exact depiction of the hippocampus in the high resoluted T2-sequence, its contrast-inverted copy (T2 CI) is also useful in the detection of heterotopias. In conjunction with the MPRAGE or MP2RAGE as a three-dimensional sequence, it could offer an equivalent and time-saving alternative to the T1 IR in the investigation of this type of malformation of cortical development.
Clinical advances in obsessive-compulsive disorder: a position statement by the International College of Obsessive-Compulsive Spectrum Disorders
Authors: Fineberg Naomi A. , Hollander Eric , Pallanti Stefano , Walitza Susanne , Grünblatt Edna , Dell’Osso Bernardo Maria , Albert Umberto , Geller Daniel A. , Brakoulias Vlasios , Janardhan Reddy Y.C. , Arumugham Shyam Sundar , Shavitt Roseli G. , Drummond Lynne , Grancini Benedetta , De Carlo Vera , Cinosi Eduardo , Chamberlain Samuel R. , Ioannidis Konstantinos , Rodriguez Carolyn I. , Garg Kabir , Castle David , Van Ameringen Michael , Stein Dan J. , Carmi Lior , Zohar Joseph , Menchon Jose M.
Published: May 2020

In this position statement, developed by The International College of Obsessive-Compulsive Spectrum Disorders, a group of international experts responds to recent developments in the evidence-based management of obsessive-compulsive disorder (OCD). The article presents those selected therapeutic advances judged to be of utmost relevance to the treatment of OCD, based on new and emerging evidence from clinical and translational science. Areas covered include refinement in the methods of clinical assessment, the importance of early intervention based on new staging models and the need to provide sustained well-being involving effective relapse prevention. The relative benefits of psychological, pharmacological and somatic treatments are reviewed and novel treatment strategies for difficult to treat OCD, including neurostimulation, as well as new areas for research such as problematic internet use, novel digital interventions, immunological therapies, pharmacogenetics and novel forms of psychotherapy are discussed.
Preparation and properties of amphiphilic hydrophobically associative polymer/ montmorillonite nanocomposites
Authors: Bai Cancan , Ke Yangchuan , Hu Xu , Xing Liang , Zhao Yi , Lu Shichao , Lin Yuan
Published: May 2020

In this research, a novel amphiphilic hydrophobically associative polymer nanocomposite (ADOS/OMMT) was prepared using acrylamide (AM), sodium 4-vinylbenzenesulfonate (SSS), N, N′-dimethyl octadeyl allyl ammonium bromide (DOAAB) and organo-modified montmorillonite (OMMT) through
in situ
polymerization. Both X-ray diffraction patterns and transmission electron microscopy images verified the dispersion morphology of OMMT in the copolymer matrix. Then, the effect of the introduction of OMMT layers on the copolymer properties was studied by comparing with pure copolymer AM/SSS/DOAAB (ADOS). The thermal degradation results demonstrated that the thermal stability of the ADOS/OMMT were better than pure copolymer ADOS. During the solution properties tests, ADOS/OMMT nanocomposite was superior to ADOS in viscosifying ability, temperature resistance, salt tolerance, shear resistance and viscoelasticity, which was because OMMT contributed to enhance the hydrophobic association structure formed between polymer molecules. Additionally, the ADOS/OMMT nanocomposite exhibited more excellent interfacial activity and crude oil emulsifiability in comparison to pure copolymer ADOS. These performances indicated ADOS/OMMT nanocomposite had good application prospects in tertiary recovery.
Tracking the genome of four Pseudomonas aeruginosa isolates that have a defective Las quorum-sensing system, but are still virulent
Authors: Martínez-Carranza Enrique , García-Reyes Selene , González-Valdez Abigail , Soberón-Chávez Gloria
Published: May 2020

In this work we analysed the whole genome extended multilocus sequence typing (wgMLST) of four

Pseudomonas aeruginosa

strains that are characterized by being virulent despite having a defective Las quorum-sensing (QS) system, and compare them with the wgMLST of the PAO1 and PA14 type strains. This comparison was done to determine whether there was a genomic characteristic that was common to the strains with an atypical QS response. The analysed strains include two environmental isolates (ID 4365 isolated from the Indian Ocean, and M66 isolated from the Churince water system in Cuatro Ciénegas Coahuila, México), one veterinary isolate (strain 148 isolated from the stomach of a dolphin) and a clinical strain (INP43 that is a cystic fibrosis pediatric isolate). We determine that the six analysed strains have a core genome of 4689 loci that was used to construct a wgMLST-phylogeny tree. Using the cano-wgMLST_BacCompare software we found that there was no common genomic characteristic to the strains with an atypical QS-response and we identify ten loci that are highly discriminatory of the six strains’ phylogeny so that their MLST can reconstruct the wgMLST-phylogeny tree of these strains. We discuss here the nature of these ten highly discriminatory genes in the context of

P. aeruginosa

virulence and evolution.
Negligible effect of chicken cytokine IL-12 integration into recombinant fowlpox viruses expressing avian influenza virus neuraminidase N1 on host cellular immune responses
Authors: Majid Nadzreeq Nor , Omar Abdul Rahman , Mariatulqabtiah Abdul Razak
Published: May 2020

In comparison to the extensive characterization of haemagglutinin antibodies of avian influenza virus (AIV), the role of neuraminidase (NA) as an immunogen is less well understood. This study describes the construction and cellular responses of recombinant fowlpox viruses (rFWPV) strain FP9, co-expressing NA N1 gene of AIV A/Chicken/Malaysia/5858/2004, and chicken IL-12 gene. Our data shows that the N1 and IL-12 proteins were successfully expressed from the recombinants with 48 kD and 70 kD molecular weights, respectively. Upon inoculation into specific-pathogen-free (SPF) chickens at 105 p.f.u. ml−1, levels of CD3+/CD4+ and CD3+/CD8+ populations were higher in the wild-type fowlpox virus FP9 strain, compared to those of rFWPV-N1 and rFWPV-N1-IL-12 at weeks 2 and 5 time points. Furthermore, rFWPV-N1-IL-12 showed a suppressive effect on chicken body weight within 4 weeks after inoculation. We suggest that co-expression of N1 with or without IL-12 offers undesirable quality as a potential AIV vaccine candidate.
In vitro inhibitory effect of statins on planktonic cells and biofilms of the Sporothrix schenckii species complex
Authors: Brilhante Raimunda Sâmia Nogueira , Fonseca Xhaulla Maria Quariguasi Cunha , Pereira Vandbergue Santos , Araújo Géssica dos Santos , Oliveira Jonathas Sales de , Garcia Lana Glerieide Silva , Rodrigues Anderson Messias , Camargo Zoilo Pires de , Pereira-Neto Waldemiro Aquino , Castelo-Branco Débora de Souza Collares Maia , Cordeiro Rossana de Aguiar , Sidrim José Júlio Costa , Rocha Marcos Fábio Gadelha
Published: May 2020

Introduction. Sporotrichosis, caused by species of the Sporothrix schenckii complex, is the most prevalent subcutaneous mycosis in many areas of Latin America. Statins are a class of drugs widely used for lowering high sterol levels through their action on 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the synthesis of sterol.

Aim. In this study, the antifungal activity of statins (simvastatin, atorvastatin, pravastatin) against planktonic cells and biofilms of S. schenckii complex species was evaluated, as well as the interaction of pravastatin with classical antifungals (amphotericin B, itraconazole, terbinafine).

Methodology. Eighteen strains of Sporothrix species were used. The antifungal susceptibility assay was performed using the broth microdilution method. Mature biofilms were exposed to statins and metabolic activity was measured by the XTT reduction assay.

Results. MICs of statins ranged from 8 to 512 μg ml−1 and from 8 to 256 μg ml−1 for filamentous and yeast forms, respectively. Regarding mature biofilms, MICs of 50 % inhibition (SMIC50) were 128 μg ml−1 for simvastatin and atorvastatin and >2048 μg ml−1 for pravastatin. MICs of 90 % inhibition (SMIC90) were 512 μg ml−1 for simvastatin and >2048 μg ml−1 for atorvastatin and pravastatin.

Conclusion. These results highlight the antifungal and antibiofilm potential of statins against S. schenckii complex species.
Revisiting neoantigen depletion signal in the untreated cancer genome
Authors: Wang Shixiang , Wang Xuan , Wu Tao , He Zaoke , Li Huimin , Sun Xiaoqin , Liu Xue-Song
Published: May 2020

This study is arising from Van den Eynden J. et al. Nature Genetics. Lack of detectable neoantigen depletion signals in the untreated cancer genome. Van den Eynden J.et al.tried to address a very important scientific question: could the immune system eliminate cancer cells with immunogenic mutations in untreated situation? Van den Eynden J.et al.first annotated the human exome into “HLA-binding regions” and “non HLA-binding regions” based on the predicted binding affinity of nonapeptides translated from the un-mutated reference coding genome with type I HLA alleles. They hypothesized that if neoantigen depletion signal exist, the nonsynonymous mutations in “HLA-binding regions” will be negatively selected during cancer evolution, while nonsynonymous mutation in “non HLA-binding regions” will not be negatively selected. This will lead to decreased nonsynonymous vs synonymous mutation ratio (n/s) in “HLA-binding regions” compared with “non HLA-binding regions”. They defined HLA-binding mutation ratio (HBMR) as the ratio of n/s in “HLA-binding regions” to “non HLA-binding regions”, and reported that HBMRs are close to 1 in different types of cancer after background corrections, meaning neoantigen depletion signals are not detectable in different types of cancer. The fundamental problem of their hypothesis lies in that the actual neoantigens with immunogenicity do not overlap with their defined “HLA-binding regions”. Actually, most neoantigens with immunogenicity are not located in “HLA-binding regions”, when dissimilarity between mutant and wild type peptide are considered. It is the neoantigen with immunogenicity, but not nonsynonymous mutation in their defined “HLA-binding regions” undergo immunoediting based negative selection. Thus the results reported in that study are fundamentally flawed, and at this current stage we could not draw a solid conclusion as to whether the neoantigen depletion signal exists or not.
Outcomes of Hydroxychloroquine Treatment Among Hospitalized COVID-19 Patients in the United States- Real-World Evidence From a Federated Electronic Medical Record Network
Authors: Singh Shailendra , Khan Ahmad , Chowdhry Monica , Chatterjee Arka
Published: May 2020

On March 28, 2020, in response to the rapidly accelerating COVID-19 pandemic, U.S FDA issued emergency use authorization for hydroxychloroquine (HCQ) in hospitalized COVID-19 patients based on limited in-vitro and anecdotal clinical data. Analysis of the accumulated real-world data utilizing electronic medical records (EMR) could indicate HCQ therapy benefits as we await the results of clinical trials. However, any such analysis of retrospective observational data should account for variables such as demographics and comorbidities that could affect treatment strategies or outcomes. Therefore, we report the outcomes of HCQ treatment in a propensity-matched cohort of COVID-19 hospitalized patients. Our analysis of a large retrospective cohort of hospitalized COVID-19 patients treated with HCQ did not show benefits in mortality or the need for mechanical ventilation when compared to a matched cohort of patients who did not receive HCQ.
Forecasting the COVID-19 Pandemic with Climate Variables for Top Five Burdening and Three South Asian Countries
Authors: Karimuzzaman Md. , Afroz Sabrina , Hossain Md. Moyazzem , Rahman Azizur
Published: May 2020

Background: The novel coronavirus (COVID-19) is now in a horrific situation around the world. Prediction about the number of infected and death cases may help to take immediate action to prevent the epidemic as well as control the situation of a country. The ongoing debate about the climate factors may need more validation with more studies. The climate factors of the top-five affected countries and three south Asian countries have considered in this study to have a real-time forecast and robust validation about the impact of climate variables.

Methods: The ARIMA model have included to model the univariate cumulative confirmed and death cases separately. The MLP, ELM and likelihood-based GLM count time series also considered as they consider the external variables as exogenous regressors. As the death count includes zero itself, zero-inflated count time series model has included instead of likelihood-based GLM. The better fitting of the ARIMA model will validate the underwhelm of meteorological factors was the initial hypothesis. The best model has identified through the application and comparison with the real data points.

Results: The results depict that there is an influence of meteorological variables like temperature and humidity mostly for all the selected countries cumulative confirm cases excluding Italy and Sri-Lanka. However, the best models for deaths count of each country also identify the impact of meteorological variables for each country.

Conclusion: The authors make the sixty days ahead forecast for each country which will be beneficial for the policymakers.
Limited transgenerational effects of environmental temperatures on thermal performance of a cold-adapted salmonid
Authors: Penney Chantelle M. , Burness Gary , Robertson Joshua , Wilson Chris C.
Published: May 2020

The capacity of ectotherms to cope with rising temperatures associated with climate change is a significant conservation concern as the rate of warming is likely too fast for adaptation to occur in some populations. Transgenerational plasticity, if present, could potentially buffer some of the negative impacts of warming on future generations. We examined transgenerational plasticity in lake trout to assess their inter-generational potential to cope with anticipated warming. We acclimated adult lake trout to cold or warm temperatures for several months, then bred them to produce offspring from parents of matched and mismatched temperatures. At the fry stage, offspring were also acclimated to cold or warm temperatures and their thermal performance was assessed by measuring their critical thermal maximum and metabolic rate during an acute temperature challenge. Overall, transgenerational plasticity was evident: thermal performance of offspring reflected both maternal and paternal environmental conditions, and offspring performed better when their environment matched that of their parents. There was little variation in offspring critical thermal maximum or peak metabolic rate, although cold-acclimated offspring from warm-acclimated parents exhibited elevated standard metabolic rates, suggesting that transgenerational effects can be detrimental when parent and offspring environments mismatch. These results demonstrate both the occurrence and limitations of transgenerational plasticity in a coldwater salmonid in response to elevated temperature, as well as potential ecological risks associated with transgenerational plasticity when an environmental change experienced by the parents does not persist with the next generation.
Topologically associating domains and their role in the evolution of genome structure and function inDrosophila
Authors: Liao Yi , Zhang Xinwen , Chakraborty Mahul , Emerson J.J.
Published: May 2020

Topologically associating domains (TADs) were recently identified as fundamental units of three-dimensional eukaryotic genomic organization, though our knowledge of the influence of TADs on genome evolution remains preliminary. To study the molecular evolution of TADs inDrosophilaspecies, we constructed a new reference-grade genome assembly and accompanying high-resolution TAD map forD. pseudoobscura. Comparison ofD. pseudoobscuraandD. melanogaster, which are separated by ∼49 million years of divergence, showed that ∼30-40% of their genomes retain conserved TADs. Comparative genomic analysis of 17Drosophilaspecies revealed that chromosomal rearrangement breakpoints are enriched at TAD boundaries but depleted within TADs. Additionally, genes within conserved TADs exhibit lower expression divergence than those located in nonconserved TADs. Furthermore, we found that a substantial proportion of long genes (>50 kbp) inD. melanogaster(42%) andD. pseudoobscura(26%) constitute their own TADs, implying transcript structure may be one of the deterministic factors for TAD formation. Using structural variants (SVs) identified from 14D. melanogasterstrains, its 3 closest sibling species from theD. simulansspecies complex, and two obscura clade species, we uncovered evidence of selection acting on SVs at TAD boundaries, but with the nature of selection differing between SV types. Deletions are depleted at TAD boundaries in both divergent and polymorphic SVs, suggesting purifying selection, whereas divergent tandem duplications are enriched at TAD boundaries relative to polymorphism, suggesting they are adaptive. Our findings highlight how important TADs are in shaping the acquisition and retention of structural mutations that fundamentally alter genome organization.
A Chemical-genetics and Nanoparticle Enabled Approach forin vivoProtein Kinase Analysis
Authors: Chen Fengqian , Liu Qi , Hilliard Terrell , Wang Tingzeng , Liang Hongjun , Gao Weimin , Huang Leaf , Wang Degeng
Published: May 2020

The human kinome contains >500 protein kinases, and regulates up to 30% of the proteome. Kinase study is currently hindered by a lack ofin vivoanalysis approaches due to two factors: our inability to distinguish the kinase reaction of interest from those of other kinases in live cells and the cell impermeability of the ATP analogs. Herein, we tackled this issue by combining the widely used chemical genetic method developed by Dr. Kevan Shokat and colleagues with nanoparticle-mediated intracellular delivery of the ATP analog. The critical AKT1 protein kinase, which has been successfully studied with the method, was used as our initial prototype. Briefly, enlargement of the ATP binding pocket, by mutating the gate-keeper Methionine residue to a Glycine, prompted the mutant AKT1 to preferentially use the bulky ATP analog N6-Benzyl-ATP-γ-S (A*TPγS) and, thus, differentiating AKT1-catalyzed and other phosphorylation events. The lipid/calcium/phosphate (LCP) nanoparticle was used for efficient intracellular delivery of A*TPγS, overcoming the cell impermeability issue. The mutant, but not wild-type, AKT1 used the delivered A*TPγS for autophosphorylation and phosphorylating its substrates in live cells. Thus, anin vivoprotein kinase analysis method has been developed. The strategy should be widely applicable to other protein kinases.
Robust Hierarchical Co-clustering to Explore Toxicogenomic Biomarkers and Their Regulatory Doses of Chemical Compounds
Authors: Hasan Mohammad Nazmol , Badsha Md. Bahadur , Mollah Md. Nurul Haque
Published: May 2020

Toxicogenomics combines high throughput molecular technologies with statistical and machine learning approaches to discover a similar group of doses of chemical compounds (DCCs) and genes to explore toxicogenomic biomarkers and their regulatory DCCs. This is also very important in the toxicity study of environmental stressors, synthetic chemicals and drug discovery and development process. Different clustering algorithms are concerned with the discovering of interesting clusters/groups of row or column entities of a dataset. Among those hierarchical clustering (HC) and logistic probabilistic hidden variable model (LPHVM) can identify toxicogenomic biomarkers and their regulatory DCCs forming co-cluster. However, the HC method is very sensitive to outlying observations. On the other hand, though LPHVM is a robust approach, it consumes more time for calculation since it is Expectation-Maximization (EM) based iterative approach. Additionally, the LPHVM creates artificiality problem taking absolute value of the data matrix. Therefore, to overcome these problems in this paper, we proposed a robust hierarchical co-clustering (RHCOC) algorithm to co-cluster genes and DCCs simultaneously with a view to explore toxicogenomic biomarkers and their regulatory DCCs. The performance of the proposed RHCOC algorithm over the conventional HC for clustering genes and DCCs of toxicogenomic data has been investigated based on the simulation study. The results of the simulation study have shown that the RHCOC approaches produce far lower clustering error rate (ER) than the conventional HC approaches in presence of outlying observations in the dataset. Otherwise they perform equally in absence of outlier in the dataset. To explore biomarker co-clusters consisting of toxicogenomic biomarker genes and their regulatory DCCs we used control chart for individual measurement (CCIM). We have also investigated the performance of the proposed approach in the case of the pathway level real life fold change gene expression (FCGE) toxicogenomic data analysis. The biomarker co-clusters consisting of toxicogenomic biomarker genes and their regulatory DCCs and biomarker genes explored by the proposed approaches have been validated by the literature and functional annotation. Our method is implemented in R package “rhcoclust” available on github (https://github.com/mdbahadur/rhcoclust).
Efficacy of moist heat decontamination against various pathogens for the reuse of N95 respirators in the COVID-19 emergency
Authors: Oral Ebru , Wannomae Keith K , Gil Dmitry , Connolly Rachel , Gardecki Joseph A , Leung Hui Min , Muratoglu Orhun K , Tsurumi Amy , Rahme Laurence , Jaber Tareq , Collins Cassidy , Gjore Julian , Budzilowicz Amanda
Published: May 2020

Decontamination of N95 respirators has become critical to alleviate PPE shortages for healthcare workers in the current COVID-19 emergency. The factors that are considered for the effective reuse of these masks are the fit, filter efficiency and decontamination/disinfection level both for SARS-CoV2, which is the causative virus for COVID-19, and for other organisms of concern in the hospital environment such as Staphylococcus aureus or Clostridium difficile.

The efficacy of inactivation or eradication against various pathogens should be evaluated thoroughly to understand the level of afforded disinfection. Methods commonly used in the sterilization of medical devices such as ionizing radiation, vaporized hydrogen peroxide, and ethylene oxide can provide a high level of disinfection, defined as a 6 log10 reduction, against bacterial spores, considered the most resistant microorganisms. CDC guidance on the decontamination and reuse of N95s also includes the use of moist heat (60°C, 80% relative humidity, 15-30 min) as a possible recommendation based on literature showing preservation of fit efficiency and inactivation of H1N1 on spiked masks.

Here, we explored the efficacy of using moist heat under these conditions as a decontamination method for an N95 respirator (3M 1860S, St. Paul, MN) against various pathogens with different resistance; enveloped RNA viruses, Gram (+/-) bacteria, and non-enveloped viruses.
Transmission onset distribution of COVID-19
Authors: Chun June Young , Baek Gyuseung , Kim Yongdai
Published: May 2020

Objectives

The distribution of the transmission onset of COVID-19 relative to the symptom onset is a key parameter for infection control. It is often not easy to study the transmission onset time, as is difficult to know who infected whom exactly when.

Methods

We inferred transmission onset time from 72 infector-infectee pairs in South Korea, either with known or inferred contact dates by means of incubation period. Combining this data with known information of infector’s symptom onset, we could generate the transmission onset distribution of COVID-19, using Bayesian methods. Serial interval distribution could be automatically estimated from our data.

Results

We estimated the median transmission onset to be 1.31 days (standard deviation, 2.64 days) after symptom onset with peak at 0.72 days before symptom onset. The pre-symptomatic transmission proportion was 37% (95% credible interval [CI], 16–52%). The median incubation period was estimated to be 2.87 days (95% CI, 2.33–3.50 days) and the median serial interval to be 3.56 days (95% CI, 2.72–4.44 days).

Conclusions

Considering the transmission onset distribution peaked with the symptom onset and the pre-symptomatic transmission proportion is substantial, the usual preventive measure might be too late to prevent SARS-CoV-2 transmission.
An integrated deterministic-stochastic approach for forecasting the long-term trajectories of COVID-19
Authors: Ghosh Indrajit , Chakraborty Tanujit
Published: May 2020

The ongoing COVID-19 pandemic is one of the major health emergencies in decades that affected almost every country in the world. As of June 30, 2020, it has caused an outbreak with more than 10 million confirmed infections, and more than 500 thousand reported deaths globally. Due to the unavailability of an effective treatment (or vaccine) and insufficient evidence regarding the transmission mechanism of the epidemic, the world population is currently in a vulnerable position. The daily cases data sets of COVID-19 for profoundly affected countries represent a stochastic process comprised of deterministic and stochastic components. This study proposes an integrated deterministic-stochastic approach to forecast the long-term trajectories of the COVID-19 cases for Italy and Spain. The deterministic component of the daily-cases univariate time-series is assessed by an extended version of the SIR (SIRCX) model, whereas its stochastic component is modeled using an autoregressive (AR) time series model. The proposed integrated SIRCX-AR (ISA) approach based on two operationally distinct modeling paradigms utilizes the superiority of both the deterministic SIRCX and stochastic AR models to find the long-term trajectories of the epidemic curves. Experimental analysis based on the proposed ISA model shows significant improvement in the long-term forecasting of COVID-19 cases for Italy and Spain in comparison to the ODE-based SIRCX model.
Distribution of ACE2, CD147, cyclophilins, CD26 and other SARS-CoV-2 associated molecules in human tissues and immune cells in health and disease
Authors: Radzikowska U. , Ding M. , Tan G. , Zhakparov D. , Peng Y. , Wawrzyniak P. , Wang M. , Li S. , Morita H. , Altunbulakli C. , Reiger M. , Neumann AU. , Lunjani N. , Traidl-Hoffmann C. , Nadeau K. , O’Mahony L. , Akdis CA. , Sokolowska M.
Published: May 2020

Background

Morbidity and mortality from COVID-19 caused by novel coronavirus SARS-CoV-2 is accelerating worldwide and novel clinical presentations of COVID-19 are often reported. The range of human cells and tissues targeted by SARS-CoV-2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS-CoV-2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID-19.

Methods

We performed RNA sequencing and explored available RNA-Seq databases to study gene expression and co-expression of ACE2, CD147 (BSG), CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4+and CD8+T cells, B cells and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID-19 risk factor status.

Results

ACE2andTMPRSS2were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA and PPIB), CD26 (DPP4) and related molecules were expressed in both, epithelium and in immune cells. We also observed a distinct age-related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2- and CD147-related genes in the bronchial biopsy, BAL or blood. Additionally, CD147-related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of ACE2- and CD147-related genes in the lesional skin of patients with atopic dermatitis.

Conclusions

Our data suggest different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related with age, gender, obesity and smoking, as well as with the disease status might contribute to COVID-19 morbidity and severity patterns.
Evaluating assembly and variant calling software for strain-resolved analysis of large DNA-viruses
Authors: Deng Z.-L. , Dhingra A. , Fritz A. , Götting J. , Münch P. C. , Steinbrück L. , Schulz T. F. , Ganzenmüller T. , McHardy A. C.
Published: May 2020

Infection with human cytomegalovirus (HCMV) can cause severe complications in immunocompromised individuals and congenitally infected children. Characterizing heterogeneous viral populations and their evolution by high-throughput sequencing of clinical specimens requires the accurate assembly of individual strains or sequence variants and suitable variant calling methods. However, the performance of most methods has not been assessed for populations composed of low divergent viral strains with large genomes, such as HCMV. In an extensive benchmarking study, we evaluated 15 assemblers and six variant callers on ten lab-generated benchmark data sets created with two different library preparation protocols, to identify best practices and challenges for analyzing such data.

Most assemblers, especially metaSPAdes and IVA, performed well across a range of metrics in recovering abundant strains. However, only one, Savage, recovered low abundant strains and in a highly fragmented manner. Two variant callers, LoFreq and VarScan2, excelled across all strain abundances. Both shared a large fraction of false positive (FP) variant calls, which were strongly enriched in T to G changes in a “G.G” context. The magnitude of this context-dependent systematic error is linked to the experimental protocol. We provide all benchmarking data, results and the entire benchmarking workflow named QuasiModo,QuasispeciesMetricdeterminationonomics, under the GNU General Public License v3.0 (https://github.com/hzi-bifo/Quasimodo), to enable full reproducibility and further benchmarking on these and other data.
High-fat diet-induced activation of SGK1 promotes Alzheimer’s disease-associated tau pathology
Authors: Elahi Montasir , Motoi Yumiko , Shimonaka Shotaro , Ishida Yoko , Hioki Hiroyuki , Takanashi Masashi , Ishiguro Koichi , Imai Yuzuru , Hattori Nobutaka
Published: May 2020

Type2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer’s disease (AD). However, the molecular links between T2DM and AD remain obscure. Here, we reported that serum/glucocorticoid-regulated kinase1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid-mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of AD cases. Our results suggest that SGK1 is a key modifier of tau pathology in AD, linking AD to corticosteroid effects and T2DM.
Fast lightweight accurate xenograft sorting
Authors: Zentgraf Jens , Rahmann Sven
Published: May 2020

Motivation

With an increasing number of patient-derived xenograft (PDX) models being created and subsequently sequenced to study tumor heterogeneity and to guide therapy decisions, there is a similarly increasing need for methods to separate reads originating from the graft (human) tumor and reads originating from the host species’ (mouse) surrounding tissue. Two kinds of methods are in use: On the one hand, alignment-based tools require that reads are mapped and aligned (by an external mapper/aligner) to the host and graft genomes separately first; the tool itself then processes the resulting alignments and quality metrics (typically BAM files) to assign each read or read pair. On the other hand, alignment-free tools work directly on the raw read data (typically FASTQ files). Recent studies compare different approaches and tools, with varying results.

Results

We show that alignment-free methods for xenograft sorting are superior concerning CPU time usage and equivalent in accuracy. We improve upon the state of the art sorting by presenting a fast lightweight approach based on three-way bucketed quotiented Cuckoo hashing. Our hash table requires memory comparable to an FM index typically used for read alignment and less than other alignment-free approaches. It allows extremely fast lookups and uses less CPU time than other alignment-free methods and alignment-based methods at similar accuracy.

Availability

Our software xengsort is available under the MIT license at http://gitlab.com/genomeinformatics/xengsort. It is written in numba-compiled Python and comes with Snakemake workflows for hash table construction and dataset processing.

Contact

Sven.Rahmann@uni-due.de
CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping
Authors: Putker Marrit , Wong David , Seinkmane Estere , Rzechorzek Nina Marie , Zeng Aiwei , Hoyle Nathaniel P. , Chesham Johanna E. , Edwards Mathew D. , Feeney Kevin A. , Fischer Robin , Peschel Nicolai , Chen Ko-Fan , Selby Christopher P. , Sancar Aziz , O’Neill John S.
Published: May 2020

Circadian (approximately daily) rhythms are a pervasive property of mammalian cells, tissues, and behaviour, ensuring physiological and metabolic adaptation to solar time. Models of daily cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of ‘clock proteins’ PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are thus considered essential negative regulators of the oscillation; a function supported by behavioural arrhythmicity of CRY-deficient mice when kept under constant conditions. Challenging this interpretation, however, we find evidence for persistent circadian rhythms in mouse behaviour and cellular PER2 levels when CRY is absent. CRY-less oscillations are variable in their expression and have a shorter period than wild type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and determination of period by casein kinase 1δ/ε activity to be maintained. In the absence of CRY-mediated transcriptional feedback repression and rhythmicPer2transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post-translational. Our findings suggest that PER proteins normally act as signalling hubs that transduce timing information to the nucleus, imparting daily rhythms upon the activity of transcriptional effectors.

Highlights

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PER/CRY-mediated negative feedback is dispensable for mammalian circadian timekeeping

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Circadian variation in PER2 levels persists in the absence of rhythmicPer2transcription

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CK1 and GSK3 are plausible mechanistic components of a ‘cytoscillator’ mechanism

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CRY-mediated feedback repression imparts robustness to biological timekeeping

In brief

Circadian turnover of mammalian clock protein PERIOD2 persists in the absence of canonical transcriptional feedback repression and rhythmic clock gene activity, demanding a re-evaluation of cellular clock function and evolution.
Adaptation, ancestral variation and gene flow in a ‘Sky Island’Drosophilaspecies
Authors: Hill Tom , Unckless Robert L.
Published: May 2020

Over time, populations of species can expand, contract, fragment and become isolated, creating subpopulations that must adapt to local conditions. Understanding how species maintain variation after divergence as well as adapt to these changes in the face of gene flow, is of great interest, especially as the current climate crisis has caused range shifts and frequent migrations for many species. Here, we characterize how a mycophageous fly species,Drosophila innubila, came to inhabit and adapt to its current range which includes mountain forests in southwestern USA separated by large expanses of desert. Using population genomic data from more than 300 wild-caught individuals, we examine four populations to determine their population history in these mountain forests, looking for signatures of local adaptation. We findD. innubilaspread northwards during the previous glaciation period (30-100 KYA), and has recently expanded even further (0.2-2 KYA).D. innubilashows little evidence of population structure, consistent with a recent establishment and genetic variation maintained since before geographic stratification. We also find some signatures of recent selective sweeps in chorion proteins and population differentiation in antifungal immune genes suggesting differences in the environments to which flies are adapting. However, we find little support for long-term recurrent selection in these genes. In contrast, we find evidence of long-term recurrent positive selection in immune pathways such as the Toll-signaling system and the Toll-regulated antimicrobial peptides.
Transcriptional profiling reveals potential involvement of microvillous TRPM5-expressing cells in viral infection of the olfactory epithelium
Authors: Baxter B. Dnate’ , Larson Eric D. , Merle Laetitia , Feinstein Paul , Polese Arianna Gentile , Bubak Andrew N. , Niemeyer Christy S. , Hassell James , Shepherd Doug , Ramakrishnan Vijay R. , Nagel Maria A. , Restrepo Diego
Published: May 2020

Background

Understanding viral infection of the olfactory epithelium is essential because the olfactory nerve is an important route of entry for viruses to the central nervous system. Specialized chemosensory epithelial cells that express the transient receptor potential cation channel subfamily M member 5 (TRPM5) are found throughout the airways and intestinal epithelium and are involved in responses to viral infection.

Results

Herein we performed deep transcriptional profiling of olfactory epithelial cells sorted by flow cytometry based on the expression of mCherry as a marker for olfactory sensory neurons and for eGFP in OMP-H2B::mCherry/TRPM5-eGFP transgenic mice (Mus musculus). We find profuse expression of transcripts involved in inflammation, immunity and viral infection in TRPM5-expressing microvillous cells.

Conclusion

Our study provides new insights into a potential role for TRPM5-expressing microvillous cells in viral infection of the olfactory epithelium. We find that, as found for solitary chemosensory cells (SCCs) and brush cells in the airway epithelium, and for tuft cells in the intestine, the transcriptome of TRPM5-expressing microvillous cells indicates that they are likely involved in the inflammatory response elicited by viral infection of the olfactory epithelium.