bluuebunny/crossref_metadata_2025 huggingface dataset:
Resuscitative endovascular balloon occlusion of the aorta in a pediatric swine model: Is 60 minutes too long?
Authors: Yamashiro Kaeli J. , Galganski Laura A. , Grayson J. Kevin , Johnson M. Austin , Beyer Carl A. , Spruce Marguerite W. , Caples Connor M. , Trappey A. Francois , Wishy Andrew M. , Stephenson Jacob T.
Published: February 2020

BACKGROUND

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is recommended in adults with a noncompressible torso hemorrhage with occlusion times of less than 60 minutes. The tolerable duration in children is unknown. We used a pediatric swine controlled hemorrhage model to evaluate the physiologic effects of 30 minutes and 60 minutes of REBOA.

METHODS

Pediatric swine weighing 20 kg to 30 kg underwent a splenectomy and a controlled 60% total blood volume hemorrhage over 30 minutes, followed by either zone 1 REBOA for 30 minutes (30R) or 60 minutes (60R). Swine were then resuscitated with shed blood and received critical care for 240 minutes.

RESULTS

During critical care, the 30R group's (n = 3) pH, bicarbonate, base excess, and lactate were no different than baseline, while at the end of critical care, these variables continued to differ from baseline in the 60R group (n = 5) and were worsening (7.4 vs. 7.2, p < 0.001, 30.4 mmol/L vs. 18.4 mmol/L, p < 0.0001, 5.6 mmol/L vs. −8.5 mmol/L, p < 0.0001, 2.4 mmol/L vs. 5.7 mmol/L, p < 0.001, respectively). Compared with baseline, end creatinine and creatinine kinase were elevated in 60R swine (1.0 mg/dL vs. 1.7 mg/dL, p < 0.01 and 335.4 U/L vs. 961.0 U/L, p < 0.001, respectively), but not 30R swine (0.9 mg/dL vs. 1.2 mg/dL, p = 0.06 and 423.7 U/L vs. 769.5 U/L, p = 0.15, respectively). There was no difference in survival time between the 30R and 60R pediatric swine, p = 0.99.

CONCLUSION

The physiologic effects of 30 minutes of zone 1 REBOA in pediatric swine mostly resolved during the subsequent 4 hours of critical care, whereas the effects of 60 minutes of REBOA persisted and worsened after 4 hours of critical care. Sixty minutes of zone 1 REBOA may create an irreversible physiologic insult in a pediatric population.
Proneness, urbanicity, trauma, and cannabis triggering psychotic states in large urban centers
Authors: Machado-de-Sousa João Paulo , Crippa José A.S. , Hallak Jaime
Published: February 2020

Purpose of review

The two past decades have seen the production of a vast amount of evidence about the genetic and nongenetic factors that contribute to the onset of psychosis from various fields of research. The present article reviews recent evidence from four of these fields that were shown to be strongly associated with psychosis: proneness, urbanicity, trauma, and cannabis use.

Recent findings

The evidence reviewed shows that all four sets of factors investigated here are implicated in the occurrence of psychosis. The specificity and complexity of these associations, however, are not yet clear and recent findings show that the directions of the associations described may be different than we first thought.

It is clear that psychosis is strongly affected by a number of environmental determinants that act in concert with genetic determinants to cause psychotic disorders; however, these influences are complex and their actual impact may be difficult to establish because of poor definitions and specificity. Urbanicity in special is a poorly defined concept that seems to encompass different sets of factors in each study, which hinders discussions and conclusions regarding its impact.
Integrating blue-green and grey infrastructure through an adaptation pathways approach to surface water flooding
Authors: Kapetas Leon , Fenner Richard
Published: February 2020

A range of solutions to future flood risk are available ranging from blue-green infrastructure (BGI) as commonly incorporated in sustainable drainage systems (SuDS) to traditional grey infrastructure (e.g. pipe networks, storage tanks, flood walls). Each offers a different profile with respect to costs, flexibility of implementation and the ability to deliver a range of wider benefits beyond their flood protection function. An important question that must be addressed when considering these approaches is what is the most suitable mix of grey and blue-green solutions to urban flooding at any location and at any future time? This paper uses an adaptation pathways approach to compare a range of alternative options to deal with current and expected future flood risk in part of a London borough. Solutions considered separately and in combination include grey pipe expansion, bioretention cells, permeable pavements and storage ponds. A methodological framework combines a range of existing tools to develop, assess and characterize each pathway, including a storm water management model (SWMM), a SuDs opportunity selection tool, an adaptation pathway generator and the CIRIA B£ST tool for monetizing multiple benefits. Climate change is represented by the UK Water Industry Research method for establishing future rainfall intensities for sewer and BGI design. The results showed that by extending the way in which adaptation pathways are compared and evaluated through the wider consideration of multiple benefits there is a trade-off between deferring interventions until they are needed for flood risk mitigation and delivering the multiple benefits associated with interventions so that performance thresholds do not need to be met before introducing new options. The relative contribution of each option's capital and operation and maintenance costs has implications on when the option is implemented as well as the rate of implementation. The monetization of the multiple benefits associated with each pathway shows that their economic co-evaluation alongside infrastructure costs can change the preference for one pathway over another.

This article is part of the theme issue ‘Urban flood resilience’.
Were the floods in the UK 2007 and Germany 2013 game-changers?
Authors: Platt Stephen , Mahdavian Farnaz , Carpenter Oliver , Wiens Marcus , Schultmann Frank
Published: February 2020

This paper examines recovery after major floods in the UK and Germany. It focuses on two areas that were badly hit by flooding: Catcliffe, near Sheffield in the UK, and Passau in Bavaria, Germany. It reports on surveys of residents and businesses in each place and on surveys of national flood experts in both countries. The two events were comparable in terms of impacts, levels of preparedness and government response and show similar patterns of speed and quality of recovery. In Germany, it took about 18 months for 90% or more of residents to get back to normal, while in the UK it took a year longer. This difference may be related to funding; in the UK, over 90% of funding came from household insurance while in Germany over 60% came from federal aid, which may have been quicker. In both countries, the economy had recovered to near normal within 12–18 months. The majority of people surveyed in both countries (74% in Germany and 67% in the UK) believe that their homes and businesses are as just as vulnerable now as they were before the respective floods. However, in the UK, half of the respondents thought their neighbourhood was safer and better prepared compared to only 11% in Germany. This may be because substantial progress has been made in improving protection in the UK in areas flooded in 2007. Both floods were considered to be ‘game-changers’ and resulted in a heightened awareness of flood risk, increased investment in flood defences and an increasing emphasis on citizens taking more responsibility for flood preparedness. However, the Environment Agency in the UK lacks powers to prevent development in flood-prone areas, in Germany there are issues of coordination across large catchments that cross state boundaries and the insurance sector could play a bigger role in ‘building back better’. Many homes and businesses continue to be at risk from major floods and more progress needs to be made in making them more resilient.

This article is part of the theme issue ‘Urban flood resilience’.
The case report of Mycobacterium arupense wound infection in diabetes mellitus patients; the first report and literature review
Authors: Navid Sepehr , Sadegh-Ehdaei Bahar , Shabani Mehdi , Hasani Melika , Mirzaei Arezoo , Ghazvini Kiarash , Youssefi Masoud , Keikha Masoud
Published: February 2020

Mycobacterium arupense

is among the opportunist pathogens of atypical mycobacteria emergence (atypical mycobacteria) that is one of the isolated and reported environmental and clinical specimens. Numerous cases of osteo-articular infections of this bacterium are reported nowadays, while the pulmonary infection is rare. We identified

Mycobacterium arupense

in non-healing wound infection of an elderly woman with history of diabetes mellitus. She has negative tests for HIV, HBV and HCV, but was positive for HTLV-1. The patient was referred according to mild-fever, non-healing, destructive, and swelled lesion on her left foot. The mycobacterial wounds infection was suspected due to her non-conclusive previous treatment. The pathology, acid-fast staining, conventional and 16S rRNA sequencing confirmed the micro-organism to be

M. arupense

. Finally, the patient recovered following two-week consumption of clarithromycin, ethambutol and rifabutin. The results of this study provide evidence on the potential pathogenicity, clinical outcomes and treatment of infections caused by this bacterium.
Genome structure reveals the diversity of mating mechanisms in Saccharomyces cerevisiae x Saccharomyces kudriavzevii hybrids, and the genomic instability that promotes phenotypic diversity
Authors: Morard Miguel , Benavent-Gil Yaiza , Ortiz-Tovar Guadalupe , Pérez-Través Laura , Querol Amparo , Toft Christina , Barrio Eladio
Published: February 2020

Interspecific hybridization has played an important role in the evolution of eukaryotic organisms by favouring genetic interchange between divergent lineages to generate new phenotypic diversity involved in the adaptation to new environments. This way, hybridization between Saccharomyces species, involving the fusion between their metabolic capabilities, is a recurrent adaptive strategy in industrial environments. In the present study, whole-genome sequences of natural hybrids between Saccharomyces cerevisiae and Saccharomyces kudriavzevii were obtained to unveil the mechanisms involved in the origin and evolution of hybrids, as well as the ecological and geographic contexts in which spontaneous hybridization and hybrid persistence take place. Although Saccharomyces species can mate using different mechanisms, we concluded that rare-mating is the most commonly used, but other mechanisms were also observed in specific hybrids. The preponderance of rare-mating was confirmed by performing artificial hybridization experiments. The mechanism used to mate determines the genomic structure of the hybrid and its final evolutionary outcome. The evolution and adaptability of the hybrids are triggered by genomic instability, resulting in a wide diversity of genomic rearrangements. Some of these rearrangements could be adaptive under the stressful conditions of the industrial environment.
The role of absolute humidity on transmission rates of the COVID-19 outbreak
Authors: Luo Wei , Majumder Maimuna S. , Liu Diambo , Poirier Canelle , Mandl Kenneth D , Lipsitch Marc , Santillana Mauricio
Published: February 2020

A novel coronavirus (COVID-19) was identified in Wuhan, Hubei Province, China, in December 2019 and has caused over 40,000 cases worldwide to date. Previous studies have supported an epidemiological hypothesis that cold and dry (low absolute humidity) environments facilitate the survival and spread of droplet-mediated viral diseases, and warm and humid (high absolute humidity) environments see attenuated viral transmission (i.e., influenza). How-ever, the role of absolute humidity in transmission of COVID-19 has not yet been established. Here, we examine province-level variability of the basic reproductive numbers of COVID-19 across China and find that changes in weather alone (i.e., increase of temperature and humidity as spring and summer months arrive in the North Hemisphere) will not necessarily lead to declines in COVID-19 case counts without the implementation of extensive public health interventions.
A NKp80-based identification strategy reveals that CD56negNK cells are not completely dysfunctional in health and disease
Authors: Orrantia Ane , Terrén Iñigo , Izquierdo-Lafuente Alicia , Alonso-Cabrera Juncal A. , Sandá Victor , Vitallé Joana , Moreno Santiago , Tasias María , Uranga Alasne , González Carmen , Mateos Juan J. , García-Ruiz Juan C. , Zenarruzabeitia Olatz , Borrego Francisco
Published: February 2020

Natural killer (NK) cells are usually identified by the absence of other lineage markers, due to the lack of a cell surface specific marker. CD56negNK cells, classically identified as CD56negCD16+are known to be expanded in some pathological conditions. However, studies on CD56negNK cells had revealed different results regarding the phenotype and functionality of these cells. This could be due to, among others, the unstable expression of CD16, which hinders CD56negNK cells identification. Hence, we aim to determine an alternative surface marker to CD16 to better identify CD56negNK cells. Using multiparametric flow cytometry, we have found that NKp80 is a good alternative to CD16 not only in healthy donors but also in HIV-1 infected subjects and multiple myeloma patients. Furthermore, we found differences between the functionality of CD56negNKp80+and CD56negCD16+NK cells both in healthy donors and patients, suggesting that the effector functions of CD56negNK cells are not as diminished as previously thought. We proposed NKp80 as a noteworthy marker to identify and accurately re-characterize human CD56negNK cells.
The dynamic interplay of host and viral enzymes in type III CRISPR-mediated cyclic nucleotide signalling
Authors: Athukoralage Januka S. , Graham Shirley , Rouillon Christophe , Grüschow Sabine , Czekster Clarissa M. , White Malcolm F.
Published: February 2020

Cyclic nucleotide second messengers are increasingly implicated in prokaryotic anti-viral defence systems. Type III CRISPR systems synthesise cyclic oligoadenylate (cOA) upon detecting foreign RNA, activating ancillary nucleases that can be toxic to cells, necessitating mechanisms to remove cOA in systems that operate via immunity rather than abortive infection. Previously, we demonstrated that theSulfolobus solfataricustype III-D CRISPR complex generates cyclic tetra-adenylate (cA4), activating the ribonuclease Csx1, and showed that subsequent RNA cleavage and dissociation acts as an “off-switch” for the cyclase activity (Rouillonet al., 2018). Subsequently, we identified the cellular ring nuclease Crn1, which slowly degrades cA4to reset the system, and demonstrated that viruses can subvert type III CRISPR immunity by means of a potent anti-CRISPR ring nuclease variant. Here, we present a comprehensive analysis of the dynamic interplay between these enzymes, governing cyclic nucleotide levels and infection outcomes in virus-host conflict.
Optimizing diagnostic strategy for novel coronavirus pneumonia, a multi-center study in Eastern China
Authors: Ai Jing-Wen , Zhang Hao-Cheng , Xu Teng , Wu Jing , Zhu Mengqi , Yu Yi-Qi , Zhang Han-Yue , Li Yang , Zhou Xian , Shen Zhongliang , Zang Guo-Qing , Xu Jie , Chen Wen-Jing , Li Yong-Jun , Xie De-Sheng , Zhou Ming-Zhe , Sun Jing-Ying , Chen Jia-Zhen , Zhang Wen-Hong
Published: February 2020

COVID-19 caused by a novel coronavirus SARS-CoV-2 emerged in Wuhan, Hubei province since December 2019, and caused a rapid outbreak throughout China and globally. Cities outside Hubei are also facing great challenge and require implementing of effective and feasible strategy in precision diagnosing novel coronavirus pneumonia (NCP).

We described a multicenter prospective study on diagnostic strategy of suspected NCP patients from January 22nd to February 9th, 2020 in Eastern China cities. Nasopharyngeal swabs were collected from the patients. The epidemiological characteristics, clinical symptoms, laboratory assessments, and computed tomographic (CT) scans were obtained. Pathogen screen were performed including RT-PCR, multiplex PCR, rapid flu antigen tests and mNGS.

We enrolled 53 suspected NCP patients, among whom 20 were laboratory-confirmed. Fourteen (70%) and 3 (15%) patients were positive for the first and second SARS-CoV-2 RT-PCR test, respectively. All NCP patients were positive for mNGS. Chest CT images and the symptoms of early stage NCP patients were similar to other viral pneumonia patients. We identified 11 of 20 co-infections in NCP cases, including regular respiratory virus, fungi and bacteria synchronously. Genomic analysis showed that 8 of 10 cases had no mutation in virus genome, while 2 cases had only one single mutation in N gene.

Our study discovered that a combination of chest CT, SARS-CoV-2 RT-PCR and multi-plex PCR is recommended in regions outside Hubei province. Co-infection of other pathogens with SARS-CoV-2 exists and should be acknowledged. Repeated sampling, change of specimen type or metagenomics sequencing could further facilitate during critical clinical cases.
Modeling the post-translational modifications and its effects in the NF-κB pathway
Authors: Mobeen Ahmed , Ramachandran Srinivasan
Published: February 2020

The transcriptional activities of NFKB1 and NFKB2 complexes are regulated by several post-translational modifications at different sites of these complexes. The post-translational modifications reported in the literature include phosphorylation, methylation, acetylation, sulphydration, nitrosylation, ubiquitination and sumoylation. We present a pathway network model with 172 proteins, 313 molecular species and 476 reactions including degradation of IkB (NFKBIA), proteolytic processing, and posttranslational modifications on p65 (RELA), RELB, p50 (NFKB1), and p52 (NFKB2) proteins. Comparing with experimental data on the over expression or knockouts of specific genes afforded qualitative agreement between model predictions and the experimental results. NFKB1:RELA complex is activated by active IKBKB, PIN1, MAP3K14 but repressed by PPARG and PDLIM2. MAP3K14 and UBE2I enhance the NFKB2:RELB activity, whereas NLRP12 is its repressor. The constitutive activation of NFKB1 complex through positive regulation of group of cytokines (IL1, IL1B and IL6) and IKK complex (alpha, beta and gamma) could be annulled by activation of PPARG, PIAS3 and P50-homodimer together instead of individual activations. Thus, the presented network pathway model has predictive utility in inferring NF-κB activity.
Democratizing water monitoring: Implementation of a community-based qPCR monitoring program for recreational water hazards
Authors: Rudko Sydney P , Reimink Ronald R , Peter Bradley , White Jay , Hanington Patrick C
Published: February 2020

Recreational water monitoring can be challenging due to the highly variable nature of pathogens and indicator concentrations, the myriad of potential biological hazards to measure for, and numerous access points, both official and unofficial, that are used for recreation. The aim of this study was to develop, deploy, and assess the effectiveness of a quantitative polymerase chain reaction (qPCR) community-based monitoring (CBM) program for the assessment of bacterial and parasitic hazards in recreational water. This study developed methodologies for performing qPCR ‘in the field’, then engaged with water management and monitoring groups, and tested the method in a real-world implementation study to evaluate the accuracy of CBM using qPCR both quantitatively and qualitatively. This study found high reproducibility between qPCR results performed by non-expert field users and expert laboratory results, suggesting that qPCR as a methodology could be amenable to a CBM program.
Gene expression noise can promote the fixation of beneficial mutations in fluctuating environments
Authors: Schmutzer Michael , Wagner Andreas
Published: February 2020

Nongenetic phenotypic variation can either speed up or slow down adaptive evolution. We show that it can speed up evolution in environments in which available carbon and energy sources change over time. To this end, we use an experimentally validated model ofEscherichia coligrowth on two alternative carbon sources, glucose and acetate. On the superior carbon source (glucose), all cells achieve high growth rates, while on the inferior carbon source (acetate) only a small fraction of the population manages to initiate growth. Consequently, populations experience a bottleneck when the environment changes from the superior to the inferior carbon source. Growth on the inferior carbon source depends on a circuit under the control of a transcription factor that is repressed in the presence of the superior carbon source. We show that noise in the expression of this transcription factor can increase the probability that cells start growing on the inferior carbon source. In doing so, it can decrease the severity of the bottleneck and increase mean population fitness whenever this fitness is low. A modest amount of noise can also enhance the fitness effects of a beneficial allele. It can accelerate the spreading of such an allele, increase its likelihood of going to fixation, and reduce its fixation time. Central to the adaptation-enhancing principle we identify is the ability of noise to mitigate population bottlenecks. Because such bottlenecks are frequent in fluctuating environments, and because fluctuating environments themselves are ubiquitous, this principle may apply to a broad range of environments and organisms.

Author summary

Individuals that grow in the same environment and share the same genes may still differ in their behaviour and their traits. These differences between individuals arise from uncertainty inherent in all biological processes, and they are found in all domains of life. Although this random individual variability is itself short-lived, it still has the potential to shape evolution in the long term. For example, if a population encounters a harsh environment, random (nongenetic) differences between individuals can cause some individuals to cope better with the new environment than others. These rare individuals may give a population an advantage compared to populations with fewer such differences between individuals. Furthermore, if some of these rare individuals carry a beneficial gene variant, the beneficial effect of this gene variant may become amplified, and consequently spread faster in a population with more random variation. Using a realistic model of cell growth, we show that this mechanism not only works in unfavourable environments that are stable, but also in environments that switch back and forth between a favourable and an unfavourable state. Because many natural environments undergo such periodic changes, and because random differences between individuals are ubiquitous, the mechanism we have identified may be widespread in nature.
Formicine ants swallow their highly acidic poison for gut microbial selection and control
Authors: Tragust Simon , Herrmann Claudia , Häfner Jane , Braasch Ronja , Tilgen Christina , Hoock Maria , Milidakis Margarita Artemis , Gross Roy , Feldhaar Heike
Published: February 2020

Animals continuously encounter microorganisms that are essential for health or cause disease. They are thus challenged to control harmful microbes while allowing acquisition of beneficial microbes. This challenge is likely especially important for social insects with respect to microbes in food, as they often store food and exchange food among colony members. Here we show that formicine ants actively swallow their antimicrobial, highly acidic poison gland secretion. The ensuing acidic environment in the stomach, the crop, limits establishment of pathogenic and opportunistic microbes ingested with food and improves survival of ants when faced with pathogen contaminated food. At the same time, crop acidity selectively allows acquisition and colonization by Acetobacteraceae, known bacterial gut associates of formicine ants. This suggests that swallowing of the poison gland secretion acts as a microbial filter in formicine ants and indicates a potentially widespread but so far underappreciated dual role of antimicrobials in host-microbe interactions.
ToxoplasmaGRA15 and GRA24 are important activators of the host innate immune response in the absence of TLR11
Authors: Mukhopadhyay Debanjan , Arranz-Solís David , Saeij Jeroen P.J.
Published: February 2020

The murine innate immune response againstToxoplasma gondiiis predominated by the interaction of TLR11/12 withToxoplasmaprofilin. However, mice lackingTlr11or humans, who do not have functional TLR11 or TLR12, still elicit a strong innate immune response uponToxoplasmainfection. The parasite factors that determine this immune response are largely unknown. Herein, we investigated two dense granule proteins (GRAs) secreted byToxoplasma,GRA15 and GRA24, for their role in stimulating the innate immune response inTlr11-/-mice and in human cells, which naturally lack TLR11/TLR12. Our results show that GRA15 and GRA24 synergistically shape the early immune response and parasite virulence inTlr11-/-mice, with GRA15 as the predominant effector. Nevertheless, acute virulence inTlr11-/-mice is still dominated by allelic combinations ofROP18andROP5, which are effectors that determine evasion of the immunity-related GTPases. In human macrophages, GRA15 and GRA24 play a major role in the induction of IL12, IL18 and IL1β secretion. We further show that GRA15/GRA24-mediated IL12, IL18 and IL1β secretion activates IFNγ secretion by peripheral blood mononuclear cells (PBMCs), which controlsToxoplasmaproliferation. Taken together, our study demonstrates the important role of GRA15 and GRA24 in activating the innate immune response in hosts lacking TLR11.

Importance

In mice, the early immune response againstToxoplasmais dominated by TLR11-mediated release of IL-12, which subsequently induces protective IFNγ. Here we show that inTlr11-/-mice and in human cells, which do not have TLR11, theToxoplasmaGRA15 and GRA24 effectors play an important role in induction of IL12, IL18 and IL1β, and thus in the subsequent protective IFNγ secretion.
Promoter CpG density predicts downstream gene loss-of-function intolerance
Authors: Boukas Leandros , Bjornsson Hans T. , Hansen Kasper D.
Published: February 2020

The aggregation and joint analysis of large numbers of exome sequences has recently made it possible to de-rive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoF-intolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich pro-moters (top 10% CpG density) have a 67.2% probability of being highly LoF-intolerant, using the LOEUF metric from gnomAD. This is in contrast to 7.4% of genes downstream of the most CpG-poor (bottom 10% CpG density) promoters. Combining promoter CpG density with exonic and promoter conservation explains 33.4% of the variation in LOEUF, and the contribution of CpG density exceeds the individual contributions of exonic and promoter conservation. We leverage this to train a simple and easily interpretable predictive model that out-performs other existing predictors and allows us to classify 1,760 genes – which currently lack reliable LOEUF estimates – as highly LoF-intolerant or not. These predictions have the potential to aid in the interpretation of novel patient variants. Moreover, our results reveal that high CpG density is not merely a generic feature of human promoters, but is preferentially encountered at the promoters of the most selectively constrained genes, calling into question the prevailing view that CpG islands are not subject to selection.
AS-Quant: Detection and Visualization of Alternative Splicing Events with RNA-seq Data
Authors: Fahmi Naima Ahmed , Yeh Hsin-Sung , Chang Jae-Woong , Nassereddeen Heba , Fan Deliang , Yong Jeongsik , Zhang Wei
Published: February 2020

A simplistic understanding of the central dogma falls short in correlating the number of genes in the genome to the number of proteins in the proteome. Post-transcriptional alternative splicing contributes to the complexity of proteome and are critical in understanding gene expression. mRNA-sequencing (RNA-seq) has been widely used to study the transcriptome and provides opportunity to detect alternative splicing events among different biological conditions. Despite the popularity of studying transcriptome variants with RNA-seq, few efficient and user-friendly bioinformatics tools have been developed for the genome-wide detection and visualization of alternative splicing events. We have developed AS-Quant (AlternativeSplicingQuantitation), a robust program to identify alternative splicing events and visualize the short-read coverage with gene annotations. AS-Quant works in three steps: (i) calculate the read coverage of the potential splicing exons and the corresponding gene; (ii) categorize the splicing events into five different types based on annotation, and assess the significance of the events between two biological conditions; (iii) generate the short reads coverage plot with a complete gene annotation for user specified splicing events. To evaluate the performance, two significant alternative splicing events identified by AS-Quant between two biological contexts were validated by RT-PCR.

Implementation

AS-Quant is implemented in Python. Source code and a comprehensive user’s manual are freely available athttps://github.com/CompbioLabUCF/AS-Quant
Solubility-Weighted Index: fast and accurate prediction of protein solubility
Authors: Bhandari Bikash K. , Gardner Paul P. , Lim Chun Shen
Published: February 2020

Motivation

Recombinant protein production is a widely used technique in the biotechnology and biomedical industries, yet only a quarter of target proteins are soluble and can therefore be purified.

Results

We have discovered that global structural flexibility, which can be modeled by normalised B-factors, accurately predicts the solubility of 12,216 recombinant proteins expressed inEscherichia coli. We have optimised B-factors, and derived a new set of values for solubility scoring that further improves prediction accuracy. We call this new predictor the ‘Solubility-Weighted Index’ (SWI). Importantly, SWI outperforms many existing protein solubility prediction tools. Furthermore, we have developed ‘SoDoPE’ (Soluble Domain for Protein Expression), a web interface that allows users to choose a protein region of interest for predicting and maximising both protein expression and solubility.

Availability

The SoDoPE web server and source code are freely available athttps://tisigner.com/sodopeandhttps://github.com/Gardner-BinfLab/TISIGNER-ReactJS, respectively. The code and data for reproducing our analysis can be found athttps://github.com/Gardner-BinfLab/SoDoPE_paper2020.
A novel two-indenter based micro-pump for lab-on-a-chip application: modeling and characterizing flows for a non-Newtonian fluid
Authors: Avvari Ravi Kant
Published: February 2020

Inspired by the feeding mechanisms of a nematode, a novel two-indenter (2I) micro-pump is analyzed theoretically for transport and mixing of a non-Newtonian fluid for the purpose of lab-on-a-chip applications. Considering that the viscous forces dominate the flows in microscopic regime, the concept lubrication theory was adopted to device the two-dimensional flow model of the problem. By approximating the movements of the indenter as a sinusoidal function, the details of the flow were investigated for variations in – frequency of contraction of the first value keeping the second valve at higher occlusion, and occlusion. The study indicates that occlusive nature of the second valve leads to the large pressure barrier which prevents the fluid to enter into the neighboring compartment. Transport occurs as the lumen opens to develop a suction pressure. Pressure barrier is found to be highest for dilatants followed by Newtonian and pseudo-plastics. Shear stress dependency on frequency the contraction of the first value is highest for lower values of flow behavior index. In conclusion, the study provides details connecting the flows resulting from the indentation of the front-end indenter to the frequency of indentation, geometry and rheology of the fluid, thus facilitating optimal design of the micro-pumps.
Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation
Authors: Haughey Charles M. , Mukherjee Debayan , Steele Rebecca E. , Popple Amy , Dura-Perez Lara , Pickard Adam , Jain Suneil , Mullan Paul B. , Williams Rich , Oliveira Pedro , Buckley Niamh E. , Honeychurch Jamie , McDade Simon , Illidge Timothy , Mills Ian G. , Eddie Sharon L.
Published: February 2020

Background

Allograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT).

Methods

The DVL3 cell line was derived from a transgenic trp53-/-/Pten-/-mouse model and characterised bothin vitroandin vivo. The DVL3 cells were allografted and response to RT was investigated and compared to the TRAMP-C1 model. Extensive tumour profiling in the DVL3 model was performed using flow cytometry, immunohistochemistry and RNA-seq.

Results

In vitrothe DVL3 cells expressed basal and luminal markers. DVL3 cells formed tumours with distinct glandular morphology which expressed androgen receptor, similar to human localised PC. DVL3 tumour growth was delayed following administration of fractionated RT, with infiltration of myeloid derived suppressor cells (MDSC).

Conclusions

The DVL3 allograft model represents substantial progress in PCa modelling, displaying; luminal differentiation, strong AR expression, and an immunosuppressive microenvironment, similar to observations in high-risk PCa patients. This model is ideally suited for development and validation of novel therapeutics, in particular immune-modulatory agents in combination with RT.
Convergent network effects along the axis of gene expression during prostate cancer progression
Authors: Charmpi Konstantina , Guo Tiannan , Zhong Qing , Wagner Ulrich , Sun Rui , Toussaint Nora C. , Fritz Christine E. , Yuan Chunhui , Chen Hao , Rupp Niels J. , Christiansen Ailsa , Rutishauser Dorothea , Rüschoff Jan H. , Fankhauser Christian , Saba Karim , Poyet Cedric , Hermanns Thomas , Oehl Kathrin , Moore Ariane L. , Beisel Christian , Calzone Laurence , Martignetti Loredana , Zhang Qiushi , Zhu Yi , Martínez María Rodríguez , Manica Matteo , Haffner Michael C. , Aebersold Ruedi , Wild Peter J. , Beyer Andreas
Published: February 2020

Background

Tumor-specific genomic aberrations are routinely determined by high throughput genomic measurements. It remains unclear though, how complex genome alterations affect molecular networks through changing protein levels, and consequently biochemical states of tumor tissues.

Results

Here, we investigated the propagation of genomic effects along the axis of gene expression during prostate cancer progression. For that, we quantified genomic, transcriptomic and proteomic alterations based on 105 prostate samples, consisting of benign prostatic hyperplasia regions and malignant tumors, from 39 prostate cancer patients. Our analysis revealed convergent effects of distinct copy number alterations impacting on common downstream proteins, which are important for establishing the tumor phenotype. We devised a network-based approach that integrates perturbations across different molecular layers, which identified a sub-network consisting of nine genes whose joint activity positively correlated with increasingly aggressive tumor phenotypes and was predictive of recurrence-free survival. Further, our data revealed a wide spectrum of intra-patient network effects, ranging from similar to very distinct alterations on different molecular layers.

Conclusions

This study uncovered molecular networks with remarkably convergent alterations across tumor sites and patients, but it also exposed a diversity of network effects: we could not identify a single sub-network that was perturbed in all high-grade tumor regions.
A Single Nucleotide Polymorphism assay sheds light on the extent and distribution of genetic diversity, population structure and functional basis of key traits in cultivated North American Cannabis
Authors: Henry Philippe , Khatodia Surender , Kapoor Karan , Gonzales Britni , Middleton Alexis , Hong Kevin , Hilyard Aaron , Johnson Steve , Allen Davis , Chester Zachary , Jin Dan , Jule José Carlos Rodriguez , Wilson Iain , Gangola Manu , Broome Jason , Caplan Deron , Adhikary Dinesh , Deyholos Michael K. , Morgan Michael , Hall Oliver W. , Guppy Brent , Orser Cindy
Published: February 2020

Background

The taxonomic classification of the Cannabis genus has been delineated through three main types:sativa(long and less branched plant with long and narrow leaves),indica(short but highly branched plant with broader leaves) andruderalis(wild type with short stature, less branching and small thick leaves). While still under discussion, particularly whether the genus is polytypic or monotypic, this broad classification reflects putative geographical origin of each group and putative chemotypic and pharmacology.

Methods

Here we describe a thorough investigation of cannabis accessions using a set of 22 highly informative and polymorphic SNP markers associated with important traits such as cannabinoid and terpenoid expression as well as fibre and resin production. The assay offers insight into cannabis population structure, phylogenetic relationship, population genetics and correlation to secondary metabolite concentrations and demonstrate the utility of this assay for rapid, repeatable and cost-efficient genotyping of commercial and industrial cannabis accessions for use in product traceability, breeding programs, regulatory compliance and consumer education.

Results

The main outcomes are the identification of 5 clusters in the sample set available, including industrial hemp, resin hemp which likely underwent a bottleneck to stabilize CBDA accumulation (Type II & III). THC resin (type I) make up the other three clusters with terpinolene (colloquial “sativa” or “NLD”), myrcene/pinene and myrcene/limonene (colloquial “indica”, “BLD”), which also putatively harbour an active CBCAS.

Conclusion

The functional basis of key traits is also discussed as recently enabled by the NCBI Cannabis sativa Annotation Release 100, allowing for hypothesis testing with regards to secondary metabolite production as well as other key traits of importance for adaptable and compliant large-scale seed production under the new US Domestic Hemp Production Program.
Digital transformation in supply chain, challenges and opportunities in SMEs: a case study of Al-Rumman Pharma
Authors: Faridi Mohammad Rishad , Malik Azam
Published: February 2020

Learning outcomes

Digital skills change management skills problem solving skills.

Case overview/synopsis

Al-Rumman Pharma is headquartered in Dubai, is an integrated international pharmaceutical company providing a wide range of pharmaceutical solutions to manufacture high quality and affordable generic medicines. It holds credibility amongst healthcare professionals and patients, across the Middle East and North African (MENA) markets. Their quality assurance is fostered by high levels of reliability and order fulfillment, which differentiates them from their competitors. Recently, they have been facing technology fatigue meant as an organization suffering from overwhelming options and choices in technology, this contributes to turbulent and confused states of mind when considering technology adaptation. This case evolves specifically from a procurement perspective, the pressure of high expectation and severe compliance clauses from key suppliers, particularly large corporations with monopolies in supplies who have the tendency to dominate and dictate terms to the small and medium enterprises (SMEs). For example, forcing SME’s to adopt specific technological frameworks to be trade partners. Another conflict is that while the SME’s do value the contribution of the procurement function, the shift from tactical to strategic mindset is not robust enough. Is this a dilemma? Ms Mary buyer at Al-Rumman Pharma, which is SME in operation, is facing challenges from key suppliers because of her tactical buying approach and adoption of multiple technological frameworks from various key suppliers, which are neither integrated nor compatible with each other. Her transition from traditional buying to a more strategic sourcing approach is what the need of the hour is. Prior information technology role was more as support at Al-Rumman Pharma and Chief Executive Officer Dr Mubeen Ahmad Khan did technology adopted decisions in isolation but today the company needs an integrative approach with forward thinking and also kept the legacy intact. Resistance to change was very inevitable once it was integrated.

Complexity academic level

This case has been particularly focused on undergraduates in the final semester of management courses, as well as masters level students specializing in supply chain and operation management courses. It is also for practitioner procurement and supply chain managers going for various supply chain management related certification courses. Students who have studied procurement management are most suitable to accomplish this case study. Executives pursuing a business program are also recommended to study this case.

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS 9: Operations and logistics.
A study of the balancing of lean thinking and stakeholder salience in decision-making
Authors: Bader Bruce H. , Badar M. Affan , Rodchua Suhansa , McLeod Alister
Published: February 2020

Purpose

This research brings together two streams of thought applied to decision-making: lean thinking and stakeholder theory. Both have been identified as ways to improve organizational value. Previous studies disagree regarding whether they can work together. This study investigates if managers balance stakeholders and lean thinking in decision-making.

Design/methodology/approach

This research investigates if both lean thinking and stakeholder salience share common literature by using data mining. It surveys organizations that perceive themselves as lean and have multiple diverse stakeholders to determine whether waste and salience are considered when making decisions. An ANOVA is done to see if organization type, management level, organization size, geographic location, or lean maturity has an effect on the priority of stakeholder salience or lean thinking's waste variants when making decisions.

Findings

Findings of this research are: 1) stakeholders salience criteria are considered more often than lean thinking's waste variants in decision-making by managers as a whole and in particular by middle-level managers and senior managers. However, lean thinking's waste variants are considered as often as stakeholder salience criteria by first-line managers. 2) The ranking of stakeholder salience in making decisions is not affected by organization type, respondent position, organization size, perceived lean experience, or geographic location. The organization type, organization size, lean experience, and location do not affect the ranking of lean thinking variants either. But the ranking of lean thinking's waste variants is significantly different for first-line, middle-level, and senior managers. Middle-level managers rank lean thinking higher than that of either first-line or senior-level. Because of this, middle managers have a more balanced approach in using lean thinking and stakeholder salience than other managers. 3) Stakeholder salience criteria have a significantly higher ranking than lean thinking variants in making decisions for all organization types: manufacturing and nonmanufacturing.

Originality/Value

This research demonstrates a significant disconnect exists between lean thinking and demands of stakeholders that impacts the value of an organization, and only middle-level managers bring balance and awareness of both streams of thought. An empirical instrument has been developed to balance the stakeholder salience criteria with the lean thinking variants.
Microhabitat partitioning correlates with opsin gene expression in coral reef cardinalfishes (Apogonidae)
Authors: Luehrmann Martin , Cortesi Fabio , Cheney Karen L. , de Busserolles Fanny , Marshall N. Justin
Published: February 2020

Fish are the most diverse vertebrate group, and they have evolved equally diverse visual systems, varying in terms of eye morphology, number and distribution of spectrally distinct photoreceptor types, visual opsin genes and opsin gene expression levels.

This variation is mainly due to adaptations driven by two factors: differences in the light environments and behavioural tasks. However, while the effects of large‐scale habitat differences are well described, it is less clear whether visual systems also adapt to differences in environmental light at the microhabitat level.

To address this, we assessed the relationship between microhabitat use and visual system features in fishes inhabiting coral reefs, where habitat partitioning is particularly common.

We suggest that differences in microhabitat use by cardinalfishes (Apogonidae) drive morphological and molecular adaptations in their visual systems. To test this, we investigated diurnal microhabitat use in 17 cardinalfish species and assessed whether this correlated with differences in visual opsin gene expression and eye morphology.

We found that cardinalfishes display six types of microhabitat partitioning behaviours during the day, ranging from specialists found exclusively in the water column to species that are always hidden inside the reef matrix.

Species predominantly found in exposed microhabitats had higher expression of the short‐wavelength‐sensitive violet opsin (SWS2B) and lower expression of the dim‐light active rod opsin (RH1). Species of intermediate exposure, on the other hand, expressed opsins that are mostly sensitive to the blue‐green central part of the light spectrum (SWS2As and RH2s), while fishes entirely hidden in the reef substrate had a higher expression of the long‐wavelength‐sensitive red opsin.

We also found that eye size relative to body size differed between cardinalfish species, and relative eye size decreased with an increase in habitat exposure.

Retinal topography did not show co‐adaptation with microhabitat use, but data suggested co‐adaptation with feeding mode.

We suggest that, although most cardinalfishes are nocturnal foragers, their visual systems—and possibly those of other (reef) fishes—have also adapted to the light intensity and the light spectrum of their preferred diurnal microhabitats.

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