bluuebunny/crossref_metadata_2025 huggingface dataset:
Does A Longer Waiting Period After Neoadjuvant Radio-chemotherapy Improve the Oncological Prognosis of Rectal Cancer?
Authors: Lefèvre Jérémie H. , Mineur Laurent , Cachanado Marine , Denost Quentin , Rouanet Philippe , de Chaisemartin Cécile , Meunier Bernard , Mehrdad Jafari , Cotte Eddy , Desrame Jérome , Karoui Mehdi , Benoist Stéphane , Kirzin Sylvain , Berger Anne , Panis Yves , Piessen Guillaume , Saudemont Alain , Prudhomme Michel , Peschaud Frédérique , Dubois Anne , Loriau Jérome , Tuech Jean-Jacques , Meurette Guillaume , Lupinacci Renato , Goasguen Nicolas , Creavin Ben , Simon Tabassome , Parc Yann
Published: September 2019

Objective:

The aim of this study was to report the 3-year survival results of the GRECCAR-6 trial.

Summary Background Data:

Current data on the effect of an extended interval between radiochemotherapy (RCT) and resection for rectal cancer on the rate of complete pathological response (pCR = ypT0N0) is controversial. Furthermore, its effect on oncological outcomes is unknown.

Methods:

The GRECCAR-6 trial was a phase III, multicenter, randomized, open-label, parallel-group, controlled trial. Patients with cT3/T4 or TxN+ tumors of the mid or lower rectum who had received RCT (45–50 Gy with 5-fluorouracil or capecitabine) were included and randomized into a 7- or 11-week waiting period. Primary endpoint was the pCR rate. Secondary endpoints were 3-year overall (OS), disease-free survival (DFS), and recurrence rates.

Results:

A total of 265 patients from 24 participating centers were enrolled. A total of 253 patients underwent a mesorectal excision. Overall pCR rate was 17% (43/253). Mean follow-up from surgical resection was 32 ± 8 months. Twenty-four deaths occurred with an 89% OS at 3 years. DFS was 68.7% at 3 years (75 recurrences). Three-year local and distant recurrences were 7.9% and 23.8%, respectively. The randomization group had no impact on the 3-year OS (P = 0.8868) or DFS (P = 0.9409). Distant (P = 0.7432) and local (P = 0.3944) recurrences were also not influenced by the waiting period. DFS was independently influenced by 3 factors: circumferential radial margin (CRM) ≤1 mm [hazard ratio (HR) = 2.03; 95% confidence interval (CI), 1.17–3.51], ypT3-T4 (HR = 2.69; 95% CI, 1.19–6.08) and positive lymph nodes (HR = 3.62; 95% CI, 1.89–6.91).

Conclusion:

Extending the waiting period by 4 weeks following RCT has no influence on the oncological outcomes of T3/T4 rectal cancers.
Anastomotic Techniques and Associated Morbidity in Total Minimally Invasive Transthoracic Esophagectomy
Authors: Schröder Wolfgang , Raptis Dimitri A. , Schmidt Henner M. , Gisbertz Suzanne S. , Moons Johnny , Asti Emanuele , Luyer Misha D. P. , Hölscher Arnulf H. , Schneider Paul M. , van Berge Henegouwen Mark I. , Nafteux Philippe , Nilsson Magnus , Räsanen Jari , Palazzo Francesco , Mercer Stuart , Bonavina Luigi , Nieuwenhuijzen Grard A. P. , Wijjnhoven Bas P. L. , Pattyn Piet , Grimminger Peter P. , Bruns Christiane J. , Gutschow Christian A.
Published: September 2019

Objective:

The aim of this study was to describe anastomotic techniques used for total minimally invasive transthoracic esophagectomy (ttMIE) and to analyze the associated morbidity.

Background:

ttMIE faces increasing application in surgical treatment of esophageal cancer. For esophagogastric reconstruction, different anastomotic techniques are currently used, but their effect on postoperative anastomotic leakage and morbidity has not been investigated.

Patients and Methods:

Patients were selected from a basic dataset, collected during a 5-year period from 13 international surgical high-volume centers. Endpoints were anastomotic leakage rate and postoperative morbidity in correlation to anastomotic techniques, measured by the Clavien-Dindo classification and the Comprehensive Complication Index (CCI).

Results:

Five anastomotic techniques were identified in 966 patients after ttMIE: intrathoracic end-to-side circular-stapled technique in 427 patients (double-stapling n = 90, purse-string n = 337), intrathoracic (n = 109) or cervical (n = 255) side-to-side linear-stapled, and cervical end-to-side hand-sewn (n = 175). Leakage rates were similar in intrathoracic and cervical anastomoses (15.9% vs 17.2%, P = 0.601), but overall complications (56.7%% vs 63.7%, P = 0.029) and median 90-day CCI {21 [interquartile range (IQR) 0–36] vs 29 [IQR 0–40], P = 0.019} favored intrathoracic reconstructions. Leakage rates after intrathoracic end-to-side double-stapling (23.3%) and cervical end-to-side hand-sewn (25.1%) techniques were significantly higher compared with intrathoracic side-to-side linear (15.6%), end-to-side purse-string (13.9%), and cervical side-to-side linear-stapled esophagogastrostomies (11.8%) (P < 0.001). Multivariable analysis confirmed anastomotic technique as independent predictor of leakage after ttMIE.

Conclusion:

Results of this analysis present the current status of the technical evolution of ttMIE with anastomotic leakage as predominant surgical complication. However, technique-related morbidity requires cautious interpretation considering the long learning curve of this complex surgical procedure.
Interrater Agreement Between Critical Care Providers for Background Classification and Seizure Detection After Implementation of Amplitude-Integrated Electroencephalography in Neonates, Infants, and Children
Authors: Bourgoin Pierre , Barrault Victoire , Loron Gauthier , Roger Alexandre , Bataille Emmanuelle , Leclair-Visonneau Laurène , Joram Nicolas , Chenouard Alexis
Published: September 2019

Purposes:

Amplitude-integrated EEG (aEEG) has been widely developed in neonatal intensive care unit, but few studies focused on pediatric intensive care unit. Furthermore, reliability of aEEG under real-life conditions is unknown.

Methods:

Participants were nurses from a 12-bed pediatric intensive care unit in a referral university hospital in France. Amplitude EEG was implemented after standardized training, including e-learning course, individual feedback and bedside teaching concerning monitoring installation, background classification patterns recognition, artefact analysis, and seizure detection. The primary judgment criterion was the agreement (Cohen Kappa) between nurses and aEEG experts for the detection of abnormal aEEG traces (moderately or severely altered background pattern according to Hellström–Westas classification and/or seizure activity).

Results:

During the study period, 196 consecutives traces from 79 patients were analyzed by 51 nurses. According to expert's classification, 53% of traces were abnormal, including 17.5% of severely abnormal traces (severely altered traces and/or seizure activity) and 14% exhibiting seizure activity. Moderate agreement between experts and nurses was found for detection of any abnormal trace (k = 0.53; 95% confidence interval [CI]: 0.39–0.67). Substantial agreement was found for severely altered traces (k = 0.71; 95% CI: 0.57–0.85). Finally, fair agreement was found for seizure detection (irrespective of background classification, k = 0.40; 95% CI: 0.25–0.54).

Conclusions:

These results suggest that aEEG monitoring may be implemented in routine nursing care in pediatric intensive care unit. Further training courses are needed to enhance nurses' skill in detecting seizures activity at the bedside.
HIV control strategies for sex worker–client contact networks
Authors: Mulberry Nicola , Rutherford Alexander R. , Wittenberg Ralf W. , Williams Brian G.
Published: September 2019

Controlling the spread of HIV among hidden, high-risk populations such as survival sex workers and their clients is becoming increasingly important in the ongoing fight against HIV/AIDS. Several sociological and structural factors render general control strategies ineffective in these settings; instead, focused prevention, testing and treatment strategies which take into account the nature of survival sex work are required. Using a dynamic bipartite network model of sexual contacts, we investigate the optimal distribution of treatment and preventative resources among sex workers and their clients; specifically, we consider control strategies that randomly allocate antiretroviral therapy and pre-exposure prophylaxis within each subpopulation separately. Motivated by historical data from a South African mining community, three main asymmetries between sex workers and clients are considered in our model: relative population sizes, migration rates and partner distributions. We find that preventative interventions targeted at female sex workers are the lowest cost strategies for reducing HIV prevalence, since the sex workers form a smaller population and have, on average, more sexual contacts. However, the high migration rate among survival sex workers limits the extent to which prevalence can be reduced using this strategy. To achieve a further reduction in HIV prevalence, testing and treatment in the client population cannot be ignored.
Further discussion on the reaction behaviour of triallyl isocyanurate in the UV radiation cross-linking process of polyethylene: a theoretical study
Authors: Zhang Hui , Shang Yan , Zhao Hong , Wang Xuan , Han Baozhong , Li Zesheng
Published: September 2019

Further theoretical investigation on the reaction behaviour of triallyl isocyanurate (TAIC) in the UV radiation cross-linking process of polyethylene (PE) is accomplished by density functional theory for high voltage cable insulation materials. The reaction potential energy information of the 13 reaction channels at B3LYP/6–311 + G(
d,p
) level are identified. These have been explored that the TAIC take part in the reaction behaviour on ground state during UV radiation cross-linking process and TAIC intra-molecular isomerization reaction itself. In addition, the results show that the effect of multiplication and acceleration for the cross-linking reaction of trimethylopropane trimethacrylate (TMPTMA) would be better than that of TAIC. It has further clarified the reasons why UV radiation cross-linking reaction of PE had been initiated by benzophenone (Bp), and the TAIC or TMPTMA needed to take part. The results obtained in the present study could directly guide both the optimization of UV radiation cross-linking PE process and the development of the insulation material of high-voltage cable in real application.
Zinc binding proteome of a phytopathogen
Xanthomonas translucens
pv.
undulosa
Authors: Sharma Ankita , Sharma Dixit , Verma Shailender Kumar
Published: September 2019

Xanthomonas translucens
pv.
undulosa
(
Xtu
) is a proteobacteria which causes bacterial leaf streak (BLS) or bacterial chaff disease in wheat and barley. The constant competition for zinc (Zn) metal nutrients contributes significantly in plant–pathogen interactions. In this study, we have employed a systematic
in silico
approach to study the Zn-binding proteins of
Xtu.
From the whole proteome of
Xtu
, we have identified approximately 7.9% of proteins having Zn-binding sequence and structural motifs
.
Further, 115 proteins were found homologous to plant–pathogen interaction database. Among these 115 proteins, 11 were predicted as putative secretory proteins. The functional diversity in Zn-binding proteins was revealed by functional domain, gene ontology and subcellular localization analysis. The roles of Zn-binding proteins were found to be varied in the range from metabolism, proteolysis, protein biosynthesis, transport, cell signalling, protein folding, transcription regulation, DNA repair, response to oxidative stress, RNA processing, antimicrobial resistance, DNA replication and DNA integration. This study provides preliminary information on putative Zn-binding proteins of
Xtu
which may further help in designing new metal-based antimicrobial agents for controlling BLS and bacterial chaff infections on staple crops.
Information and genetic counselling for psychiatric risks in children with rare genomic disorders
Authors: Cuthbert Andrew , Challenger Aimee , Hall Jeremy , van den Bree Marianne BM
Published: September 2019

Purpose

Genomic medicine has transformed the diagnosis of neurodevelopmental disorders. Evidence of increased psychiatric comorbidity associated with genomic copy number and single nucleotide variants (CNV and SNV) may not be fully considered when providing genetic counselling. We explored parents’ experiences of genetics services and how they obtained information concerning psychiatric manifestations.

Methods

Parents of children diagnosed with genomic variants completed an online survey exploring, (i) how they experienced the genetic diagnosis, and (ii) how they acquired information about psychiatric, developmental and physical manifestations.

Results

Two-hundred and 86 respondents completed the survey. Thirty percent were unsatisfied with receiving genetic diagnoses. Satisfaction was predicted if communication was by geneticists (p = 0.004); provided face-to-face (p = 0.003); clearly explained (p < 0.001); and accompanied by support (p = 0.017). Parents obtained psychiatric information from non-professional sources more often than developmental (ϕ 0.26, p < 0.001) and physical manifestations (ϕ 0.21, p = 0.003), which mostly came from health professionals. Information from support organisations was more helpful than from geneticists (odds ratio [OR] 21.0, 95% CI 5.1 – 86.8, p < 0.001); paediatricians (OR 11.0, 1.4 – 85.2, p = 0.004); and internet sites (OR 15.5, 3.7 – 64.8, p < 0.001).

Conclusion

A paucity of professional information about psychiatric risks after genetic diagnosis may impede early diagnosis and intervention for children with high genotypic risks. Planned integration of genomic testing into mainstream services should include genetic counselling training to address the full spectrum of developmental, physical and psychiatric manifestations and timely provision of high-quality information.
Futility of combining griseofulvin and terbinafine in current epidemic of altered dermatophytosis in India: Results of a randomized pragmatic trial
Authors: Singh Sanjay , Anchan Vinayak N , Raheja Radhika
Published: September 2019

Background

Treatment responsiveness of tinea has decreased considerably in recent past in India. We tested effectiveness of oral terbinafine plus griseofulvin versus terbinafine alone in tinea corporis, tinea cruris and tinea faciei in a randomized pragmatic open trial.

Methods

One hundred and thirty two microscopy confirmed patients were randomly allocated (ratio 1:1) to two groups, terbinafine (T) and terbinafine plus griseofulvin (T+G). Doses given were as follows: T, oral terbinafine (6 mg/kg/day, maximum 500 mg/day, once daily); T+G, terbinafine (as above) plus oral griseofulvin (children [<18 years] 10 mg/kg/day, adults [18 years or more] 10 mg/kg/day, but not <500 mg and not >1000 mg per day, in two divided doses). Patients were treated for 8 weeks or cure, whichever occurred earlier.

Results

At 4 weeks, none of the patients were cured in both groups. At 6 weeks, 1(1.5%) and 4 (6.1%) patients were cured in T and T+G groups, respectively (P=0.417). At 8 weeks, 17 (25.8%) and 19 (28.8%) patients were cured in T and T+G groups, respectively (P=0.845). For cure rate at 8 weeks, number needed to treat (NNT) for T+G (versus T), was 33.

Conclusions

Addition of griseofulvin to terbinafine does not increase effectiveness of terbinafine in current epidemic of altered dermatophytosis in India.
Three-Compartment Model of CAR T-cell Immunotherapy
Authors: de Jesus Rodrigues Brendon , Barros Luciana R. Carvalho , Almeida Regina C.
Published: September 2019

Immunotherapy has gained great momentum with chimeric antigen receptor T-cell (CAR T) therapy, in which patient’s T lymphocytes are genetically manipulated to recognize tumor-specific antigens to increase tumor elimination efficiency. Improved CAR T cell immunotherapy requires a better understanding of the interplay between CAR T cell doses and tumor burden, administration protocol, toxicity, resistance to immunotherapy, among other features. We developed a three-compartment mathematical model to describe tumor response to CAR T cell immunotherapy in immunodeficient mouse models. It encompasses interactions between tumor cells, effector and long-term memory CAR T cells such as tumor induced immunosuppression effects, conversion of memory T cells into effector T cells in the presence of tumor cells, and individual specificities considered as uncertainties in the parameters of the model. The model was able to represent two different immunotherapy scenarios with different CAR receptors and tumor targets reported in the literature. Further in silico studies considering different dosing quantities and tumor burden showed that the proposed model can represent the three possible therapy outcomes: tumor elimination, equilibrium, and escape. We found that therapy effectiveness may also depend on small variations in the parameter values, regarded as intrinsic individual specificities, as T cell proliferation capacity, as well as immunosuppressive tumor microenvironment factors. These issues may significantly reduce the chance of tumor elimination. In this way, the developed model provides potential use for assessing different CAR T cell protocols and associated efficacy without further in vivo experiments.
Range sizes of the world’s mammals, birds and amphibians from 5000 BCE to 2100 CE
Authors: Beyer Robert M. , Manica Andrea
Published: September 2019

Species’ vulnerability to extinction is strongly impacted by their geographical range size. Formulating effective conservation strategies therefore requires a better understanding of how the ranges of the world’s species have changed in the past, and how they will change under alternative future scenarios. Here, we used reconstructions of global land use and biomes of the past 7,000 years, and 16 possible climatic and socio-economic scenarios until the year 2100, to map the habitat ranges of 16,511 individual mammal, bird, and amphibian species through time. We estimate that extant species have lost an average of 19% of their natural range sizes thus far, and may lose up to 32% by 2100. Changes in range size vary greatly between species, with tropical, small-ranged, and threatened species being especially impacted. Our data reveal that range losses have been increasing disproportionately in relation to the size of destroyed habitat, driven by a long-term increase of land use in tropical biodiversity hotspots. The outcomes of different future land use and climate trajectories for global habitat ranges vary considerably, providing important quantitative evidence for conservation planners and policy makers of the costs and benefits of alternative pathways for the future of global biodiversity.
Dynamics of genetic code evolution: The emergence of universality
Authors: Argyriadis John-Antonio , He Yang-Hui , Jejjala Vishnu , Minic Djordje
Published: September 2019

Abstract

We study the dynamics of genetic code evolution. The algorithm of Vetsigian et al. [1] provides a solution that is both optimal and universal. We reproduce and analyze the algorithm as a dynamical system. All the parameters used in the model are varied to assess their impact on achieving universality. We show that by allowing specific parameters to vary with time, the algorithm converges much faster to a universal solution. Finally, we study automorphisms of the genetic code arising due to this model. We use this to examine the scaling of the solutions in order to understand the origin of universality and find that there is a direct link to mutation rate.
United States wildlife and wildlife product imports from 2000-2014
Authors: Eskew Evan A. , White Allison M. , Ross Noam , Smith Kristine M. , Smith Katherine F. , Rodríguez Jon Paul , Zambrana-Torrelio Carlos , Karesh William B. , Daszak Peter
Published: September 2019

The global wildlife trade network is a massive system that has been shown to threaten biodiversity conservation, introduce non-native species and pathogens, and cause chronic animal welfare concerns. Despite its scale and impact, comprehensive characterization of the global wildlife trade is hampered by data that are limited in their temporal or taxonomic scope and detail. To help fill this gap, we present data on 15 years of the importation of wildlife and their derived products into the United States (2000-2014), originally collected by the United States Fish and Wildlife Service. We curated and cleaned the data and added taxonomic information to improve data usability. These data include > 2 million wildlife or wildlife product shipments, representing > 60 biological classes and > 3.2 billion live organisms. These data will be broadly useful to both scientists and policymakers seeking to better understand the volume, sources, biological composition, and potential risks of the global wildlife trade.
Pancreatic Islets Communicate With the Brain via Vagal Sensory Neurons
Authors: Makhmutova Madina , Weitz Jonathan , Tamayo Alejandro , Pereira Elizabeth , Almaça Joana , Rodriguez-Diaz Rayner , Caicedo Alejandro
Published: September 2019

Depleting visceral sensory nerves affects pancreatic islet function, glucose metabolism and diabetes onset, but how islet endocrine cells interact with sensory neurons has not been studied. Here we show that the pancreatic islet is innervated by vagal sensory axons expressing substance P, calcitonin-gene related peptide, and serotonin receptor 5HT3R. Vagal neurons projecting to the pancreas terminate in the commissural nucleus of the solitary tract. These neurons respond to chemical but not mechanical stimulation of the pancreas. By recording activity from nodose neurons in vivo and from sensory axons in living pancreas slices, we show that sensory nerves respond to serotonin secreted from stimulated beta cells. Serotonin is co-released with insulin and therefore conveys information about the secretory state of beta cells via vagal afferent nerves. Our study thus establishes that pancreatic islets communicate with the brain using the neural route and identifies serotonin signaling as a peripheral transduction mechanism.
Large single-locus effects for maturation timing are mediated via body condition in Atlantic salmon
Authors: Debes Paul V , Piavchenko Nikolai , Ruokolainen Annukka , Ovaskainen Outi , Moustakas-Verho Jacqueline E , Parre Noora , Aykanat Tutku , Erkinaro Jaakko , Primmer Craig R
Published: September 2019

Maturation timing is a pivotal life-history trait balancing probabilities between mortality and reproduction. Environmental vs. genetic contributions to traits associated with maturation initiation, such as growth and body condition, remain uncertain because of difficulties in determining causality. In Atlantic salmon, maturation timing associates with a large-effect locus around vgll3, but how this locus affects maturation remains unknown. We combined controlled breeding with common-garden experimentation at two temperatures and show that vgll3 effects on maturation of males express primarily via body condition, which we demonstrate in the males’ non-maturing female relatives, thus avoiding reverse causality. Between homozygous vgll3 genotypes, maturation probability differed several folds and female condition differed 2% in both temperature environments. Vgll3 effects explained 25 and 16% of maturation probability heritability and 15 and 6% of female condition heritability, in the warm and cold environment, respectively. Non-significant vgll3 effects on female length were antagonistic to those on condition but of equal proportional size. When controlling for vgll3 effects, genetic correlations changed antagonistically between both maturation and condition vs. growth, suggesting vgll3 as a resource-allocation locus. The results support large vgll3 maturation effects being mediated via environmentally stable body condition effects, enabling rapid co-evolution between the life-history traits.
Unusual genome expansion and transcription suppression in ectomycorrhizal Tricholoma matsutake by repetitive insertions of transposable elements
Authors: Min Byoungnam , Yoon Hyeokjun , Park Julius , Oh Youn-Lee , Kong Won-Sik , Kim Jong-Guk , Choi In-Geol
Published: September 2019

Genome sequence of Tricholoma matsutake was revealed as the one of the large fungal genomes published up to date at 189.0 Mbp with 15,305 predicted genes. The unusual size of this fungal genome contained frequent colonization of transposable elements (TEs) occupying more than half of the entire genome. We identified that 702 genes were surrounded by TEs and 83.2% of those genes were never transcribed at any development stage. This observation corroborated that the insertion of transposable elements alters the transcription of the genes neighboring TEs.

Repeat-induced point mutation such as C to T hypermutation with a bias over ’CpG’ dinucleotides was also recognized in this genome, representing a typical defense mechanism against TEs during evolution. Many transcription factor genes were activated in both primordia and fruiting body, which indicates that many regulatory processes are shared during developmental stages. Small secreted protein genes (<300 aa) were dominantly transcribed in hyphae, where symbiotic interactions occur with hosts. Comparative analysis with 37 Agaricomycetes genomes revealed that IstB-like domain (PF01695) was conserved in taxonomically diverse mycorrhizal genomes, where the T. matsutake genome contained four copies of this domain. Three of the IstB-like genes were overexpressed in hyphae. In the CAZyme analysis, reduced CAZyme genes were found as other ectomycorrhizal genomes including a lot of loss of glycoside hydrolase genes. Also, auxiliary activity genes were dominantly transcribed in primordia. The T. matsutake genome sequence provides insight into the large genome size and clues to understand unusual fungal genome expansion.
Seasonal influenza circulation patterns and projections for September 2019 to September 2020
Authors: Bedford Trevor , Huddleston John , Potter Barney , Neher Richard A.
Published: September 2019

This report details current seasonal influenza circulation patterns as of August 2019 and makes projections up to September 2020 to coincide with selection of the 2020 Southern Hemisphere vaccine strain. This is not meant as a comprehensive report, but is instead intended as particular observations that we’ve made that may be of relevance. Please also note that observed patterns reflect the GISAID database and may not be entirely representative of underlying dynamics. All analyses are based on the nextflu/nextstrain pipeline [1,2] with continual updates posted to nextstrain.org/flu. A/H3N2: A/H3N2 viruses continue to show substantial diversity in HA sequences with a deep split between 3c3.A and 3c2.A1b viruses. The most notable recent developments are the rapid rise of clade A1b/137F – a subclade of A1b/135K – in China and Bangladesh and clade A1b/197R – a subclade of A1b/131K – which dominates the ongoing season in Australia. Our models predict that A1b/137F and A1b/197R will be the dominant clades next year with A1b/197R accounting for most circulation. There is, however, large uncertainty in the true extent of A1b/137F circulation. A/H1N1pdm: The S183P substitution has risen to near fixation. The most successful subclade carrying this mutation is 183P-5 which has essentially replaced competing variants. A variant with substitutions 129D/185I is at 60% prevalence globally, while a second variant with substitution 130N is at 50% in North America and ~10% elsewhere. Substitutions at site 156 to D or K have arisen sporadically and result in loss of recognition by antisera raised against viruses with asparagine at position 156. Despite the large antigenic effect, viruses with mutations at site 156 don’t seem to spread. Beyond variants at site 156, little to no antigenic evolution is evident in assays with ferret antisera. B/Vic: Antigenically drifted deletion variants at HA1 sites 162, 163 and 164 are now dominating global circulation and have all but taken over. The double deletion variant V1A.1 had previously been circulating at high frequency in the Americas. However, over the course of 2009, the triple deletion variant V1A.3 has increased in frequency globally and is now dominating in all geographic regions. Importantly, V1A.1 and V1A.3 variants appear antigenically distinct by HI assays with 4-8 fold reductions in log2 titer in both directions. B/Yam: B/Yam has not circulated in large numbers since the Northern Hemisphere season 2017/2018 and displays relatively little amino acid variation in HA or antigenic diversity. Amino acid variants at sites 229 and 232 have begun to circulate and population is now split between 229D/232D, 229N/232D and 229D/232N variants. These variants show little sign of antigenic difference in HI assays.
Quantitative analysis of the ubiquitin-proteasome system under proteolytic and folding stressors
Authors: Work Jeremy J. , Brandman Onn
Published: September 2019

Aging, disease, and environmental stressors are associated with failures in the ubiquitin-proteasome system (UPS), yet a quantitative understanding of how stressors affect the proteome and how the UPS responds is lacking. Here we assessed UPS performance and adaptability in yeast under stressors using quantitative measurements of misfolded substrate stability and stress-dependent UPS regulation by the transcription factor Rpn4. We found that impairing degradation rates (proteolytic stress) and generating misfolded proteins (folding stress) elicited distinct effects on the proteome and on UPS adaptation. Folding stressors stabilized proteins via aggregation rather than overburdening the proteasome, as occurred under proteolytic stress. Still, the UPS productively adapted to both stressors using separate mechanisms: proteolytic stressors caused Rpn4 stabilization while folding stressors increasedRPN4transcription. In some cases, adaptation completely prevented loss of UPS substrate degradation. Our work reveals the distinct effects of proteotoxic stressors and the versatility of cells in adapting the UPS.
Comparative genomics for the elucidation of multidrug resistance (MDR) inCandida lusitaniae
Authors: Kannan Abhilash , Asner Sandra A. , Trachsel Emilie , Kelly Steve , Parker Josie , Sanglard Dominique
Published: September 2019

Multidrug resistance (MDR) has emerged in hospitals due to the use of several agents administered in combination or sequentially to the same individual. We reported earlier MDR inCandida lusitaniaeduring therapy with amphotericin B (AmB), azoles and candins. We used here comparative genomic approaches between the initial susceptible isolate and 4 other isolates with different MDR profiles. From a total of 18 non-synonymous SNPs (NSS) in genome comparisons with the initial isolate, six could be associated with MDR. One of the SNPs occurred in a putative transcriptional activator (MRR1) resulting in a V668G substitution in isolates resistant to azoles and 5-fluorocytosine (5-FC). We demonstrated by gene editing thatMMR1acted by upregulation ofMFS7(a multidrug transporter) in the presence of the V668G substitution.MFS7itself mediated not only azole resistance but also 5-FC resistance, which represents a novel resistance mechanism for this drug class. Three other distinct NSS occurred inFKS1(a glucan synthase that is targeted by candins) in three candin-resistant isolates. Lastly, two other NSS inERG3andERG4(ergosterol biosynthesis) resulting in non-sense mutations were revealed in AmB-resistant isolates, one of which accumulated the 2ERGNSS. AmB-resistant isolates lacked ergosterol and exhibited sterol profiles consistent withERG3andERG4defects. In conclusion, this genome analysis combined with genetics and metabolomics helped to decipher the resistance profiles identified in this clinical case. MDR isolates accumulated 6 different mutations conferring resistance to all antifungal agents used in medicine. This case study illustrates the capacity ofC. lusitaniaeto rapidly adapt under drug pressure within the host.

Importance

Antifungal resistance is an inevitable phenomenon when fungal pathogens get exposed to antifungal drugs. These drugs can be grouped in 4 distinct classes (azoles, candins, polyenes, pyrimidine analogs) and are used in different clinical settings. Failures in therapy implicates the sequential or combined use of these different drug classes, which can result in some cases in the development of multidrug resistance (MDR). MDR is particularly challenging in the clinic since it drastically reduces possible treatment alternatives. In this study, we report the rapid development of MDR inCandida lusitaniaein a patient, which became resistant to all known antifungal agents used up to now in medicine. To understand how MDR developed inC. lusitaniae, whole genome sequencing followed by comparative genome analysis was undertaken in sequential MDR isolates. This helped to detect all specific mutations linked to drug resistance and explained the different MDR patterns exhibited by the clinical isolates.
Strain-dependent impact of G and SH deletions provide new insights for live-attenuated HMPV vaccine development
Authors: Dubois Julia , Pizzorno Andrés , Cavanagh Marie-Hélène , Padey Blandine , de Lamballerie Claire Nicolas , Uyar Olus , Venable Marie-Christine , Carbonneau Julie , Traversier Aurélien , Julien Thomas , Couture Christian , Lina Bruno , Hamelin Marie-Ève , Terrier Olivier , Rosa-Calatrava Manuel , Boivin Guy
Published: September 2019

Human metapneumovirus (HMPV) is a major pediatric respiratory pathogen with currently no specific treatment or licensed vaccine. Different strategies to prevent this infection have been evaluated, including live-attenuated vaccines (LAV) based on SH and/or G protein deletions. This approach showed promising outcomes but has not been evaluated further using different viral strains. In that regard, we previously showed that different HMPV strains harbor distinct in vitro fusogenic and in vivo pathogenic phenotypes, possibly influencing the selection of vaccine strains. In this study, we investigated the putative contribution of the low conserved SH or G accessory proteins in such strain-dependent phenotypes and generated recombinant wild type (WT) and SH- or G-deleted viruses derived from two different patient-derived HMPV strains, A1/C-85473 and B2/CAN98-75.

The ΔSH and ΔG deletions led to different strain-specific phenotypes in both LLC-MK2 cell and reconstituted human airway epithelium models. More interestingly, the ΔG-85473 and especially ΔSH-C-85473 recombinant viruses conferred significant protection against HMPV challenge and induced immunogenicity against a heterologous strain. In conclusion, our results show that the viral genetic backbone should be considered in the design of live-attenuated HMPV vaccines, and that a SH-deleted virus based on the A1/C-85473 HMPV strain could be a promising LAV candidate as it is both attenuated and protective in mice while being efficiently produced in a cell-based system.
Evidence of adaptive host and vector manipulation by plant viruses revealed through combined meta-analysis and modeling approaches
Authors: Chesnais Quentin , Bahlai Christie A. , Peace Angela , Crowder David W. , Bosque-Pérez Nilsa A. , Mauck Kerry
Published: September 2019

A growing number of studies indicate that plant viruses enhance their own transmission by modifying host phenotypes and vector behavior, leading to the hypothesis that such effects are manipulations resulting from virus adaptations. However, few studies have linked putative manipulations with virus components, and the true frequency and magnitude of host and vector manipulation across virus taxa remains unknown. To address this knowledge gap, we performed a meta-analysis to quantify convergence in virus effects on hosts and vectors across taxonomic groups that share transmission mechanism traits, and thereby stand to benefit from similar sequences of vector behavior. We then combined meta-analysis outputs with an epidemiological model to assess consequences of manipulation for virus spread. Overall, transmission mechanism traits strongly predicted the magnitude and nature of virus effects on vector preferences and performance. Models parameterized with meta-analysis data demonstrate that manipulation effects enhance virus spread, and that viruses with long acquisition times and retention durations are under strong selection pressure to manipulate transmission. By combining meta-analysis with epidemiological modeling, our results confirm that host and vector manipulation are important aspects of plant virus ecology and evolution while emphasizing the need to incorporate more pathosystems and transmission mechanism traits in future studies.
Persistent Cyfip1 expression is required to maintain the adult subventricular zone neurogenic niche
Authors: Habela Christa Whelan , Yoon Ki-Jun , Kim Namshik , Taga Arens , Bell Kassidy , Bergles Dwight E. , Maragakis Nicholas J. , Ming Guo-li , Song Hongjun
Published: September 2019

Neural stem cells (NSCs) persist throughout life in the subventricular zone (SVZ) niche of the lateral ventricles as B1 cells. Maintaining this population of NSCs depends on the balance between quiescence and self-renewing or self-depleting proliferation. Interactions between B1 cells and the surrounding niche are important in regulating this balance, but the mechanisms governing these processes have not been fully elucidated in adult mammals. The cytoplasmic FMRP-interacting protein (CYFIP1) regulates apical-basal polarity in the embryonic brain. Loss of Cyfip1 during embryonic development in mice disrupts the embryonic niche and affects cortical neurogenesis. However, a direct role for Cyfip1 in the regulation of adult NSCs has not been established. Here, we demonstrate that Cyfip1 expression is preferentially localized to B1 cells in the adult SVZ. Loss of Cyfip1 in the embryonic mouse brain results in altered adult SVZ architecture and expansion of the adult B1 cell population at the ventricular surface. Furthermore, acute deletion ofCyfip1in adult NSCs results in a rapid change in adherens junction proteins as well as increased proliferation and the number of B1 cells at the ventricular surface. Together, these data indicate that CYFIP1 plays a critical role in the formation and maintenance of the adult SVZ niche and, furthermore, deletion of Cyfip1 unleashes the capacity of adult B1 cells for symmetric renewal to increase the adult NSC pool.

SIGNIFICANCE

Neural stem cells (NSCs) persist in the subventricular zone (SVZ) of the lateral ventricles in adult mammals and their population is determined by the balance between quiescence and self-depleting or renewing cell division. The mechanisms regulating their biology are not fully understood. This study establishes that the cytoplasmic FMRP interacting protein 1 (Cyfip1) regulates NSC fate decisions in the adult SVZ and NSCs that are quiescent or typically undergo self-depleting divisions retain the ability to self-renew in the adult. This contributes to our understanding of how adult NSCs are regulated throughout life and has potential implications for human brain disorders.
Information asymmetry, third party certification and the integration of organic food value chain in China
Authors: Zhao Jiang , Gerasimova Ksenia , Peng Yala , Sheng Jiping
Published: September 2019

Purpose

The purpose of this paper is to discuss characteristics of organic food value chain governance and policy tools that can increase the supply of good quality of agri-products.

Design/methodology/approach

This paper discusses a national organic food supply system in China, identifying the link between an organization form with a social confidence crisis and information asymmetry as the main challenges. It develops an analytical model of the market structure of organic certification based on the contract theory, which considers the certification incentive driven by both farmers and processors. Two cases of raw milk producers and processors provide empirical data.

Findings

The argument which is brought forward is that product information asymmetry together with strict requirement for ensuring organic food integrity brings the organic milk value chain into a highly integrated organization pattern. A tight value chain is effective in the governance of organic food supply chain under third party certification (TPC), while a loose value chain discourages producing organic products because of transaction costs. TPC is found to be a positively correlation with a tight value chain, but it brings high organizational cost and it raises cost for consumers.

Originality/value

This is the first paper discussing the governance of organic food value chain in Chinese milk industry.
Capital market penalties to radical and incremental innovation
Authors: Hain Daniel Stefan , Lindgaard Christensen Jesper
Published: September 2019

Purpose

The purpose of this paper is to investigate how access to financing for incremental as well as radical innovation activities is affected by firm-specific structural and behavioral characteristics.

Design/methodology/approach

Deploying a two-stage Heckman probit model on survey data spanning the period 2000–2013 and covering 1,169 firms, this paper analyzes the effect of a firm’s engagement in incremental and radical innovation on its likelihood to get constrained in their access to external finance, and how this effect is moderated by the firm’s age and size.

Findings

In line with earlier research, it is confirmed that the type of innovation matters for the access to external finance, but in a more nuanced way than generally portrayed. While incremental innovation activities have little negative effect on the access to external finance, radical innovation activities tend to be penalized by capital markets. This effect appears to be particularly strong for small firms.

Originality/value

This paper provides nuanced insights into the interplay between types of firm-level innovation activities, structural characteristic and access to external finance.
A new typology to characterize Italian digital entrepreneurs
Authors: Ammirato Salvatore , Sofo Francesco , Felicetti Alberto Michele , Helander Nina , Aramo-Immonen Heli
Published: September 2019

Purpose

Strong agreement in the extant business literature emphasizes that digital developments are key to economic growth internationally. This is in spite of the recorded high levels (up to 50 percent) of failure among digital companies and entrepreneurs. The purpose of this paper is to identify the digital debates in Italy, explore current policies and develop a typology that characterizes digital entrepreneurs (DEs) and their start-up companies in Italy.

Design/methodology/approach

The digital debates and policies are explored through an extensive telephone survey of the self-perceptions and identified supports required by 348 Italian active DEs. Quantitative statistical techniques were used including factor analysis, cluster analysis and ANOVA, to identify motivations, profiles and critical success factors relevant to the sample.

Findings

The study identifies three main clusters among the DEs: emerging very young; emerging business focused and experienced. These clusters vary with the entrepreneurs’ background and competence base, motivation and satisfaction factors. The different kinds of profiles require specific kinds of supporting policies identified by the sample that focus on financial, educational and/or networking provision.

Originality/value

The paper affirms the central role of digital entities in modern economies expressed in the current literature and increases knowledge of the perceived success factors identified by DEs. The identification and classification of self-reported characteristics of Italian DEs and to what extent these characterizations might be useful for tailored interventions to support their success are the main contributions of this study. Accordingly, an authentic, original and self-reported portrayal has been constructed of the self-perceptions of Italian DEs. Finally, the study explores the implications for actions and new policies considering self-perceived profiles, needs and expectations of DEs.
Does trade interdependency lead linkages between stock markets? A case of South Asian countries
Authors: Kumar Rakesh
Published: September 2019

Purpose

The purpose of this paper is to test the dynamic linkages among the stock markets of four South Asian countries (India, Pakistan, Bangladesh and Sri Lanka) in the backdrop of trade interdependency.

Design/methodology/approach

Listed indices are used to serve the proxy of stock markets of four countries for the period: January 2000–December 2018. The study uses the autoregressive distributed lag model and Granger causality techniques in multivariate frameworks while focusing on intraregional trade as an exogenous factor for testing the long- and short-run causality in the given data set, hence raising the quality of statistical inference.

Findings

The results highlight that India and Pakistan are net exporters to the South Asian region, while Bangladesh and Sri Lanka are net importers from the region. While testing the stock markets linkages, the expanded intraregional trade volumes (exports plus imports) have occurred with the significant cointegration of stock markets of India and Pakistan with the other stock markets in the long run. In the short run, the stock markets of India, Pakistan and Sri Lanka report bidirectional causality without having significant spillovers of intraregional trade on the stock prices.

Research limitations/implications

The study relies on the multivariate techniques with stock prices and regional trade share as the exogenous variables. Further the regulatory, political and economic conditions of sample countries are fundamentally different which in turn affect their degree of trade interdependency and integration between the stock markets.

Practical implications

Nonsignificant cointegration of the stock markets of Sri Lanka and Bangladesh highlights the possibility of portfolio diversification in the long run, while the significant bidirectional causalities between the stock markets highlight the lesser degree of portfolio diversifications in the short run.

Originality/value

Pioneer efforts are made to examine the dynamic linkages between the South Asian stock markets while focusing on regional trade interdependency. The results provide new insight in the dynamics of stock returns of South Asian stock markets in the backdrop of intraregional trade.
The importance of university, students and students’ union partnerships in student-led projects
Authors: Briggs Sarah Jayne , Robinson Zoe P. , Hadley Rachel Louise , Laycock Pedersen Rebecca
Published: September 2019

Purpose

This paper aims to explore a single-institution case study of partnership working between students, the University and Students’ Union, through four student-led sustainability projects. The paper analyses the role and value of these partnerships and provides advice for other institutions on effective partnership working between these stakeholders.

Design/methodology/approach

A single case study of partnership working with multiple embedded units of analysis (four projects) is presented based on reflections of practitioners involved in the projects who have different roles within the University and Students’ Union.

Findings

The longevity and effectiveness of student-led projects, and disciplinary-breadth of students engaged, can be enhanced by greater collaboration with, and integration into, University and Students’ Union systems. Partnership working between different stakeholders is key to overcoming challenges and the success of student-led projects, helped by key staff “enablers”. These projects provide myriad learning opportunities for developing change agency skills, even where projects are relatively short-lived and could be seen as failures in terms of longevity.

Research limitations/implications

This analysis is based solely on practitioner reflections, with limited direct quantification or qualitative data on the projects’ impacts on the students themselves.

Originality/value

This paper draws together the experiences and reflections of four practitioners with different roles within the University and Students’ Union across four different projects and provides advice to generate student-led sustainability projects which have longevity and impact for wider student populations and future generations of cohorts.