bluuebunny/crossref_metadata_2025 huggingface dataset:
Duroc boars have lower progeny mortality and lower fertility than Pietrain boars1
Authors: Pedersen Marie Louise M , Velander Ingela H , Nielsen Mai Britt F , Lundeheim Nils , Nielsen Bjarne
Published: April 2019

In pig production, Pietrain and Duroc lines are often used as terminal sire lines to produce crossbred slaughter pigs. The objective of this study was to identify the differences in paternal fertility and mortality during the suckling period of crossbred progeny from Pietrain and Duroc terminal sire lines. In total, 87 purebred Duroc boars and 68 purebred Pietrain boars were used as terminal sires to produce 1,823 crossbred Duroc litters (D-litters) and 1,705 crossbred Pietrain litters (P-litters) in two production herds. The sows were crosses between DanBred Landrace and Yorkshire (F1). All boars were kept at the same artificial insemination (AI) station, and all semen doses were produced in the same laboratory. The experiment was balanced according to herd, boars, and time, with approximately 13 sows from each herd mated to each boar within each breed. The results showed higher fertility expressed as litter size at birth in P-litters compared with D-litters led to 0.5 higher total number born (TNB) for P-litters (P = 0.0076). However, piglet mortality including number of stillborn piglets was lower in D-litters compared with P-litters (P < 0.0001), and 5 d after farrowing, the average litter size in P-litters ranged 0.4 below the litter size in D-litters (P < 0.027). At 21 d after birth, mean litter size in P- and D-litters were 14.5 and 14.9 piglets per litter, respectively (P < 0.015). This indicated that Pietrain progenies were weaker than Duroc progenies, and it was concluded that use of Duroc boars as the terminal sire line led to lower piglet mortality. In the two herds, the mean piglet mortality rate including still born piglets ranged from 19.5% to 23.6% and from 17.6% to 19.1% in P- and D-litters, respectively.
New pieces in the transmission cycle of the hepatitis E virus in South America: first viral detection in wild boars from Argentina
Authors: Pisano María Belén , Winter Marina , Raimondo Natalia , Martínez-Wassaf Maribel G , Abate Sergio D , Ré Viviana E
Published: April 2019

Background

The hepatitis E virus (HEV) causes hepatitis worldwide. In Europe, wild boars are known to be viral reservoirs and sources of infection. In South America, there is a lack of information about HEV in these animals.

Methods

A total of 102 wild boar serum samples from Argentina (2014–2017) were studied for serological and molecular HEV detection.

Results

We obtained a seroprevalence of 19.6%, similar to that recently described in Uruguay (the only antecedent in South America). HEV ribonucleic acid (RNA) was amplified in two anti-HEV-positive samples.

Conclusions

This is the first report of HEV circulation in wild boars from Argentina, adding evidence to the findings obtained in Uruguay indicating that wild boars could be viral reservoirs in South America.
Cost-Effectiveness Analysis of Total Neoadjuvant Therapy Followed by Radical Resection Versus Conventional Therapy for Locally Advanced Rectal Cancer
Authors: Wright Moriah E. , Beaty Jennifer S. , Thorson Alan G. , Rojas Ruben , Ternent Charles A.
Published: April 2019

BACKGROUND:

Definitive surgery with total mesorectal excision is the mainstay of treatment for locally advanced rectal cancer. Multimodality therapy improves long-term survival. Current standards advise neoadjuvant chemoradiation followed by radical surgery and adjuvant chemotherapy. Nationally, compliance with adjuvant chemotherapy is only 32%. New research evaluates the effectiveness of total neoadjuvant therapy: complete chemotherapy and chemoradiation before surgery.

OBJECTIVE:

The aim of this study is to determine the favored treatment for locally advanced rectal cancer by comparing the cost-effectiveness of total neoadjuvant therapy and the current standard of care.

DESIGN:

Decision analytical modeling using long-term costs and 5-year disease-free survival was performed to determine the cost-effectiveness after total neoadjuvant therapy and the current standard of care. Sensitivity analysis was used to investigate the effect of uncertainty in model parameters.

SETTINGS:

Centers for Medicare & Medicaid Services billing data perspective was adopted and outcomes modeled according to local and national databases and literature consensus.

PATIENTS:

Adult patients with stage II or III rectal cancer were selected.

MAIN OUTCOME MEASURES:

Cost-effectiveness in disease-free life-years, incremental cost-effectiveness ratio, and net monetary benefit were determined over a 5-year posttreatment period. The favored strategy was determined based on cost-effectiveness and sensitivity analyses.

RESULTS:

Cost-effectiveness for total neoadjuvant therapy was 40,708 $/life-year, and, for conventional therapy, cost-effectiveness was 44,248 $/life-year. Sensitivity analysis showed that, for an estimated total neoadjuvant therapy completion rate of 90%, total neoadjuvant therapy would remain the dominant strategy for any adjuvant chemotherapy completion rate of less than 93%.

LIMITATIONS:

The samples used to calculate completion rates are small, and survival probabilities are based on existing literature, local database values, and consensus estimates. The model encompasses a 5-year time period from diagnosis.

CONCLUSIONS:

Cost-effectiveness analysis shows that a strategy of total neoadjuvant therapy followed by radical surgery is favored over the current standard of care for locally advanced rectal cancer. Sensitivity analysis shows that a low rate of adjuvant chemotherapy administration plays a key role in decreasing the cost-effectiveness of the current standard of care. See Video Abstract at http://links.lww.com/DCR/A942.
Would Stronger Seat Belt Laws Reduce Motor Vehicle Crash Deaths?
Authors: Harper Sam
Published: April 2019

Background:

For policy questions where substantial empirical background information exists, conventional frequentist policy analysis is hard to justify. Bayesian analysis quantitatively incorporates prior knowledge, but is not often used in applied policy analysis.

Methods:

We combined 2000–2016 data from the Fatal Analysis Reporting System with priors based on past empirical studies and policy documents to study the impact of mandatory seat belt laws on traffic fatalities. We used a Bayesian data augmentation approach to combine information from prior studies with difference-in-differences analyses of recent law changes to provide updated evidence on the impact that upgrading to primary enforcement of seat belt laws has on fatalities.

Results:

After incorporating the evidence from past studies, we find limited evidence to support the hypothesis that recent policy upgrades affect fatality rates. We estimate that upgrading to primary enforcement reduced fatality rates by 0.37 deaths per billion vehicle miles traveled (95% posterior interval -0.90, 0.16), or a rate ratio of 0.96 (95% posterior interval 0.91, 1.02), and increased the proportion of decedents reported as wearing seat belts by 7 percentage points (95% posterior interval 5, 8), or a risk ratio of 1.18 (95% posterior interval 1.13, 1.24).

Conclusions:

Bayesian methods can provide credible estimates of future policy impacts, especially for policy questions that occur in dynamic environments, such as traffic safety.
Factors Affecting Corneal Organ Culture Contamination: A 6-year Study at the New South Wales Tissue Bank
Authors: Ling Melvin L. H. , Wells Matthew , Petsoglou Constantinos , Luo Kehui , Georges Pierre , Devasahayam Raj , Hodge Christopher , Treloggen Jane , Sutton Gerard , Zhu Meidong
Published: April 2019

Purpose:

To report the rate of microbial contamination and analyze possible risk factors for contamination of banked corneas stored using the organ culture method.

Methods:

Data from the New South Wales Tissue Banks incorporating the Lions NSW Eye Bank, between September 1, 2011, and November 30, 2017, were reviewed retrospectively. All corneas collected during this period and stored in organ culture storage media were tested for microbial contamination. The influence of potential factors on the rate of contamination was analyzed using the χ2 test and logistic regression using generalized estimating equations.

Results:

A total of 4410 corneas were included in this study, of which 110 were medium culture positive, representing a microbial contamination rate of 2.5%. The main contaminants were Candida species followed by Staphylococcus species. Corneal tissue collected in summer and autumn had a significantly higher contamination rate (P = 0.006). All other factors studied were not shown to have a statistically significant association with contamination after accounting for within-pair correlation and confounders.

Conclusions:

A relatively low contamination rate of 2.5% observed in our study reflects the stringent laboratory protocols, strict donor selection criteria, and high level of experience among staff at the Lions NSW Eye Bank. Our study demonstrated that the season of collection had a strong association with the rate of organ culture contamination. Because Candida species contributed the largest percentage of contamination, specific measures to reduce and eliminate fungal proliferation should be considered by eye banks particularly in warm seasons.
Corneal Edema Associated With Systemic Dopaminergic Agents
Authors: Mancera Norberto , Wadia Hormuz P.
Published: April 2019

Purpose:

To describe the development and resolution of corneal edema in 3 patients who were exposed to compounds that stimulate dopaminergic pathways.

Methods:

We conducted a review of the literature on bilateral corneal edema secondary to amantadine use and report a case series of corneal edema seen in an outpatient ophthalmology specialty clinic, shortly after exposure to agents that enhance dopamine transmission.

Results:

Cases 1 and 2 report a 25-year-old man with attention-deficit hyperactivity disorder and a 73-year-old man with Parkinson disease who were placed on dopaminergic medications to treat their conditions. The former was administered methylphenidate and the latter patient was administered ropinirole. Both patients developed corneal edema soon afterward. Case 3 is a 67-year-old man with a recent exposure to resin from Euphorbia resinifera, a cactus in his garden. After cessation of the offending medications and treatment for exposure to resiniferatoxin, the corneal edema progressively resolved and visual acuity returned to baseline in all 3 cases.

Conclusions:

Methylphenidate, ropinirole, and resiniferatoxin have different mechanisms of actions but have a common end point leading to increased dopamine. We believe that these agents are linked with the reversible corneal edema seen in our 3 patients. This strongly correlates with previous studies that have linked amantadine, a drug that blocks dopamine reuptake, to reversible corneal edema.
Relationship between pre-sarcopenia and quality of life in patients with chronic liver disease: a cross-sectional study
Authors: Ohashi Kazuki , Ishikawa Toru , Imai Michitaka , Suzuki Mitsuyuki , Hoshii Asami , Abe Hiroko , Koyama Fujiko , Nakano Tomomi , Ueki Aya , Noguchi Hirohito , Hasegawa Erina , Hirosawa Shiori , Kobayashi Miki , Hirosawa Hiroshi , Sato Kaede , Munakata Miyu , Yoshida Toshiaki
Published: April 2019

Aim

This study aimed to clarify the relationship between pre-sarcopenia (PS) and quality of life (QOL) in patients with chronic liver disease (CLD).

Patients and methods

This cross-sectional study evaluated 335 patients with CLD. PS was diagnosed on the basis of the assessment criteria by the Japan Society of Hepatology. QOL was evaluated using the short form-36.

Results

Patients’ mean age was 69.52 ± 10.17 years, and 169 (50.4%) participants were men. The prevalence of PS was 53.7%. Patients were divided into the PS and non-pre-sarcopenia (NPS) groups. Patients in the PS group were older (71.84 ± 9.78 vs. 66.81 ± 9.97, P < 0.01) and mostly women (65.2 vs. 37.8%, P < 0.01) compared with those in the NPS group. QOL, physical function (38.30 ± 17.63 vs. 44.02 ± 14.76, P < 0.01), physical role functioning (RP) (40.63 ± 15.38 vs. 44.88 ± 13.89, P < 0.01), and bodily pain (BP) (48.42 ± 11.45 vs. 51.24 ± 10.19, P = 0.02) were significantly lower in the PS group than in the NPS group. Logistic regression analyses identified that the independent predictive factors for PS were female sex (odds ratio: 3.16, 95% confidence interval: 2.01–4.98; P < 0.01) and RP (odds ratio: 1.97, 95% confidence interval: 1.24–3.12; P < 0.01).

Conclusion

QOL characteristics of PS patients with CLD were low physical function, RP, and BP in short form-36. In addition, social role functioning was low in the PS patients aged 65–74 years, whereas RP and BP were low in those aged at least 75 years. Female sex and RP were independent predictors of PS according to the multivariate analysis. Maintaining and increasing muscle mass in patients with CLD may contribute toward improving physical QOL.
Lung donation after circulatory death
Authors: Ceulemans Laurens J. , Inci Ilhan , Van Raemdonck Dirk
Published: April 2019

Purpose of review

The current review presents a concise update on published literature on donation after circulatory death (DCD) and lung transplantation (LTx). Worldwide an increasing need for lungs is evident, however the utilization rate of DCD lung donors is still considerably low. In this summary article, we reviewed both the experimental background and international clinical experience.

Recent findings

Our analysis confirmed satisfactory results for LTx from DCD donors, which equals the results from donation after brain death. Although most studies reported on short-term results, some confirmed these results on the long-term and development of chronic lung allograft dysfunction. Our review summarizes the different DCD categories and underlines the potential of the DCD V category. We analyze the barriers to implement a DCD program, discuss the more recent advances like ex-vivo lung perfusion and describe the future challenges.

Based on the current short-term and long-term clinical results, we believe that barriers for DCD utilization should be overcome, resulting in a safe implementation of more DCD LTx programs worldwide.

Video abstract

http://links.lww.com/MOT/A23
Immersive Virtual Reality Mirror Therapy for Upper Limb Recovery After Stroke
Authors: Weber Lynne M. , Nilsen Dawn M. , Gillen Glen , Yoon Jin , Stein Joel
Published: April 2019

Objective

This study was designed to examine the feasibility of immersive virtual reality mirror therapy for upper limb paresis after stroke using a head-mounted display and provide preliminary evidence of efficacy.

Design

Ten outpatients with chronic stroke, upper limb hemiparesis, and a low predisposition for motion sickness completed a 12-session program of 30 mins each of immersive virtual reality mirror therapy. The virtual reality system provided the illusion of movement in the hemiparetic upper limb while suppressing the visual representation of the nonparetic side. Feasibility was assessed via patient compliance, adverse event tracking, the System Usability Scale, and the Simulator Sickness Questionnaire. Preliminary efficacy was evaluated using the Fugl-Meyer Upper Extremity and Action Research Arm Test.

Results

Immersive virtual reality mirror therapy for patients with chronic stroke was safe, well-tolerated, and without adverse events, such as simulator sickness. Motor outcomes revealed a small improvement for the Fugl-Meyer Upper Extremity from 21.7 (SD = 8.68) to 22.8 (SD = 9.19) that did not achieve statistical significance (P = 0.084).

Conclusions

Four weeks of immersive virtual reality mirror therapy was well-tolerated by chronic stroke patients. Our findings support further clinical trials of immersive virtual reality technologies and visually enhanced mirror therapies for stroke survivors.
Renal Lymphangiectasia in the Transplanted Kidney: Case Series and Literature Review
Authors: Dawidek Mark T. , Aquil Shahid , Alogaili Rafid , Gabril Manal , Moussa Madeleine , Sener Alp , Luke Patrick P.
Published: April 2019

Background.

Renal lymphangiectasia is a rare and poorly understood lymphatic disease associated with lymphatic dilation and leakage. To our knowledge, no cases have been described in the context of a transplanted kidney.

Methods.

We describe 2 cases of renal lymphangiectasia in transplanted kidneys, both from pediatric donors.

Results.

The cases of allograft lymphangiectasia are characterized by severe, symptomatic ascites refractory to attempts at medical and surgical management, and ultimately requiring allograft nephrectomy.

Conclusions.

While lymphatic complications, particularly lymphoceles, are not uncommon in renal transplantation, lymphangiectasia is a distinct condition which should be considered in renal transplant patients with ascites, after all other sources have been ruled out.
SHMT2 Promotes Liver Regeneration Through Glycine-activated Akt/mTOR Pathway
Authors: Wang Menghao , Yuan Fangchao , Bai He , Zhang Jie , Wu Hao , Zheng Kaiwen , Zhang Wenfeng , Miao Mingyong , Gong Jianping
Published: April 2019

Background.

The development of liver transplantation (LT) is increasingly being limited by the unavailability of liver grafts. Unique regenerative capacity of liver in response to injuries makes living-donor liver transplantation (LDLT) a feasible strategy to meet clinical demands. Serine hydroxymethyl-transferase 2 (SHMT2) serves as the key enzyme in the biosynthesis of glycine. Glycine affects the activity of mammalian target of rapamycin (mTOR), which is important for cellular growth and proliferation. In this study, the effects of SHMT2 on mouse liver regeneration were investigated using a classical partial hepatectomy (PH) model.

Methods.

In vivo, PH was performed on mice with or without knockdown of SHMT2. In vitro, SHMT2 was overexpressed in primary hepatocytes, which were cultured in customized Dulbecco’s modified eagle media and LY294002 (an Akt inhibitor). Relevant indexes of liver regeneration, cell proliferation, and Akt/mTOR signal pathways were analyzed.

Results.

After PH, the expression levels of SHMT2 fluctuated with time and knockdown of SHMT2 in vivo lowered the regenerative ability of liver, with reduced glycine levels compared to the scramble group. In addition, overexpression of SHMT2 in hepatocytes boosted glycine production while enhancing Akt/mTOR pathway activity. These results were validated by the application of LY294002 in vitro.

Conclusions.

SHMT2 can contribute to liver regeneration after PH, and this is likely related to the activation of Akt/mTOR signaling pathway by its metabolic product, glycine, in hepatocytes. These results might have therapeutic implications for the prognosis of patients undergoing hepatic resection or transplantation.
An epithelial organoid model with Langerhans cells for assessing virus-host interactions
Authors: Jackson Robert , Eade Statton , Zehbe Ingeborg
Published: April 2019

Persistent infection with oncogenic human papillomavirus (HPV) may lead to cancer in mucosal and skin tissue. Consequently, HPV must have developed strategies to escape host immune surveillance. Nevertheless, most HPV infections are cleared by the infected host. Our laboratory investigates Langerhans cells (LCs), acting at the interface between innate and adaptive immunity. We hypothesize that this first line of defence is vital for potential HPV elimination. As an alternative to animal models, we use smaller-scale epithelial organoids grown from human primary keratinocytes derived from various anatomical sites. This approach is amenable to large sample sizes—an essential aspect for scientific rigour and statistical power. To evaluate LCs phenotypically and molecularly during the viral life cycle and onset of carcinogenesis, we have included an engineered myeloid cell line with the ability to acquire an LC phenotype. This model is accurately tailored for the crucial time-window of early virus elimination in a complex organism and will shed more light on our long-standing research question of how naturally occurring HPV variants influence disease development. It may also be applied to other microorganism–host interaction research or enquiries of epithelium immunobiology. Finally, our continuously updated pathogen–host analysis tool enables state-of-the-art bioinformatics analyses of next-generation sequencing data.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
The rabbit papillomavirus model: a valuable tool to study viral–host interactions
Authors: Cladel Nancy M. , Peng Xuwen , Christensen Neil , Hu Jiafen
Published: April 2019

Cottontail rabbit papillomavirus (CRPV) was the first DNA virus shown to be tumorigenic. The virus has since been renamed and is officially known as
Sylvilagus floridanus
papillomavirus 1 (SfPV1). Since its inception as a surrogate preclinical model for high-risk human papillomavirus (HPV) infections, the SfPV1/rabbit model has been widely used to study viral–host interactions and has played a pivotal role in the successful development of three prophylactic virus-like particle vaccines. In this review, we will focus on the use of the model to gain a better understanding of viral pathogenesis, gene function and host immune responses to viral infections. We will discuss the application of the model in HPV-associated vaccine testing, in therapeutic vaccine development (using our novel HLA-A2.1 transgenic rabbits) and in the development and validation of novel anti-viral and anti-tumour compounds. Our goal is to demonstrate the role the SfPV1/rabbit model has played, and continues to play, in helping to unravel the intricacies of papillomavirus infections and to develop tools to thwart the disease.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Infection and immune control of human oncogenic γ-herpesviruses in humanized mice
Authors: McHugh Donal , Caduff Nicole , Murer Anita , Engelmann Christine , Deng Yun , Zdimerova Hana , Zens Kyra , Chijioke Obinna , Münz Christian
Published: April 2019

Epstein–Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) comprise the oncogenic human γ-herpesvirus family and are responsible for 2–3% of all tumours in man. With their prominent growth-transforming abilities and high prevalence in the human population, these pathogens have probably shaped the human immune system throughout evolution for near perfect immune control of the respective chronic infections in the vast majority of healthy pathogen carriers. The exclusive tropism of EBV and KSHV for humans has, however, made it difficult in the past to study their infection, tumourigenesis and immune control
in vivo
. Mice with reconstituted human immune system components (humanized mice) support replication of both viruses with both persisting latent and productive lytic infection. Moreover, B-cell lymphomas can be induced by EBV alone and KSHV co-infection with gene expression hallmarks of human malignancies that are associated with both viruses. Furthermore, cell-mediated immune control by primarily cytotoxic lymphocytes is induced upon infection and can be probed for its functional characteristics as well as putative requirements for its priming. Insights that have been gained from this model and remaining questions will be discussed in this review.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Integrating measures of viral prevalence and seroprevalence: a mechanistic modelling approach to explaining cohort patterns of human papillomavirus in women in the USA
Authors: Brouwer Andrew F. , Meza Rafael , Eisenberg Marisa C.
Published: April 2019

Incidence of human papillomavirus (HPV) related cancers is increasing, generating substantial interest in understanding how trends in population prevalence of HPV infection are changing. However, there are no direct, population-scale measurements of HPV prevalence prior to 2003. Previous work using models to reconstruct historical trends have focused only on genital infection or seroprevalence (prevalence of antibodies) separately, and the results of these single-measure studies have been hard to reconcile. Here, we develop a mechanistic disease model fit jointly to cervicogential prevalence and seroprevalence in unvaccinated women in the USA using National Health and Nutrition Examination Survey data (2003–2010) and compare it to fits of statistical age–cohort models. We find that including a latent HPV state in our model significantly improves model fit and that antibody waning may be an important contributor to observed patterns of seroprevalence. Moreover, we find that the mechanistic model outperforms the statistical model and that the joint analysis prevents the inconsistencies that arise when estimating historical cohort trends in infection from genital prevalence and seroprevalence separately. Our analysis suggests that while there is substantial uncertainty associated with the estimation of historic HPV trends, there has likely been an increase in the force of infection for more recent birth cohorts.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Essential role of inverted repeat in Epstein–Barr virus IR-1 in B cell transformation; geographical variation of the viral genome
Authors: Bridges Ray , Correia Samantha , Wegner Fanny , Venturini Cristina , Palser Anne , White Robert E. , Kellam Paul , Breuer Judith , Farrell Paul J.
Published: April 2019

Many regions of the Epstein–Barr virus (EBV) genome, repeated and unique sequences, contribute to the geographical variation observed between strains. Here we use a large alignment of curated EBV genome sequences to identify major sites of variation in the genome of type 1 EBV strains; the CAO deletion in latent membrane protein 1 (LMP1) is the most frequent major indel present in the unique regions of EBV strains from various parts of the world. Principal component analysis was used to identify patterns of sequence variation and nucleotide positions in the sequences that can distinguish EBV from some different geographical regions. Viral genome sequence variation also affects interpretation of genetic content; known genes, origins of replication and gene expression control regions explain most of the viral genome but there are still a few sections of unknown function. One of these EBV genome regions contains a large inverted repeat sequence (invR) within the IR-1 major internal repeat array. We deleted this invR sequence and showed that this abolished the ability of the virus to transform human B cells into lymphoblastoid cell lines.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Small size, big impact: how studies of small DNA tumour viruses revolutionized biology
Authors: DiMaio Daniel
Published: April 2019

Intense study of three families of small tumour viruses with double-stranded DNA genomes, carried out over 50 years, has had a profound impact on biology. The polyomaviruses and papillomaviruses have circular DNA genomes of approximately 5000 and approximately 8000 base-pairs, respectively, and thus encode only a handful of proteins. Adenoviruses have a 32 000-base-pair linear DNA genome, still far smaller than the three billion-base-pair human genome. Members of all three virus families can transform cultured cells to tumorigenicity and cause tumours in experimental animals. Several human papillomaviruses (HPV) and at least one polyomavirus are oncogenic in humans. Early analysis of these viruses, particularly the polyomavirus SV40, led to the development of many powerful experimental tools, including restriction mapping, site-directed mutagenesis, gene transfer, genome-wide sequencing and recombinant DNA. These tools have since been refined and used to study cellular genes, revolutionizing our understanding of biology. These tools were also applied to the viruses themselves. Analysis of the virus life cycle and the effect of these viruses on cells yielded important new insights into many aspects of gene expression, DNA replication, cell biology and carcinogenesis. These studies have also led to vaccination strategies to prevent infection and cancer in humans.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Intra-patient viral evolution in polyomavirus-related diseases
Authors: McIlroy Dorian , Halary Franck , Bressollette-Bodin Céline
Published: April 2019

Human polyomaviruses show relatively little genetic polymorphism between isolates, indicating that these viruses are genetically stable between hosts. However, it has become increasingly clear that intra-host molecular evolution is a feature of some polyomavirus (PyV) infections in humans. Mutations inducing premature stop codons in the early region of the integrated Merkel cell PyV genome lead to the expression of a truncated form of the large tumour (LT) antigen that is critical for the transformation of Merkel cell carcinoma (MCC) cells. Non-coding control region (NCCR) rearrangements and point mutations in virion protein (VP) 1 have been described in both JCPyV and BKPyV infections. In the context of JCPyV infection, molecular evolution at both these loci allows the virus to replicate effectively in the central nervous system, thereby leading to the development of progressive multifocal leukoencephalopathy (PML). In BKPyV infection, NCCR rearrangements have been linked to higher rates of virus replication in the kidney, and are proposed to play a direct causal role in the development of PyV-associated nephropathy. In all three of these infections, therefore, intra-host viral evolution appears to be an essential component of the disease process.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Detection of SHV, CTX-M and TEM genes in extended spectrum beta lactamase producing multi-drug resistant Escherichia coli from clinical isolates in Calabar, Nigeria
Authors: Ogba Ofonime , Esiere Miracle , Esiere Rosemary
Published: April 2019

Background

The emergence of multi-drug resistant strains of Escherichia coli complicates the treatment of infections. The detection of ESBL genes in bacteria and their antimicrobial resistance patterns can provide information about their epidemiology and transmission. The study aimed to detect ESBL genes that encode; CTX-M, TEM and SHV in E. coli isolatesin our locality.

Methods

Clinical E. coli isolates were obtained from public and private clinics within Calabar metropolis. Biochemical method was used to re-identify the isolates. Antibiotics susceptibility testing was done using Kirby-Bauer disc diffusion method. Phenotypic detection of ESBL in isolates was done by double disc synergy test (DDST). The ESBL genes were detected using conventional PCR method.

Results

The ESBL phenotypic positive isolates was (56.6 %). The most prevalent gene in the study was CTX-M gene. Antibiotic susceptibility of E. coli isolates to commonly used antibiotics was low. Isolates were most susceptible to quinolones (54.7 %) and fluoroquinolones (34.0 %). The ESBL producing isolates were more susceptible to quinolones but less susceptible to the third generation cephalosporins. There was significant association between gene expression by isolates and antibiotic resistance (P≤0.05). Isolates with the SHV and TEM genes showed 100 % resistance to some tested antibiotics. Isolates with CTX-M genes were also highly resistant.

Conclusion

The SHV, CTX-M and TEM genes were detected in Escherichia coli isolates in our locality. These may have resulted in the high resistance of isolates to commonly used antibiotics which may pose challenges to patient’s management.
Association of milk microbiome in bovine clinical mastitis and their functional implications in cows in Bangladesh
Authors: Hoque M. Nazmul , Istiaq Arif , Clement Rebecca A. , Sultana Munawar , Crandall Keith A. , Siddiki Amam Zonaed , Hossain M. Anwar
Published: April 2019

Milk microbiomes impose a significant influence on the pathophysiology of bovine mastitis. To assess the association, we compared the microbiome of clinical mastitis (CM) and healthy (H) milk samples through whole metagenomic deep sequencing. A total of 483.38 million reads generated from both metagenomes were analyzed through PathoScope and MG-RAST, and mapped to 380 bacterial, 56 archaeal, and 39 viral genomes. We observed distinct shifts and differences in abundance between the microbiome of CM and H milk in phyla Proteobacteria, Bacteroidetes, Firmicutes and Actinobacteria with an inclusion of 68.04% unreported and/or opportunistic species in CM milk. Additionally, 14 archaeal and 14 viral genera were found to be solely associated with CM. The functional metagenomics identified several pathways related to bacterial proliferation and colonization such as metabolism, chemotaxis and invasion, immune-diseases, oxidative stress, regulation and cell signaling, phage and prophases, antibiotic and heavy metal resistance to be associated with CM. Therefore, the present study provides conclusive data on milk microbiome diversity associated with bovine CM and its role in udder health.
Infectious disease phylodynamics with occurrence data
Authors: Featherstone Leo A. , Di Giallonardo Francesca , Holmes Edward C. , Vaughan Timothy G. , Duchêne Sebastián
Published: April 2019

Point 1

Phylodynamic models use pathogen genome sequence data to infer epidemiological dynamics. With the increasing genomic surveillance of pathogens, especially amid the SARS-CoV-2 outbreak, new practical questions about their use are emerging.

Point 2

One such question focuses on the inclusion of un-sequenced case occurrence data alongside sequenced data to improve phylodynamic analyses. This approach can be particularly valuable if sequencing efforts vary over time.

Point 3

Using simulations, we demonstrate that birth-death phylodynamic models can employ occurrence data to eliminate bias in estimates of the basic reproductive number due to misspecification of the sampling process. In contrast, the coalescent exponential model is robust to such sampling biases, but in the absence of a sampling model it cannot exploit occurrence data. Subsequent analysis of the SARS-CoV-2 epidemic in the northwest USA supports these results.

Point 4

We conclude that occurrence data are a valuable source of information in combination with birth-death models. These data should be used to bolster phylodynamic analyses of infectious diseases and other rapidly spreading species in the future.
Short Neurorobotics Workshop for High School Students Promotes Competence and Confidence in Computational Neuroscience
Authors: Harris Christopher A. , Mircic Stanislav , Reining Zachary , Amorim Marcio , Jović Đorđe , Guerri Lucia , Wallace William , Gage Gregory J.
Published: April 2019

Understanding the brain is a fascinating challenge, captivating the scientific community and the public alike. The lack of effective treatment for most brain disorders makes the training of the next generation of neuroscientists, engineers and physicians a key concern. Over the past decade there has been a growing effort to introduce neuroscience in primary and secondary schools, however hands-on laboratories have been limited to anatomical or electrophysiological activities. Modern neuroscience research labs are increasingly using computational tools to model circuits of the brain to understand information processing. Here we introduce the use of neurorobots - robots controlled by computer models of biological brains - as an introduction to computational neuroscience in the K-12 classroom. Neurorobotics has enormous potential as an education technology because it combines multiple activities with clear educational benefits including neuroscience, active learning, and robotics. We describe an introductory neurorobot workshop that teaches high school students how to use neurorobots to investigate key concepts in neuroscience, including spiking neural networks, synaptic plasticity, and adaptive action selection. Our do-it-yourself (DIY) neurorobot uses wheels, a camera, a speaker, and a distance sensor to interact with its environment, and can be built from generic parts costing about $150 in under 4 hrs. Our Neurorobot App visualizes the neurorobot's visual input and brain activity in real-time, and enables students to design new brains and deliver dopamine-like reward signals to reinforce chosen behaviors. We have tested the Neurorobot Workshop with high school students (n = 3 workshops, 9 students total) and have found that students were able to complete all exercises in under 3 hrs. In a post-workshop survey, students reported having gained the ability to develop neural networks that perform specific functions, including goal-directed behavior and memory. Here we provide DIY hardware assembly instructions, discuss our open-source Neurorobot App and demonstrate how to teach the Neurorobot Workshop. By doing this we hope to accelerate research in educational neurorobotics and promote the use of neurorobots to teach computational neuroscience in high school.
Cholesterol binding to the transmembrane region of a group 2 HA of Influenza virus is essential for virus replication affecting both virus assembly and HA’s fusion activity
Authors: Hu Bodan , Höfer Chris Tina , Thiele Christoph , Veit Michael
Published: April 2019

Hemagglutinin (HA) of Influenza virus is incorporated into cholesterol enriched, nanodomains of the plasma membrane. Phylogenetic group 2 HAs contain the conserved cholesterol consensus motif (CCM) YKLW in the transmembrane region. We previously reported that mutations in the CCM retarded intracellular transport of HA and decreased its nanodomain association. Here we analyzed whether cholesterol interacts with the CCM. Incorporation of photocholesterol into HA was significantly reduced if the whole CCM is replaced by alanine, both using immunoprecipitated HA and when HA is embedded in the membrane. Next, we used reverse genetics to investigate the significance of the CCM for virus replication. No virus was rescued if the whole motif is exchanged (YKLW4A); single (LA) or double (YK2A and LW2A) mutated virus showed decreased titers and a comparative fitness disadvantage. In polarized cells transport of HA mutants to the apical membrane was not disturbed. Reduced amounts of HA and cholesterol were incorporated into the viral membrane. Mutant viruses exhibit a decrease in hemolysis, which is only partially corrected if the membrane is replenished with cholesterol. More specifically, viruses have a defect in hemifusion as demonstrated by fluorescence dequenching. Cells expressing HA-YKLW4A fuse with erythrocytes, but the number of events are reduced. Even after acidification unfused erythrocytes remain cell-bound, a phenomenon not observed with wildtype HA. We conclude that cholesterol-binding to a group 2 HA is essential for virus replication. It has pleiotropic effects on virus assembly and membrane fusion, mainly on lipid mixing and possibly a preceding step.

IMPORTANCE

The glycoprotein hemagglutinin (HA) is a major pathogenicity factor of Influenza viruses. Whereas the structure and function of HA’s ectodomain is known in great detail, similar data for the membrane-anchoring part of the protein are missing. Here we demonstrate that the transmembrane region of a group 2 HA interacts with cholesterol, the major lipid of the plasma membrane and the defining element of the viral budding site nanodomains of the plama membrane. The cholesterol binding motif is essential for virus replication. Its partial removal affects various steps of the viral life cycle, such as assembly of new virus particles and their subsequent cell entry via membrane fusion. A cholesterol-binding pocket in group 2 HAs might be a promising target for a small lipophilic drug that inactivates the virus.
Implications of data-driven analyses for personalized therapy in psychosis: a systematic review of cluster- and trajectory-based modelling studies
Authors: Habtewold Tesfa Dejenie , Rodijk Lyan H. , Liemburg Edith J. , Sidorenkov Grigory , Boezen H. Marike , Bruggeman Richard , Alizadeh Behrooz Z.
Published: April 2019

Introduction

To tackle the phenotypic heterogeneity of schizophrenia, data-driven methods are often applied to identify subtypes of its (sub)clinical symptoms though there is no systematic review.

Aims

To summarize the evidence from cluster- and trajectory-based studies of positive, negative and cognitive symptoms in patients with schizophrenia spectrum disorders, their siblings and healthy people. Additionally, we aimed to highlight knowledge gaps and point out future directions to optimize the translatability of cluster- and trajectory-based studies.

Methods

A systematic review was performed through searching PsycINFO, PubMed, PsycTESTS, PsycARTICLES, SCOPUS, EMBASE, and Web of Science electronic databases. Both cross-sectional and longitudinal studies published from 2008 to 2019, which reported at least two statistically derived clusters or trajectories were included. Two reviewers independently screened and extracted the data.

Results

Of 2,285 studies retrieved, 50 studies (17 longitudinal and 33 cross-sectional) conducted in 30 countries were selected for review. Longitudinal studies discovered two to five trajectories of positive and negative symptoms in patient, and four to five trajectories of cognitive deficits in patient and sibling. In cross-sectional studies, three clusters of positive and negative symptoms in patient, four clusters of positive and negative schizotypy in sibling, and three to five clusters of cognitive deficits in patient and sibling were identified. These studies also reported multidimensional predictors of clusters and trajectories.

Conclusions

Our findings indicate that (sub)clinical symptoms of schizophrenia are more heterogeneous than currently recognized. Identified clusters and trajectories can be used as a basis for personalized psychiatry.
Peptidoglycan layer and disruption processes inBacillus subtiliscells visualized using quick-freeze, deep-etch electron microscopy
Authors: Tulum Isil , Tahara Yuhei O , Miyata Makoto
Published: April 2019

Peptidoglycan, which is the main component of the bacterial cell wall, is a heterogeneous polymer of glycan strands crosslinked with short peptides and is synthesized in cooperation with the cell division cycle. Although it plays a critical role in bacterial survival, its architecture is not well understood. Herein, we visualized the architecture of the peptidoglycan surface inBacillus subtilisat the nanometer resolution, using quick-freeze, deep-etch electron microscopy. Filamentous structures were observed on the entire surface of the cell, where filaments about 11-nm wide formed concentric circles on cell poles, filaments about 13-nm wide formed a circumferential mesh-like structure on the cylindrical part, and a “piecrust” structure was observed at the boundary. When growing cells were treated with lysozyme, the entire cell mass migrated to one side and came out from the cell envelope. Fluorescence labeling showed that lysozyme preferentially bound to a cell pole and cell division site, where the peptidoglycan synthesis was not complete. Ruffling of surface structures was observed during electron microscopy. When cells were treated with penicillin, the cell mass came out from a cleft around the cell division site. Outward curvature of the protoplast at the cleft seen using electron microscopy suggested that turgor pressure was applied as the peptidoglycan was not damaged at other positions. When muropeptides were depleted, surface filaments were lost while the rod shape of the cell was maintained. These changes can be explained on the basis of the working points of the chemical structure of peptidoglycan.
Age-related clonal haemopoiesis is associated with increased epigenetic age
Authors: Robertson Neil A. , Deary Ian J. , Kirschner Kristina , Marioni Riccardo E. , Chandra Tamir
Published: April 2019

Age-related clonal haemopoiesis (ARCH) in healthy individuals was initially observed through an increased skewing in X chromosome inactivation. More recently, several groups reported that ARCH is driven by somatic mutations. The most prevalent ARCH mutations are in the DNMT3A and TET2 genes, previously described as drivers of myeloid malignancies. ARCH is associated with an increased risk for haematological cancers. ARCH also confers an increased risk for non-haematological diseases such as cardiovascular disease, atherosclerosis, and chronic ischemic heart failure, for which age is a main risk factor. Whether ARCH is linked to accelerated ageing has remained unexplored. The most accurate and commonly-used tools to measure age acceleration are epigenetic clocks. They are based on age-related methylation differences at specific CpG sites correlating chronological age accurately with epigenetic age. Deviations from chronological age towards an increased epigenetic age have been associated with increased risk of earlier mortality and age-related morbidities. Here we present evidence of accelerated epigenetic age in individuals with ARCH.
Destabilization of the Tumor-Inducing Plasmid from an Octopine-TypeAgrobacterium tumefaciensLineage Drives a Large Deletion in the Co-Resident At Megaplasmid
Authors: Barton Ian S. , Platt Thomas G. , Rusch Douglas B. , Fuqua Clay
Published: April 2019

Bacteria with multi-replicon genome organizations, including members of the familyRhizobiaceae, often carry a variety of niche-associated functions on large plasmids. While evidence exists for cross-replicon interactions and co-evolution between replicons in many of these systems, remarkable strain-to-strain variation is also observed for extrachromosomal elements, suggesting increased genetic plasticity. Here, we show that curing of the tumor-inducing virulence plasmid (pTi) of an octopine-typeAgrobacterium tumefacienslineage leads to a large deletion in the co-resident At megaplasmid (pAt). The deletion event is mediated by a repetitive IS-element, IS66, and results in a variety of environment-dependent fitness consequences, including loss of independent conjugal transfer of the plasmid. Interestingly, a related and otherwise wild-typeA. tumefaciensstrain is missing exactly the same large pAt segment as the pAt deletion derivatives, suggesting a similar event over its natural history. Overall, the findings presented here uncover a novel genetic interaction between the two large plasmids ofA. tumefaciensand provide evidence for cross-replicon integration and co-evolution of these plasmids.