bluuebunny/crossref_metadata_2025 huggingface dataset:
Alterations in gp37 Expand the Host Range of a T4-Like Phage
Authors: Chen Mianmian , Zhang Lei , Abdelgader Sheikheldin Adam , Yu Li , Xu Juntian , Yao Huochun , Lu Chengping , Zhang Wei
Published: September 2017

The use of phages as antibacterial agents is limited by their generally narrow host ranges. The aim of this study was to make a T4-like phage, WG01, obtain the host range of another T4-like phage, QL01, by replacing its host-determinant gene region with that of QL01. This process triggered a direct expansion of the WG01 host range. The offspring of WG01 obtained the host ranges of both QL01 and WG01, as well as the ability to infect eight additional host bacteria in comparison to the wild-type strains. WQD had the widest host range; therefore, the corresponding fragments, named QD, could be used for constructing a homologous sequence library. Moreover, after a sequencing analysis of gene 37, we identified two different mechanisms responsible for the expanded host range: (i) the first generation of WG01 formed chimeras without mutations, and (ii) the second generation of WG01 mutants formed from the chimeras. The expansion of the host range indicated that regions other than the C-terminal region may indirectly change the receptor specificity by altering the supportive capacity of the binding site. Additionally, we also found the novel means by which subsequent generations expanded their host ranges, namely, by exchanging gene 37 to acquire a wider temperature range for lysis. The method developed in this work offers a quick way to change or expand the host range of a phage. Future clinical applications for screening phages against a given clinical isolate could be achieved after acquiring more suitable homologous sequences.

IMPORTANCET4-like phages have been established as safe in numerous phage therapy applications. The primary drawbacks to the use of phages as therapeutic agents include their highly specific host ranges. Thus, changing or expanding the host range of T4-like phages is beneficial for selecting phages for phage therapy. In this study, the host range of the T4-like phage WG01 was expanded using genetic manipulation. The WG01 derivatives acquired a novel means of expanding their host ranges by acquiring a wider temperature range for lysis. A region was located that had the potential to be used as a sequence region for homologous sequence recombination.
Biochemical Characteristics and Variable Alginate-Degrading Modes of a Novel Bifunctional Endolytic Alginate Lyase
Authors: Cheng Yuanyuan , Wang Dandan , Gu Jingyan , Li Junge , Liu Huihui , Li Fuchuan , Han Wenjun
Published: September 2017

Bifunctional alginate lyases can efficiently degrade alginate comprised of mannuronate (M) and guluronate (G), but their substrate-degrading modes have not been thoroughly elucidated to date. In this study, we present Aly1 as a novel bifunctional endolytic alginate lyase of the genus
Flammeovirga
. The recombinant enzyme showed optimal activity at 50°C and pH 6.0. The enzyme produced unsaturated disaccharide (UDP2) and trisaccharide fractions as the final main alginate digests. Primary substrate preference tests and further structure identification of various size-defined final oligosaccharide products demonstrated that Aly1 is a bifunctional alginate lyase and prefers G to M. Tetrasaccharide-size fractions are the smallest substrates, and M, G, and UDP2 fractions are the minimal product types. Remarkably, Aly1 can vary its substrate-degrading modes in accordance with the terminus types, molecular sizes, and M/G contents of alginate substrates, producing a series of small size-defined saturated oligosaccharide products from the nonreducing ends of single or different saturated sugar chains and yielding unsaturated products in distinct but restricted patterns. The action mode changes can be partially inhibited by fluorescent labeling at the reducing ends of oligosaccharide substrates. Deletion of the noncatalytic region (NCR) of Aly1 caused weak changes of biochemical characteristics but increased the degradation proportions of small size-defined saturated M-enriched oligosaccharide substrates and unsaturated tetrasaccharide fractions without any size changes of degradable oligosaccharides, thereby enhancing the M preference and enzyme activity. Therefore, our results provided insight into the variable action mode of a novel bifunctional endolytic alginate lyase to inform accurate enzyme use.

IMPORTANCE
The elucidated endolytic alginate lyases usually degrade substrates into various size-defined unsaturated oligosaccharide products (≥UDP2), and exolytic enzymes yield primarily unsaturated monosaccharide products. However, it is poorly understood whether endolytic enzymes can produce monosaccharide product types when degrading alginate. In this study, we demonstrated that Aly1, a bifunctional alginate lyase of
Flammeovirga
sp. strain MY04, is endolytic and monosaccharide producing. Using various sugar chains as testing substrates, we also proved that key factors causing Aly1's action mode changes are the terminus types, molecular sizes, and M/G contents of substrates. Furthermore, the NCR fragment's effects on Aly1's biochemical characteristics and alginate-degrading modes and corresponding mechanisms were discovered by gene truncation and enzyme comparison. In summary, this study provides a novel bifunctional endolytic tool and a variable action mode for accurate use in alginate degradation.
The Type IX Secretion System Is Required for Virulence of the Fish Pathogen Flavobacterium columnare
Authors: Li Nan , Zhu Yongtao , LaFrentz Benjamin R. , Evenhuis Jason P. , Hunnicutt David W. , Conrad Rachel A. , Barbier Paul , Gullstrand Connor W. , Roets Jack E. , Powers Jonathan L. , Kulkarni Surashree S. , Erbes Devon H. , García Julio C. , Nie Pin , McBride Mark J.
Published: September 2017

Flavobacterium columnare
, a member of the phylum
Bacteroidetes
, causes columnaris disease in wild and aquaculture-reared freshwater fish. The mechanisms responsible for columnaris disease are not known. Many members of the phylum
Bacteroidetes
use type IX secretion systems (T9SSs) to secrete enzymes, adhesins, and proteins involved in gliding motility. The
F. columnare
genome has all of the genes needed to encode a T9SS.
gldN
, which encodes a core component of the T9SS, was deleted in wild-type strains of
F. columnare
. The
F. columnare
Δ
gldN
mutants were deficient in the secretion of several extracellular proteins and lacked gliding motility. The Δ
gldN
mutants exhibited reduced virulence in zebrafish, channel catfish, and rainbow trout, and complementation restored virulence. PorV is required for the secretion of a subset of proteins targeted to the T9SS. An
F. columnare
Δ
porV
mutant retained gliding motility but exhibited reduced virulence. Cell-free spent media from exponentially growing cultures of wild-type and complemented strains caused rapid mortality, but spent media from Δ
gldN
and Δ
porV
mutants did not, suggesting that soluble toxins are secreted by the T9SS.

IMPORTANCE
Columnaris disease, caused by
F. columnare
, is a major problem for freshwater aquaculture. Little is known regarding the virulence factors produced by
F. columnare
, and control measures are limited. Analysis of targeted gene deletion mutants revealed the importance of the type IX protein secretion system (T9SS) and of secreted toxins in
F. columnare
virulence. T9SSs are common in members of the phylum
Bacteroidetes
and likely contribute to the virulence of other animal and human pathogens.
5-year disease progression of patients across the glaucoma spectrum assessed by structural and functional tools
Authors: Seth Natasha Gautam , Kaushik Sushmita , Kaur Savleen , Raj Srishti , Pandav Surinder Singh
Published: September 2017

Background

Assessment of spectral-domain optical coherence tomography (SD-OCT) compared with visual fields, to detect progression across the glaucoma spectrum.

Methods

In this study, adult glaucoma suspects and patients, with baseline retinal nerve fibre layer (RNFL) thickness on SD-OCT and reliable visual field (VF) tests on Humphrey Field Analyser (HFA) prior to March 2010, were recruited. Functional and structural progression over at least 5 years was compared using Glaucoma Progression Analysis (GPA) and VF index (VFI) on HFA and Guided Progression Analysis (GPA-OCT) on SD-OCT, respectively. Agreement of progression detection between the two modalities was computed using κ statistics.

Results

122 subjects (63 glaucoma suspects; 59 glaucoma patients) were enrolled. Of 18 suspects who progressed to glaucoma, 13 showed progression by GPA-OCT, 4 by GPA, 7 by VFI and 2 were concordant. In the 14 glaucoma patients who progressed, GPA-OCT detected progression in 6, GPA in five and VFI in six. GPA-OCT had poor agreement with GPA in glaucoma suspects (Kappa 0.15; p=0.13) and patients (Kappa 0.10; p=0.45). VFI had better agreement with GPA-OCT in glaucoma suspects (Kappa 0.34; p=0.01) than glaucoma patients (Kappa 0.12; p=0.36). Progressors by VF in both groups had similar percentage change from baseline RNFL thickness (−9.9% vs −8.6% p=0.46), even though the absolute change was significantly greater in suspects(−8.75µ vs−6.4µ p=0.03).

Conclusion

Structural change appears to be more useful to detect progression in glaucoma suspects, while functional change is a better indicator as the disease progresses. Percentage change from baseline RNFL thickness was a better measure than absolute change in RNFL.
Effect of low-dose versus higher-dose antenatal iron supplementation on child health outcomes at 36 months of age in Viet Nam: longitudinal follow-up of a cluster randomised controlled trial
Authors: Hanieh Sarah , Ha Tran T , Simpson Julie A , Braat Sabine , Thuy Tran T , Tran Thach D , King Janet , Tuan Tran , Fisher Jane , Biggs Beverley-Ann
Published: September 2017

Introduction

Intermittent iron-folic acid supplementation (IFA) is currently recommended for pregnant women in populations where anaemia prevalence among pregnant women is <20% or if daily iron is not acceptable. The effect of providing lower doses of antenatal elemental iron through intermittent regimes on longer-term health outcomes in childhood is unclear.

Methods

A prospective cohort study conducted between May 2012 and May 2014 in Viet Nam among children of 36 months of age, born to women previously enrolled in a cluster randomised controlled trial of antenatal micronutrient supplementation (daily IFA (60 mg elemental iron) vs twice-weekly IFA (60 mg elemental iron) vs twice-weekly multiple micronutrient (MMN) supplementation (60 mg elemental iron)). Primary outcomes were height-for-age z-scores (HAZ), according to WHO growth standards and cognitive composite scores (Bayley Scales of Infant and Toddler Development, third edition) at 36 months of age.

Results

A total of 1017 children born to mothers enrolled in the cluster randomised trial were assessed at 36 months of age. Adjusted mean differences (MDs) in HAZ were –0.14 (95% CI –0.28 to –0.01) and –0.15 (95% CI –0.29 to –0.01) in children born to mothers who received twice-weekly IFA or MMN compared with those who received daily IFA. Children born to mothers who received twice-weekly MMN had lower composite motor scores compared with those who received daily IFA (MD –2.07, 95% CI –4.11 to –0.03). There were no differences in composite cognitive scores in the twice-weekly compared with daily regimens.

Conclusions

Low-dose antenatal IFA supplementation (120 mg elemental iron per week) resulted in lower HAZ and motor composite scores in children compared with higher-dose antenatal IFA supplementation (420 mg elemental iron per week). This highlights the importance of adequate iron stores during pregnancy and the need for careful monitoring when lower-dose antenatal iron regimens are used.

Trial registration number

Australia New Zealand Clinical Trials Registry: 12610000944033.
Effects of nutrition interventions during pregnancy on low birth weight: an overview of systematic reviews
Authors: da Silva Lopes Katharina , Ota Erika , Shakya Prakash , Dagvadorj Amarjargal , Balogun Olukunmi Omobolanle , Peña-Rosas Juan Pablo , De-Regil Luz Maria , Mori Rintaro
Published: September 2017

Introduction

Low birth weight (LBW, birth weight less than 2500 g) is associated with infant mortality and childhood morbidity. Poor maternal nutritional status is one of several contributing factors to LBW. We systematically reviewed the evidence for nutrition-specific (addressing the immediate determinants of nutrition) and nutrition-sensitive (addressing the underlying cause of undernutrition) interventions to reduce the risk of LBW and/or its components: preterm birth (PTB) and small-for-gestational age (SGA).

Methods

We conducted a comprehensive literature search in MEDLINE, EMBASE, CINAHL and the Cochrane Database of Systematic Reviews (September 2015). Systematic reviews of randomised controlled trials focusing on nutritional interventions before and during pregnancy to reduce LBW and its components were eligible for inclusion into the overview review. We assessed the methodological quality of the included reviews usingA Measurement Tool to Assess Reviews(AMSTAR), PROSPERO: CRD42015024814.

Results

We included 23 systematic reviews which comprised 34 comparisons. Sixteen reviews were of high methodological quality, six of moderate and only one review of low quality. Six interventions were associated with a decreased risk of LBW: oral supplementation with (1) vitamin A, (2) low-dose calcium, (3) zinc, (4) multiple micronutrients (MMN), nutritional education and provision of preventive antimalarials. MMN and balanced protein/energy supplementation had a positive effect on SGA, while high protein supplementation increased the risk of SGA. High-dose calcium, zinc or long-chain n-3 fatty acid supplementation and nutritional education decreased the risk of PTB.

Conclusion

Improving women’s nutritional status positively affected LBW, SGA and PTB. Based on current evidence, especially MMN supplementation and preventive antimalarial drugs during pregnancy may be considered for policy and practice. However, for most interventions evidence was derived from a small number of trials and/or participants. There is a need to further explore the evidence of nutrition-specific and nutrition-sensitive interventions in order to reach the WHO’s goal of a 30% reduction in the global rate of LBW by 2025.
Household and familial resemblance in risk factors for type 2 diabetes and related cardiometabolic diseases in rural Uganda: a cross-sectional community sample
Authors: Nielsen Jannie , Bahendeka Silver K , Whyte Susan R , Meyrowitsch Dan W , Bygbjerg Ib C , Witte Daniel R
Published: September 2017

Objectives

Prevention of type 2 diabetes (T2D) has been successfully established in randomised clinical trials. However, the best methods for the translation of this evidence into effective population-wide interventions remain unclear. To assess whether households could be a target for T2D prevention and screening, we investigated the resemblance of T2D risk factors at household level and by type of familial dyadic relationship in a rural Ugandan community.

Methods

This cross-sectional household-based study included 437 individuals ≥13 years of age from 90 rural households in south-western Uganda. Resemblance in glycosylated haemoglobin (HbA1c), anthropometry, blood pressure, fitness status and sitting time were analysed using a general mixed model with random effects (by household or dyad) to calculate household intraclass correlation coefficients (ICCs) and dyadic regression coefficients. Logistic regression with household as a random effect was used to calculate the ORs for individuals having a condition or risk factor if another household member had the same condition.

Results

The strongest degree of household member resemblances in T2D risk factors was seen in relation to fitness status (ICC=0.24), HbA1c (ICC=0.18) and systolic blood pressure (ICC=0.11). Regarding dyadic resemblance, the highest standardised regression coefficient was seen in fitness status for spouses (0.54, 95% CI 0.32 to 0.76), parent–offspring (0.41, 95% CI 0.28 0.54) and siblings (0.41, 95% CI 0.25 to 0.57). Overall, parent–offspring and sibling pairs were the dyads with strongest resemblance, followed by spouses.

Conclusions

The marked degree of resemblance in T2D risk factors at household level and between spouses, parent–offspring and sibling dyads suggest that shared behavioural and environmental factors may influence risk factor levels among cohabiting individuals, which point to the potential of the household setting for screening and prevention of T2D.
Protocol for a realist review of complex interventions to prevent adolescents from engaging in multiple risk behaviours
Authors: Cooper Christina , Lhussier Monique , Shucksmith Janet , Carr Susan Mary
Published: September 2017

Objectives

Adolescent risk behaviours are a key health concern. The purpose of this research is to gaina deeper understanding of how, why, for whom, and inwhat circumstances complex adolescent risk behaviourprevention programmes are most successful.

Methods and analysis

To understand how adolescent risk behaviour prevention programmes work in a reallife context, a realist synthesis will be undertaken, operationalised in four phases.

Phase oneDeveloping a framework to map the theoretical and conceptual landscape of adolescent risk behaviour prevention. Guided by stakeholder consultation.

Phase twoFormulating initial programme theories through exploration of the literature, along with primary data from professional stakeholder interviews.

Phase threeRefining programme theories through more purposeful, in depth screening of the literature, along with primary qualitative data, from young people and professionals. Data will be collected through semi structured focus groups, to explore specific elements of the emerging programme theories.

Phase fourTesting programme theories through interviews with youth workers, following consultation with young people, using vignettes to explore the relationship between specific programme theories. This relatively novel method of primary and secondary data integration within a realist synthesis will provide deeper insight in to young peoples lived experience of risk behaviour prevention programmes, while maintaining transparency in the process of programme theory development.

Data analysis

A realist logic of analysis will be used to align data from each phase with context mechanism outcome configurations or specific elements thereof. Substantive theory will then be sought to understand and explain the findings.

Ethics and dissemination

This study has been approved by the Ethics committee at Northumbria University, UK. Findings will be disseminated through knowledge exchange with stakeholders, publications in peer-reviewed journals, conference presentations, and formal and informal reports.
Perceptions of parents and paediatricians on pain induced by bone marrow aspiration and lumbar puncture among children with acute leukaemia: a qualitative study in China
Authors: Wang Yu , Liu Qiang , Yu Jia-Ning , Wang Hai-Xia , Gao Lu-Lu , Dai Ya-Liang , Jin Xin , Zuo Feng , Liu Juan , Bai Cai-Feng , Mu Guo-Xia , Chai Xiao-Min , Zhang Yin-Juan , Li Yu-Xiang , Yu Jian-Qiang
Published: September 2017

Objective

To obtain in-depth insight into the perceptions of parents and paediatricians in China regarding current procedural pain management on bone marrow aspirations and lumbar punctures in paediatric haemato-oncology department.

Design, setting and participants

This qualitative study was conducted in a 4500-bed university hospital in northwest China. To collect data, in-depth semistructured interviews were conducted with parents of children with acute leukaemia (n=12) and haemato-oncology paediatricians (n=11) using purposive sampling. Interviews were audiotaped and transcribed and subjected to thematic analysis.

Results

The suffering of procedural pain among paediatric patients was not adequately recognised and properly treated at the paediatric haemato-oncology department. The current paediatric procedural pain management is inadequate for paediatric patients. Crucial factors were identified including lack of awareness about the damage of uncontrolled pain in children, parents’ low supportive ability, the limited capacity to provide general analgesia by anaesthetists, inadequate knowledge in the usage of analgesia and sedation and lack of efficient analgesic for children’s procedural pain. The participants strongly expected optimal interventions to improve paediatric procedural pain management.

Conclusions

The result suggested a perceived and actual poor management of paediatric procedural pain in haemato-oncology department in northwest China. A relevant pain management education programme for paediatricians and parents as well as an effective pain medication are urgently needed in northwest China.

Trial registration

Chinese Clinical Trial Registry. Identifier: ChiCTR-INR-16007989.
Determinants of community pharmacists’ quality of care: a population-based cohort study using pharmacy administrative claims data
Authors: Winslade Nancy , Tamblyn Robyn
Published: September 2017

Objective

To determine if a prototype pharmacists’ services evaluation programme that uses linked community pharmacy claims and health administrative data to measure pharmacists’ performance can be used to identify characteristics of pharmacies providing higher quality of care.

Design

Population-based cohort study using community pharmacy claims from 1 November 2009 to 30 June 2010.

Setting

All community pharmacies in Quebec, Canada.

Participants

1742 pharmacies dispensing 8 655 348 antihypertensive prescriptions to 760 700 patients.

Primary outcome measure

Patient adherence to antihypertensive medications.

Predictors

Pharmacy level: dispensing workload, volume of pharmacist-provided professional services (eg, refusals to dispense, pharmacotherapy recommendations), pharmacy location, banner/chain, pharmacist overlap and within-pharmacy continuity of care. Patient level: sex, age, income, patient prescription cost, new/chronic therapy, single/multiple antihypertensive medications, single/multiple prescribers and single/multiple dispensing pharmacies. Dispensing level: prescription duration, time of day dispensed and antihypertensive class. Multivariate alternating logistic regression estimated predictors of the primary outcome, accounting for patient and pharmacy clustering.

Results

9.2% of dispensings of antihypertensive medications were provided to non-adherent patients. Male sex, decreasing age, new treatment, multiple prescribers and multiple dispensing pharmacies were risk factors for increased non-adherence. Pharmacies that provided more professional services were less likely to dispense to non-adherent hypertensive patients (OR: 0.60; 95% CI: 0.57 to 0.62) as were those with better scores on the Within-Pharmacy Continuity of Care Index. Neither increased pharmacists’ services for improving antihypertensive adherence per se nor increased pharmacist overlap impacted the odds of non-adherence. However, pharmacist overlap was strongly correlated with dispensing workload. There was significant unexplained variability among pharmacies belonging to different banners and chains.

Conclusions

Pharmacy administrative claims data can be used to calculate pharmacy-level characteristics associated with improved quality of care. This study supports the importance of pharmacist’s professional services and continuity of pharmacist’s care.
Does psychedelic drug use reduce risk of suicidality? Evidence from a longitudinal community-based cohort of marginalised women in a Canadian setting
Authors: Argento Elena , Strathdee Steffanie A , Tupper Kenneth , Braschel Melissa , Wood Evan , Shannon Kate
Published: September 2017

Objective

This study aimed to longitudinally investigate whether ever having used a psychedelic drug can have a protective effect on incidence of suicidality among marginalised women.

Design

Longitudinal community-based cohort study.

Setting

Data were drawn from a prospective, community-based cohort of marginalised women in Metro Vancouver, Canada.

Participants

766 women completed the baseline questionnaire between January 2010 and August 2014. Participants who did not report suicidality at baseline and who completed at least one follow-up visit were included.

Main outcome measure

Extended Cox regression was used to model predictors of new suicidality (suicide ideation or attempts) over 54-month follow-up.

Results

Nearly half (46%; n=355) of participants reported prior suicidality and were thus excluded from the present analyses. Of 290 women eligible at baseline, 11% (n=31) reported recent suicidality during follow-up, with an incidence density of 4.42 per 100 person-years (95% CI 3.10 to 6.30). In multivariable analysis, reported lifetime psychedelic drug use was associated with a 60% reduced hazard for suicidality (adjusted HR (AHR) 0.40; 95% CI 0.17 to 0.94). Crystal methamphetamine use (AHR 3.25; 95% CI 1.47 to 7.21) and childhood abuse (AHR 3.54; 95% CI 1.49 to 8.40) remained independent predictors of suicidality.

Conclusion

The high rate of suicidality identified in this study is of major concern. Alongside emerging evidence on the potential of psychedelic-assisted therapy to treat some mental illness and addiction issues, our findings demonstrate that naturalistic psychedelic drug use is independently associated with reduced suicidality, while other illicit drug use and childhood trauma predispose women to suicidality. While observational, this study supports calls for further investigation of the therapeutic utility of psychedelic drugs in treating poor mental health and promoting mental wellness.
Help-seeking behaviours, opportunistic treatment and psychological implications of adolescent acne: cross-sectional studies in schools and hospital outpatient departments in the UK
Authors: Desai Karishma Parimal , Martyn-Simmons Claire , Viner Russell , Segal Terry
Published: September 2017

Background

Acne vulgaris (acne) is a common adolescent skin condition. It is associated with negative psychological impacts and sufferers do not easily seek help, hence is undertreated.

Objectives

We investigated the self-reported prevalence, severity and psychological sequelae of acne, together with assessing help-seeking behaviour and its barriers, in separate school and hospital samples. We explored opportunistic treatment by paediatricians.

Methods

Self-reported survey with participants drawn from: (1) 120 adolescents aged 13–18 in a London tertiary paediatric outpatient department and (2) 482 adolescents from two London schools, aged 11–18. Adolescents confidentially and anonymously completed a questionnaire (paper or online) and those with acne completed the Cardiff Acne Disability Index (CADI) questionnaire.

Outcome measures

To explore if acne is being addressed opportunistically in outpatient appointments and the behaviours associated with seeking help and psychological implications of acne.

Results

Acne prevalence was reported as 58.3% in the clinic and 42.3% in schools, with 34.3% and 20.6% of participants having moderate acne (MA) or severe acne (SA), respectively. The correlation between acne severity and CADI was significant (regression coefficient=4.86, p<0.005 (MA) and 9.08, p<0.005 (SA) in the hospital; 1.92, p<0.001 (MA) and 7.41, p<0.005 (SA) in schools). Severity of acne was associated with increased likelihood of seeing a doctor in both samples (OR=8.95, 2.79–28.70 (MA) in the clinic and 1.31, 1.30–2.90 (MA) and 3.89, 0.66–22.98 (SA) in the community). Barriers to help seeking included embarrassment and believing doctors were unapproachable. Doctors addressed acne opportunistically in 2.9% of the sample, although 16.7% of those with MA and SA wished their doctor had raised it.

Conclusion

Acne is common and has negative psychological implications, correlating with severity. Young people often forego seeking help and hospital clinicians rarely address acne opportunistically. Further work is needed to investigate how to reduce barriers to help seeking for acne.
Protocol of a randomised controlled trial characterising the immune responses induced by varicella-zoster virus (VZV) vaccination in healthy Kenyan women: setting the stage for a potential VZV-based HIV vaccine
Authors: Perciani Catia T , Jaoko Walter , Walmsley Sharon , Farah Bashir , Mahmud Salaheddin M , Ostrowski Mario , Anzala Omu , Team KAVI-ICR , MacDonald Kelly S
Published: September 2017

Introduction

A protective HIV vaccine would be expected to induce durable effector immune responses at the mucosa, restricting HIV infection at its portal of entry. We hypothesise that use of varicella-zoster virus (VZV) as an HIV delivery vector could generate sustained and robust tissue-based immunity against HIV antigens to provide long-term protection against HIV. Given that HIV uniquely targets immune-activated T cells, the development of human vaccines against HIV must also involve a specific examination of the safety of the vector. Thus, we aim to evaluate the effects of VZV vaccination on the recipients’ immune activation state, and on VZV-specific circulating humoral and cellular responses in addition to those at the cervical and rectal mucosa.

Methods and analysis

This open-label, randomised, longitudinal crossover study includes healthy Kenyan VZV-seropositive women at low risk for HIV infection. Participants receive a single dose of a commercial live-attenuated VZVOkavaccine at either week 0 (n=22) or at week 12 (n=22) of the study and are followed for 48 and 36 weeks postvaccination, respectively. The primary outcome is the change on cervical CD4+T-cell immune activation measured by the coexpression of CD38 and HLA-DR 12 weeks postvaccination compared with the baseline (prevaccination). Secondary analyses include postvaccination changes in VZV-specific mucosal and systemic humoral and cellular immune responses, changes in cytokine and chemokine measures, study acceptability and feasibility of mucosal sampling and a longitudinal assessment of the bacterial community composition of the mucosa.

Ethics and dissemination

The study has ethical approval from Kenyatta National Hospital/University of Nairobi Ethics and Research Committee, the University of Toronto Research Ethics Board and by Kenyan Pharmacy and Poisons Board. Results will be presented at conferences, disseminated to participants and stakeholders as well as published in peer-reviewed journals.

Trial registration number

NCT02514018. Pre-results.
Prognostic factors for specific lower extremity and spinal musculoskeletal injuries identified through medical screening and training load monitoring in professional football (soccer): a systematic review
Authors: Hughes Tom , Sergeant Jamie C , Parkes Matthew J , Callaghan Michael J
Published: September 2017

Background

Medical screening and load monitoring procedures are commonly used in professional football to assess factors perceived to be associated with injury.

Objectives

To identify prognostic factors (PFs) and models for lower extremity and spinal musculoskeletal injuries in professional/elite football players from medical screening and training load monitoring processes.

Methods

The MEDLINE, AMED, EMBASE, CINAHL Plus, SPORTDiscus and PubMed electronic bibliographic databases were searched (from inception to January 2017). Prospective and retrospective cohort studies of lower extremity and spinal musculoskeletal injury incidence in professional/elite football players aged between 16 and 40 years were included. The Quality in Prognostic Studies appraisal tool and the modified Grading of Recommendations Assessment, Development and Evaluation synthesis approach was used to assess the quality of the evidence.

Results

Fourteen studies were included. 16 specific lower extremity injury outcomes were identified. No spinal injury outcomes were identified. Meta-analysis was not possible due to heterogeneity and study quality. All evidence related to PFs and specific lower extremity injury outcomes was of very low to low quality. On the few occasions where multiple studies could be used to compare PFs and outcomes, only two factors demonstrated consensus. A history of previous hamstring injuries (HSI) and increasing age may be prognostic for future HSI in male players.

Conclusions

The assumed ability of medical screening tests to predict specific musculoskeletal injuries is not supported by the current evidence. Screening procedures should currently be considered as benchmarks of function or performance only. The prognostic value of load monitoring modalities is unknown.
Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy
Authors: Zhou Jingying , Liu Man , Sun Hanyong , Feng Yu , Xu Liangliang , Chan Anthony W H , Tong Joanna H , Wong John , Chong Charing Ching Ning , Lai Paul B S , Wang Hector Kwong-Sang , Tsang Shun-Wa , Goodwin Tyler , Liu Rihe , Huang Leaf , Chen Zhiwei , Sung Joseph JY , Chow King Lau , To Ka Fai , Cheng Alfred Sze-Lok
Published: September 2017

Objective

Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).

Design

Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.

Results

Tumour-infiltrating CD11b+CD33+HLA-DR− MDSCs from patients with HCC potently inhibited autologous CD8+T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR− MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon γ+tumour necrosis factor-α+CD8+ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.

Conclusion

Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial
Authors: Furie Karen L , Viscoli Catherine M , Gorman Mark , Ford Gary A , Young Lawrence H , Inzucchi Silvio E , Guarino Peter D , Lovejoy Anne M , Conwit Robin , Tanne David , Kernan Walter N
Published: September 2017

Introduction

Patients with cerebrovascular disease are at increased risk for cognitive dysfunction. Modification of vascular risk factors, including insulin resistance, could improve poststroke cognitive function.

Methods

In the Insulin Resistance Intervention after Stroke (IRIS) trial, patients with a recent ischaemic stroke or transient ischaemic attack (TIA) were randomised to pioglitazone (target 45 mg daily) or placebo. All patients were insulin resistant based on a Homeostasis Model Assessment-Insulin Resistance score >3.0. For this preplanned analysis of cognitive function, we examined the Modified Mini-Mental State Examination (3MS) score (maximum score, 100) during follow-up. Patients were tested at baseline and annually for up to 5 years. Longitudinal mixed model methods were used to compare changes in the 3MS over time.

Results

Of the 3876 IRIS participants, 3398 had a 3MS score at baseline and at least once during follow-up and were included in the analysis. Median 3MS score at baseline was 97 (IQR 93–99). The average overall least squared mean 3MS score increased by 0.27 in the pioglitazone group and by 0.29 in the placebo group (mean difference between treatment groups −0.02; 95% CI −0.33 to 0.28, p=0.88).

Conclusions

Among insulin-resistant patients with a recent ischaemic stroke or TIA, pioglitazone did not affect cognitive function, as measured by the 3MS, over 5 years.

Trial registration

ClinicalTrials.gov NCT00091949; Results.
Evidence that iron accelerates Alzheimer’s pathology: a CSF biomarker study
Authors: Ayton Scott , Diouf Ibrahima , Bush Ashley Ian
Published: September 2017

Objective

To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau.

Methods

Mixed-effects models of CSF Aβ1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ1-42 for up to 5 years.

Results

In subjects with biomarker-confirmed Alzheimer’s pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer’s subjects from 18.8 to 10.8 years.

Conclusions

Iron might facilitate Aβ deposition in Alzheimer’s and accelerate the disease process.
Notch signaling modulates the electrical behavior of cardiomyocytes
Authors: Borghetti Giulia , Eisenberg Carol A. , Signore Sergio , Sorrentino Andrea , Kaur Keerat , Andrade-Vicenty Alejandro , Edwards John G. , Nerkar Mriganka , Qanud Khaled , Sun Dong , Goichberg Polina , Leri Annarosa , Anversa Piero , Eisenberg Leonard M. , Jacobson Jason T. , Hintze Thomas H. , Rota Marcello
Published: September 2017

Notch receptor signaling is active during cardiac development and silenced in myocytes after birth. Conversely, outward K+Kv currents progressively appear in postnatal myocytes leading to shortening of the action potential (AP) and acquisition of the mature electrical phenotype. In the present study, we tested the possibility that Notch signaling modulates the electrical behavior of cardiomyocytes by interfering with Kv currents. For this purpose, the effects of Notch receptor activity on electrophysiological properties of myocytes were evaluated using transgenic mice with inducible expression of the Notch1 intracellular domain (NICD), the functional fragment of the activated Notch receptor, and in neonatal myocytes after inhibition of the Notch transduction pathway. By patch clamp, NICD-overexpressing cells presented prolonged AP duration and reduced upstroke amplitude, properties that were coupled with reduced rapidly activating Kv and fast Na+currents, compared with cells obtained from wild-type mice. In cultured neonatal myocytes, inhibition of the proteolitic release of NICD with a γ-secretase antagonist increased transcript levels of the Kv channel-interacting proteins 2 (KChIP2) and enhanced the density of Kv currents. Collectively, these results indicate that Notch signaling represents an important regulator of the electrophysiological behavior of developing and adult myocytes by repressing, at least in part, repolarizing Kv currents.

NEW & NOTEWORTHY We investigated the effects of Notch receptor signaling on the electrical properties of cardiomyocytes. Our results indicate that the Notch transduction pathway interferes with outward K+Kv currents, critical determinants of the electrical repolarization of myocytes.
Role of lysophosphatidic acid and its receptors in the kidney
Authors: Park Frank , Miller Duane D.
Published: September 2017

Lysophosphatidic acid (LPA) is a bioactive phospholipid that can exert diverse biological effects in various diseased states of the kidney by activating at least six cognate G protein-coupled receptors and its complex network of heterotrimeric G proteins. In many models of acute and chronic kidney injury, pathological elevations in LPA promotes abnormal changes in renal tubular epithelial cell architecture by activating apoptotic signaling, recruits immune cells to the site of injury, and stimulates profibrotic signaling by increasing gene transcription. In renal cancers, LPA can promote vascular cell proliferation and tumor cell invasion. In this review, a summary will be provided to describe the involvement of LPA, its synthetic enzymes, and its associated receptors in normal and diseased kidneys. Further elucidation of the LPA system may open new doors in developing a lipid-receptor therapeutic platform for kidney diseases.
Cyclooxygenase 2: protein-protein interactions and posttranslational modifications
Authors: Alexanian Anna , Sorokin Andrey
Published: September 2017

Numerous studies implicate the cyclooxygenase 2 (COX2) enzyme and COX2-derived prostanoids in various human diseases, and thus, much effort has been made to uncover the regulatory mechanisms of this enzyme. COX2 has been shown to be regulated at both the transcriptional and posttranscriptional levels, leading to the development of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX2 inhibitors (COXIBs), which inhibit the COX2 enzyme through direct targeting. Recently, evidence of posttranslational regulation of COX2 enzymatic activity by s-nitrosylation, glycosylation, and phosphorylation has also been presented. Additionally, posttranslational regulators that actively downregulate COX2 expression by facilitating increased proteasome degradation of this enzyme have also been reported. Moreover, recent data identified proteins, located in close proximity to COX2 enzyme, that serve as posttranslational modulators of COX2 function, upregulating its enzymatic activity. While the precise mechanisms of the protein-protein interaction between COX2 and these regulatory proteins still need to be addressed, it is likely these interactions could regulate COX2 activity either as a result of conformational changes of the enzyme or by impacting subcellular localization of COX2 and thus affecting its interactions with regulatory proteins, which further modulate its activity. It is possible that posttranslational regulation of COX2 enzyme by such proteins could contribute to manifestation of different diseases. The uncovering of posttranslational regulation of COX2 enzyme will promote the development of more efficient therapeutic strategies of indirectly targeting the COX2 enzyme, as well as provide the basis for the generation of novel diagnostic tools as biomarkers of disease.
Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy
Authors: Huang Wen-Yen , Lai Shih-Fan , Chiu Hsien-Yi , Chang Michael , Plikus Maksim V. , Chan Chih-Chieh , Chen You-Tzung , Tsao Po-Nien , Yang Tsung-Lin , Lee Hsuan-Shu , Chi Peter , Lin Sung-Jan
Published: September 2017

Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem cells (SC) are maintained in the bulge region, and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HFs mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin 5+ basal hair bulb progenitors, rather than bulge SCs, were quickly activated to replenish matrix cells and regenerated all concentric layers of HFs, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired an SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SCs, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy. Cancer Res; 77(22); 6083–96. ©2017 AACR.
Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation
Authors: Yang Rui , Chen Lee H. , Hansen Landon J. , Carpenter Austin B. , Moure Casey J. , Liu Heng , Pirozzi Christopher J. , Diplas Bill H. , Waitkus Matthew S. , Greer Paula K. , Zhu Huishan , McLendon Roger E. , Bigner Darell D. , He Yiping , Yan Hai
Published: September 2017

Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur in approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and human oligodendroglioma cell models. Genetic deficiency in mice resulted in a partially penetrant embryonic or perinatal lethal phenotype, with the production of an aberrant proliferative neural population in surviving animals. In vitro cultured neural stem cells derived from Cic conditional knockout mice bypassed an EGF requirement for proliferation and displayed a defect in their potential for oligodendrocyte differentiation. Cic is known to participate in gene suppression that can be relieved by EGFR signal, but we found that cic also activated expression of a broad range of EGFR-independent genes. In an orthotopic mouse model of glioma, we found that Cic loss potentiated the formation and reduced the latency in tumor development. Collectively, our results define an important role for Cic in regulating neural cell proliferation and lineage specification, and suggest mechanistic explanations for how CIC mutations may impact the pathogenesis and therapeutic targeting of oligodendroglioma. Cancer Res; 77(22); 6097–108. ©2017 AACR.