bluuebunny/crossref_metadata_2025 huggingface dataset:
Pseudomonas brassicacearum Strain DF41 Kills Caenorhabditis elegans through Biofilm-Dependent and Biofilm-Independent Mechanisms
Authors: Nandi Munmun , Berry Chrystal , Brassinga Ann Karen C. , Belmonte Mark F. , Fernando W. G. Dilantha , Loewen Peter C. , de Kievit Teresa R.
Published: September 2016

Pseudomonas brassicacearumDF41 is a biocontrol agent that suppresses disease caused by the fungal pathogenSclerotinia sclerotiorum. A number of exometabolites are produced by DF41, including the lipopeptide sclerosin, hydrogen cyanide (HCN), and degradative enzymes. The production of these compounds is controlled at both the transcriptional and posttranscriptional levels by quorum sensing (QS) and the Gac two-component regulatory system. In order to be successful, a biocontrol agent must persist in the environment at levels sufficient for pathogen control. Bacterivorous predators, including nematodes, represent a challenge to the establishment of introduced microorganisms. In the current study, DF41 was investigated for its ability to resist predation byCaenorhabditis elegans. We discovered that this bacterium is capable of killingC. elegansthrough two different mechanisms: the first involves exposure to toxic metabolites, and the second entails biofilm formation on the nematode head blocking the buccal cavity. Biofilm formation on nematodes, which has been reported only forYersiniaspp. andXenorhabdus nematophila, is dependent upon the Gac system. Biofilms were not observed when bacteria were grown on NaCl-containing medium or onC. elegansbiofilm-resistant mutants. Coculturing with nematodes led to the increased expression of thepdfRI-rfiAQS genes andhcnA, which is under QS control. HCN was the most nematicidal of the exometabolites, suggesting that this bacterium can respond to predator cues and upregulate expression of toxins accordingly. In summary, DF41 is able to respond to the presence ofC. elegans, and through two distinct mechanisms, it can escape predation.

IMPORTANCEPseudomonas brassicacearumDF41 can suppress fungal pathogens through a process known as biocontrol. To be successful, a biocontrol agent must be able to persist in the environment at levels sufficient for pathogen control. Predators, including the nematodeCaenorhabditis elegans, represent a threat to persistence. The aim of the current study was to investigate the DF41-C. elegansinteraction. We discovered that DF41 is able to escape predation through two distinct mechanisms. The first involves exposure to toxic bacterial metabolites, and the second entails the formation of a sticky coating on the nematode head, called a biofilm, which blocks feeding and causes starvation. We report here a pseudomonad forming biofilms on theC. eleganssurface. When grown withC. elegans, DF41 exhibits altered gene expression and metabolite production, indicating that this bacterium can sense the presence of these predators and adjust its physiology accordingly.
Structural pathology is not related to patient-reported pain and function in patients undergoing meniscal surgery
Authors: Tornbjerg Simon Maretti , Nissen Nis , Englund Martin , Jørgensen Uffe , Schjerning Jeppe , Lohmander L Stefan , Thorlund Jonas Bloch
Published: September 2016

Background

The relationship between meniscal tears and other joint pathologies with patient-reported symptoms is not clear. We investigated associations between structural knee pathologies identified at surgery with preoperative knee pain and function in patients undergoing arthroscopic meniscal surgery.

Methods

This study included 443 patients from the Knee Arthroscopy Cohort Southern Denmark (KACS), a prospective cohort following patients 18 years or older undergoing arthroscopic meniscal surgery at 4 hospitals between 1 February 2013 and 31 January 2014. Patient-reported outcomes, including the Knee Injury and Osteoarthritis Outcome Score (KOOS), were obtained by online questionnaires prior to surgery. Knee pathology was assessed by the operating surgeons using a modified version of the International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine (ISAKOS) classification of meniscal tears questionnaire, supplemented with information extracted from surgery reports. Following hypothesis-driven preselection of candidate variables, backward elimination regressions were performed to investigate associations between patient-reported outcomes and structural knee pathologies.

Results

Regression models only explained a small proportion of the variability in self-reported pain and function (adjusted R2=0.10−0.12) and this association was mainly driven by age, gender and body mass index.

Conclusions

Specific meniscal pathology and other structural joint pathologies found at meniscal surgery were not associated with preoperative self-reported pain and function in patients with meniscal tears questioning inferences made about a direct relationship between these. Our findings question the role of arthroscopic surgery to address structural pathology as a means to improve patient-reported outcomes in patients having surgery for a meniscal tear.
Does it matter whether physicians' recommendations are given early or late in the decision-making process? An experimental study among patients with schizophrenia
Authors: Hamann Johannes , Kissling Werner , Mendel Rosmarie
Published: September 2016

Objectives

Physicians' recommendations are seen as an essential component in many models of medical decision-making, including shared decision-making. It is, however, unclear at what time in the decision-making process the recommendation is best given, not to adversely influence patient preferences. Within the present study we wanted to evaluate at what time in the decision-making process a doctor's recommendation is best given, not to adversely influence patient preferences.

Design

We performed an experimental study involving hypothetical decisions vignettes and compared the influence of 3 conditions (no advice, early advice, late advice) on patients' decision-making.

Setting

N=21 psychiatric hospitals in Germany.

Participants

N=208 inpatients suffering from schizophrenia.

Primary and secondary outcome measures

The main outcome was the number of patients choosing the option in each experimental condition that had been less preferable to most patients during pretests. Additional outcome measures were patient satisfaction and reactance.

Results

Patients in the ‘late advice’ condition more often (n=49) accepted an advice that was against their preferences compared with the other conditions (n=36 for ‘early advice’, p=0.024).

Conclusions

Although giving advice is an important part of every doctor's daily practice and is seen as an essential element of shared decision-making, hitherto there has been little empirical evidence relating to the influence of physicians' advice on patients' decision-making behaviour. With our study we could show that the point in time an advice is given by a physician does have an influence on patients' decisional behaviour even if the mechanism of this effect is not yet understood.
Effect of a national requirement to introduce named accountable general practitioners for patients aged 75 or older in England: regression discontinuity analysis of general practice utilisation and continuity of care
Authors: Barker Isaac , Lloyd Therese , Steventon Adam
Published: September 2016

Objective

To assess the effect of introducing named accountable general practitioners (GPs) for patients aged 75 years on patterns of general practice utilisation, including continuity of care.

Design

Regression discontinuity design applied to data from the Clinical Practice Research Datalink to estimate the treatment effect for compliers aged 75.

Setting

200 general practices in England.

Participants

255 469 patients aged between 65 and 85, after excluding those aged 75.

Intervention

From April 2014, general practices in England were required to offer patients aged 75 or over a named accountable GP. This study compared having named accountable GPs for patients aged just over 75 with usual care provided for patients just under 75.

Outcomes

Number of contacts (face-to-face or telephone) with GPs, longitudinal continuity of care (usual provider of care, or UPC, index), number of referrals to specialist care and numbers of common diagnostic tests. Outcomes were measured over 9 months following assignment to a named accountable GP and for a comparable period for those unassigned.

Results

The proportion of patients with a named accountable GP increased from 3.5% to 79.8% at age 75. No statistically significant effects were detected for continuity of care (estimated treatment effect 0.00, 95% CI −0.01 to 0.02) or the number of GP contacts per person (estimated treatment effect −0.11, 95% CI −0.31 to 0.09) over 9 months. No significant change was seen in the number of referrals, blood pressure or HbA1c diagnostic tests per person. A statistically significant treatment effect of −0.05 cholesterol tests per person (95% CI −0.07 to −0.02) was estimated; however, sensitivity analysis indicated that this effect predated the introduction of named accountable GPs.

Conclusions

Continuity of care is valued by patients, but the named accountable GP initiative did not improve continuity of care or change patterns of GP utilisation in the first 9 months of the policy.
Long-term responses to treatment in UK veterans with military-related PTSD: an observational study
Authors: Murphy Dominic , Spencer-Harper Lucy , Carson Carron , Palmer Emily , Hill Kate , Sorfleet Nicola , Wessely Simon , Busuttil Walter
Published: September 2016

Objectives

Military-related trauma can be difficult to treat. Evaluating longer term responses to treatment and identifying which individuals may need additional support could inform clinical practice. We assessed 1-year outcomes in UK veterans treated for post-traumatic stress disorder (PTSD).

Design

Within-participant design.

Setting

The intervention was offered by Combat Stress, a mental health charity for veterans in the UK.

Participants

The sample included 401 veterans who completed a standardised 6-week residential treatment. Of these, 268 (67%) were successfully followed up a year after the end of treatment.

Methods

A range of health outcomes were collected pretreatment and repeated at standard intervals post-treatment. The primary outcome was severity of PTSD symptoms, and secondary outcomes included measures of other mental health difficulties (depression, anxiety and anger), problems with alcohol, and social and occupational functioning.

Results

Significant reductions in PTSD severity were observed a year after treatment (PSS-I: −11.9, 95% CI −13.1 to −10.7). Reductions in the secondary outcomes were also reported. Higher levels of post-treatment functional impairment (0.24, 95% CI 0.08 to 0.41) and alcohol problems (0.18, 95% CI 0.03 to 0.32) were associated with poorer PTSD treatment response at 12 months.

Conclusions

This uncontrolled study suggests the longer term benefits of a structured programme to treat UK veterans with PTSD. Our findings point to the importance of continued support targeted for particular individuals post-treatment to improve longer term outcomes.
Education, night splinting and exercise versus usual care on recovery and conversion to surgery for people awaiting carpal tunnel surgery: a protocol for a randomised controlled trial
Authors: Lewis Karina J , Ross Leo , Coppieters Michel W , Vicenzino Bill , Schmid Annina B
Published: September 2016

Introduction

Carpal tunnel syndrome (CTS) is a prevalent upper limb condition that results in significant individual and socioeconomic costs. Large patient numbers, long outpatient waiting times and traditional referral pathways in public health systems create delays in accessing treatment for this condition. Alternative care pathways aimed at streamlining access to treatment and reducing the need for surgical intervention warrant further investigation.

Methods

A randomised, single-blind controlled clinical trial will be conducted. 128 participants aged 18–75 years with CTS will be recruited from the carpal tunnel surgery waitlists of participating public hospitals. Suitable participants will be stratified for severity and randomly allocated to either receive therapy (education, provision of splints and a home exercise programme) or standard care (continuing on the waitlist without hand therapy intervention for the duration of the study). Outcomes will be measured at baseline and after 6 weeks and 6 months. Primary outcomes are conversion to surgery ratio and perceived effect via the Global Rating of Change Scale.

Secondary measures include patient satisfaction, and monitoring of symptoms and function using outcome measures including the Boston CTS Questionnaire, Disability of Arm, Shoulder and Hand Questionnaire, Patient-Specific Functional Scale, patient completed diagram of symptoms and Self-reported Leeds Assessment of Neuropathic Symptoms and Signs pain scale.

Discussion

This paper outlines the design and rationale for a randomised controlled trial that aims to assess the efficacy of an alternative care pathway for the management of patients with CTS while on the surgery waitlist. It is anticipated that the outcomes of this study will contribute to improved and expedited management of this common condition in a public hospital setting.

Ethics and dissemination

Ethics approval was granted by the Princess Alexandra Hospital Centres for Health Research (HREC/13/QPAH/434—SSA/13/QPAH/447) and the Medical Research Ethics Committee at the University of Queensland. Results will be disseminated via conferences and peer-reviewed publications.

Trial registration number

ACTRN12613001095752.
Anti-inflammatory effect of prophylactic macrolides on children with chronic lung disease: a protocol for a double-blinded randomised controlled trial
Authors: Mosquera Ricardo A , Gomez-Rubio Ana M , Harris Tomika , Yadav Aravind , McBeth Katrina , Gonzales Traci , Jon Cindy , Stark James , Avritscher Elenir , Pedroza Claudia , Smith Keely , Colasurdo Giuseppe , Wootton Susan , Piedra Pedro , Tyson Jon E , Samuels Cheryl
Published: September 2016

Introduction

Recent studies suggest that the high mortality rate of respiratory viral infections is a result of an overactive neutrophilic inflammatory response. Macrolides have anti-inflammatory properties, including the ability to downregulate the inflammatory cascade, attenuate excessive cytokine production in viral infections, and may reduce virus-related exacerbations. In this study, we will test the hypothesis that prophylactic macrolides will reduce the severity of respiratory viral illness in children with chronic lung disease by preventing the full activation of the inflammatory cascade.

Methods and analysis

A randomised double-blind placebo-controlled trial that will enrol 92 children to receive either azithromycin or placebo for a period of 3–6 months during two respiratory syncytial virus (RSV) seasons (2015–2016 and 2016–2017). We expect a reduction of at least 20% in the total number of days of unscheduled face-to-face encounters in the treatment group as compared with placebo group. Standard frequentist and Bayesian analyses will be performed using an intent-to-treat approach.

Discussion

We predict that the prophylactic use of azithromycin will reduce the morbidity associated with respiratory viral infections during the winter season in patients with chronic lung disease as evidenced by a reduction in the total number of days with unscheduled face-to-face provider encounters.

Ethics and dissemination

This research study was approved by the Institutional Review Board of the University of Texas Health Science Center in Houston on 9 October 2014. On completion, the results will be published.

Trial registration number

NCT02544984.
Exploring senior doctors’ beliefs and attitudes regarding mental illness within the medical profession: a qualitative study
Authors: Bianchi Eleonora F , Bhattacharyya Mimi R , Meakin Richard
Published: September 2016

Objective

To explore the views of senior doctors on mental illness within the medical profession.

Background

There has been increasing interest on the issue of doctors’ mental health. However, there have been few qualitative studies on senior doctors’ general attitude towards mental illness within the medical profession.

Setting

Large North London teaching hospital.

Participants

13 hospital consultants and senior academic general practitioners.

Methods

A qualitative study involving semi-structured interviews and reflective work. The outcome measures were the themes derived from the thematic framework approach to analysis.

Results

Four main themes were identified. (1) ‘Doctors’ attitudes to mental illness’—doctors felt that there remained a significant stigma attached to suffering from a mental illness within the profession. (2) ‘Barriers to seeking help’—doctors felt that there were numerous barriers to seeking help such as negative career implications, being perceived as weak, denial and fear of prejudice. (3) ‘Support’—doctors felt that the use of support depended on certainty concerning confidentiality, which for occupational health was not thought to be guaranteed. Confiding in colleagues was rare except among close friends. Supervision for all doctors was raised. (4) ‘General Medical Council (GMC) involvement’—doctors felt that uneasy referring colleagues to the GMC and the appraisal and revalidation process was thought not to be thorough enough in picking up doctors with a mental illness.

Conclusions

Owing to the small size of this study, the conclusions are limited; however, if the findings are confirmed by larger studies, they suggest that greater efforts are needed to destigmatise mental illness in the profession and improve support for doctors. Additional research should be carried out into doctors’ views on occupational health services in managing doctors with mental illness, the provision of supervision for all doctors and the effectiveness of the current appraisal and revalidation process at identifying doctors with a mental illness.
Crash course in EPaCCS (Electronic Palliative Care Coordination Systems): 8 years of successes and failures in patient data sharing to learn from
Authors: Petrova Mila , Riley Julia , Abel Julian , Barclay Stephen
Published: September 2016

Background

Electronic Palliative Care Coordination Systems (EPaCCS) are England's pre-eminent initiative in enabling advance care planning and improved communication and coordination at the end of life. EPaCCS have been under development for 8 years after being proposed, as Locality Registers, in the 2008 End of Life Care Strategy for England. EPaCCS are electronic registers or tools and processes for sharing data which aim to enable access to information about dying patients. Striking outcomes have been reported around EPaCCS, such as 77.8% of ‘Coordinate My Care’ patients dying in their preferred place. EPaCCS have, however, been extremely challenging to develop and implement, with many projects remaining continuously ‘under development’ or folding. They also continue to be suboptimally integrated with other data sharing initiatives. Rigorous research is non-existent.

Discussion points

We discuss the current EPaCCS landscape and way forward. We summarise key facts concerning the availability, uptake, outcomes and costs of EPaCCS. We outline 5 key challenges (scope of projects, unrealistic expectations set by existing guidance, the discrepancy between IT realities in healthcare and our broader lives, information governance and ‘death register’ associations) and 6 key drivers (robust concept, striking outcomes, national support and strong clinical leadership, clinician commitment, education and funding).

Conclusions

The priorities for advancing EPaCCS we propose include linking to other work streams and reframing the concept, potentially making it less ‘end of life’, overview of current EPaCCS and lessons learnt, continuing work on information standards, rethinking of national funding and new levels of individual and community involvement.
Use of the Triglyceride/High-Density Lipoprotein Cholesterol Ratio to Identify Cardiometabolic Risk: Impact of Obesity?
Authors: Salazar M R , Carbajal H A , Espeche W G , Aizpurúa M , Marillet A G , Leiva Sisnieguez C E , Leiva Sisnieguez B C , Stavile R N , March C E , Reaven G M
Published: September 2016

There is evidence that the plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) identifies insulin resistance and increased cardiometabolic risk and outcome in apparently healthy individuals. Since use of the TG/HDL-C ratio to accomplish this task in persons over a wide range of adiposity has not been studied, the ability of previously defined sex-specific TG/HDL-C cut-points to identify increased cardiometabolic risk was evaluated in apparently healthy normal weight, overweight, and obese individuals. Data were analyzed from a population-based study of apparently healthy men (n=416) and women (n=893), subdivided into categories by body mass index (BMI, kg/m2): normal weight (BMI 20.0–24.9), overweight (BMI 25.0–29.9) and obese (BMI 30.0–34.9). The adiposity groups were further stratified on the basis of their TG/HDL-C ratio into groups defined as being either at ‘high risk’ versus ‘low risk’ of cardiometabolic disease. Multiple cardiometabolic risk factors were compared between these subgroups, as was their degree of insulin resistance assessed by fasting plasma insulin concentration and homeostasis model assessment of insulin resistance. The proportion of high-risk individuals varied with BMI category, ranging from 14% (normal weight) to 36% (obese). However, within each BMI category high-risk individuals had a significantly more adverse cardiometabolic risk profile. Finally, the adjusted OR of being insulin resistant was significantly greater in those with a high TG/HDL-C ratio in the normal (3.02), overweight (2.86), and obese (2.51) groups. Thus, irrespective of differences in BMI, the TG/HDL-C ratio identified apparently healthy persons with a more adverse cardiometabolic risk profile associated with an increased prevalence of insulin resistance.
Seismic imaging of Late Miocene (Messinian) evaporites from Western Mediterranean back-arc basins
Authors: Dal Cin M. , Del Ben A. , Mocnik A. , Accaino F. , Geletti R. , Wardell N. , Zgur F. , Camerlenghi A.
Published: September 2016

An analysis of multichannel seismic reflection data was conducted focusing on the comparison between the Messinian Salinity Crisis (MSC) and Plio-Quaternary (PQ) evolution of the eastern Sardo-Provençal and northern Algero-Balearic basins and related margins in the West Mediterranean Sea. Both basins were completely opened during the MSC and their well-defined seismic stratigraphy is very similar in the deep parts. The primary difference between these two basins is due to their different pre-MSC extensional history, including the opening age and the stretching factors. These factors influenced the occurrence of post-MSC salt tectonics on these margins.
Why are there no Messinian evaporites in the Black Sea?
Authors: Tari G. , Fallah M. , Schell C. , Kosi W. , Bati Z. , Sipahioğlu N. Ö. , Krezsek Cs. , Schleder Zs. , Kozhuharov E. , Kitchka A.
Published: September 2016

An unconformity has been observed along the Black Sea shelf on seismic reflection profiles and wells which is broadly similar to the one associated with that formed during the Messinian salinity crisis (MSC) in the Mediterranean. Therefore, this intra- (or Middle) Pontian unconformity has been traditionally interpreted as the manifestation of the MSC in the Black Sea Basin. However, the magnitude of the sea-level fall associated with this erosive surface does not appear to be nearly as significant as was assumed previously. Also, the inferred MSC surface itself cannot be easily followed into the palaeo-deep-water basin as a regional unconformity in the same manner as in the Mediterranean. Moreover, around the Black Sea, there is no evidence of major river incisions during the MSC, unlike the well-documented cases in the Mediterranean region. If the MSC evaporites in the Mediterranean indeed deposited in a subaerial setting at the basin floor, the lack of a major drawdown in the Black Sea explains why there are no Messinian evaporites in the Black Sea. Owing to the approximately 500 m MSC sea-level drop the Black Sea basin system, this basin did not even get close to the conditions required for the formation of evaporites in the basin centre. As the magnitude of the sea-level drop and the overall impact of the MSC in the Black Sea is interpreted to be less significant than in the Mediterranean, the risk of breaching pre-existing hydrocarbon traps during the MSC is less than has been suggested before.
Risking fault reactivation induced by gas injection into depleted reservoirs based on the heterogeneity of geomechanical properties of fault zones
Authors: Meng Lingdong , Fu Xiaofei , Lv Yanfang , Li Xianli , Cheng Yabin , Li Tingwei , Jin Yejun
Published: September 2016

Predictions of fault reactivation and the hydraulic seal of cap rock are integral parts of the seal integrity research programme of the Banzhongbei gas storage facility (BGS) to ensure the safe storage of natural gas in subsurface reservoirs. We attempt to combine the heterogeneity of geomechanical properties, including frictional coefficient and cohesive strength, into a workflow to estimate fault reactivation risk and the maximum sustainable fluid pressure that will not induce failure of trap-bounding faults and cap rock. Based on the Griffith – Coulomb Failure criterion, fault failure modes – including tensile failure, shear failure and hybrid failure – may occur under conditions of the same
in situ
stress field as a result of the strength heterogeneity of fault rocks, which plays a key role in the estimation of integrity of the entire fault trap. The juxtaposition of the seal on the BQ Fault with high shale gouge ratio (SGR) values makes a significant contribution to the high fluid pressure build-ups during gas injection, and its low strength properties lead to a higher reactivation risk for the Banqiao (BQ) Fault than for the B816 Fault. The increased pore-fluid pressure adjacent to the BQ Fault induced by gas injection should be lower than 9.7 MPa in order to avoid failure. Furthermore, the maximum sustainable fluid pressure of the cap rock is approximately 13.9 MPa at the locations of the injection wells.
Linking capillary and mechanical seal capacity mechanisms
Authors: Underschultz J. R.
Published: September 2016

Mechanical fault reactivation is a mechanism where high fluid pressures generated within a fault zone can change the effective stress such that an optimally orientated fault segment will rupture. This style of strain has been recognized in three settings: (1) deep crustal locations at greenschist and higher-grade metamorphism with fluid generation; (2) active plate boundaries where tectonic stresses can result in seismicity; and (3) hydrocarbon column buoyancy pressure reactivation of critically stressed fault-bound traps. This paper examines category 3 in the context of mechanical fault reactivation and capillary processes. For water-wetting fault rock, mechanical reactivation may be reached prior to the capillary seal capacity. However, the non-wetting fluid cannot access the fault rock pore space until the hydrocarbon column height reaches the capillary threshold pressure. At the threshold pressure, the non-wetting fluid enters the fault rock imparting a buoyancy pressure in excess of the mechanical reactivation threshold causing rupture. This suggests that in certain circumstances the mechanical fault reactivation by buoyancy pressure is more accurately predicted by the capillary threshold pressure than mechanical reactivation pressure.
The impact of the Messinian salinity crisis on the petroleum system of the Eastern Mediterranean: a critical assessment using 2D petroleum system modelling
Authors: Al-Balushi Abdulaziz Nasser , Neumaier Martin , Fraser Alastair J. , Jackson Christopher A-L.
Published: September 2016

The offshore Levant Basin demonstrates one of the most phenomenal natural examples of a working petroleum system associated with a relatively rapid unloading and loading cycle caused by the Messinian salinity crisis (MSC). In this study, 2D basin and petroleum systems modelling suggests that the geologically instantaneous water unloading of approximately 2070 m, and subsequent rapid salt deposition and refill, impact the subsurface pore pressure and temperature in the underlying sediments. The pressure drop is modelled to be instantaneous, whereas the impact on temperature is more of a transient response. This has important consequences for the shallow sub-Messinian biogenic petroleum system, which is assumed to have experienced fluid brecciation associated with massive fluid escape events. Deeper Oligo-Miocene sediments are far less affected, thus indicating a ‘preservation window’ for biogenic gas accumulations, which host the recent discoveries (Tamar, Leviathan, Aphrodite). Hydrocarbon accumulations of a ‘bubblepoint oil’ composition are modelled to have experienced cap expansion during the drawdown, with the pressure drop being the primary control. This study suggests that seal-limited traps are expected to have undergone a catastrophic seal failure, whereas the impact of the MSC is modelled to be less destructive for size-limited and, particularly, charge-limited traps.
Model fusion at the British Geological Survey: experiences and future trends
Authors: Peach Denis , Riddick Andrew , Hughes Andrew , Kessler Holger , Mathers Steve , Jackson Christopher , Giles Jeremy
Published: September 2016

The British Geological Survey (BGS) is developing integrated environmental models to address the grand challenges that face society. Here we describe the BGS vision for an Environmental Modelling Platform (BGS 2009) that will allow integrated models to be built, and describe case studies of emerging models in the United Kingdom.

This Environmental Modelling Platform will be founded on the data and information that the BGS holds. This will have to be made as accessible and interoperable as possible to both the academic and stakeholder decision-making community. The geological models that have been built in an
ad hoc
way over the last 5–10 years will be encompassed in a National Geological Model that will be multi-scaled, beginning with onshore UK and eventually including the offshore continental shelf. The future will be characterized by the routine delivery of 3D model products from a multi-scaled and scalable 3D geological model of the UK that can be dynamically updated. The deployment of this model will generate further significant requirements across the Information and Knowledge Exchange spectrum, from applications development (database, GIS, web and mobile device), data management, information product development, to delivery to a growing number of publics and stakeholders.
Seismic slip on the west flank of the Upper Rhine Graben (France–Germany): evidence from tectonic morphology and cataclastic deformation bands
Authors: Shipton Zoe K. , Meghraoui Mustapha , Monro Louise
Published: September 2016

The Upper Rhine Graben (URG) is a seismically active tectonic structure in intraplate Europe. Large and moderate earthquakes have occurred along the URG in the past but no coseismic surface faulting has been reported so far. We investigated active faulting along the western edge of the northern URG and identified the 25 km-long linear Riedseltz–Landau normal fault scarp as a major tectonic structure affecting late Pleistocene and Holocene deposits. The fault zone is exposed in the Riedseltz quarry where it affects Pliocene sand and gravels and overlying late Pleistocene (Wurm) units. These units have not been buried deeper than a few tens of metres and yet the fault zone contains cataclastic deformation textures. Cataclasis is demonstrated by spalling and transgranular fractures in quartz grains concentrated in deformation bands with reduced grain size. The observed microstructures suggest multiple phases of deformation with cataclasis followed by emplacement of a prominent Fe-oxide matrix into deformation bands, and later emplacement of a clay-rick matrix into fractures. Previous geological and geophysical studies along the fault show late Pleistocene (Wurm) loess deposits (
c.
24–10 ka before present) and early Holocene sand–silty deposits with individual or cumulative 1.5 and 0.7 m surface slip, respectively. Field observations and previous results from shallow geophysics provide a minimum 0.15 mm a
−1
time-averaged slip rate. The Riedseltz fault parameters integrated in a dislocation model suggest a minimum Mw 6.6 earthquake as a plausible scenario in the northern URG. The observations of cataclasis in shallowly buried sediments coupled with observations of the late Quaternary fault scarp call for palaeoseismic studies that may document the occurrence of a larger earthquake on the western edge of URG. Surface faulting of young, shallowly buried sediments associated with cataclasis provides new evidence for assessing the occurrence of large earthquakes and seismic hazard assessment in the northern URG.
Insight into the structures below the Deccan Trap-covered region of Maharashtra, India from geopotential data
Authors: Rajaram Mita , Anand S. P. , Erram V. C. , Shinde B. N.
Published: September 2016

Ground magnetic data collected at an average data spacing of 5 km over the Deccan Traps in Maharashtra, India are studied. In conjunction with a magnetic anomaly map generated from ground, aero and marine magnetic data, seven lineaments are identified below the Deccan Traps: six NW–SE-trending lineaments (Ln1 to Ln6) and a NE–SW-oriented lineament, Ln7. From the filtered Bouguer gravity data the sources at different depths are studied. From combined analysis we find that Ln1 coincides with the continuation of Bababudan Nallur Shear zone. The boundary between the Western and Eastern Dharwar cratons, the Chitradurg Boundary Shear, merges with Ln2. Ln3 is part of the Peninsular Lineament identified earlier. Ln4 coincides in part with the Bhima River, while Ln5 and Ln6 are possibly related to Godavari rifting. The region between Ln4 and Ln5 relates to the Kurudwadi Lineament Zone. The Kaladgi and Bhima sediments and the schist belts continue northwards below the Deccan Traps and are constrained to lie to the south of NE–SW-oriented Ln7. With the exception of Ln3 (the Peninsular Lineament) the other six lineaments below the Deccan Traps are identified for the first time. The crustal structure below the Deccan Traps that we derive from 2D modelling of combined gravity and magnetic data supports the presence of the identified lineaments.
Vascular function assessed by passive leg movement and flow-mediated dilation: initial evidence of construct validity
Authors: Rossman Matthew J. , Groot H. Jonathan , Garten Ryan S. , Witman Melissa A. H. , Richardson Russell S.
Published: September 2016

The vasodilatory response to passive leg movement (PLM) appears to provide a novel, noninvasive assessment of vascular function. However, PLM has yet to be compared with the established noninvasive assessment of vascular health, flow-mediated dilation (FMD). Therefore, as an initial evaluation of the construct validity of PLM and upright seated and supine PLM as well as brachial (BA) and superficial femoral (SFA) artery FMDs were performed in 10 young (22 ± 1) and 30 old (73 ± 2) subjects. During upright seated PLM, the peak change in leg blood flow (ΔLBF) and leg vascular conductance (ΔLVC) was significantly correlated with BA ( r = 0.57 and r = 0.66) and SFA ( r = 0.44 and r = 0.41, ΔLBF and ΔLVC, respectively) FMD. Furthermore, although the relationships were not as strong, the supine PLM response was also significantly correlated with BA ( r = 0.38 and r = 0.35) and SFA ( r = 0.39 and r = 0.35, ΔLBF and ΔLVC, respectively) FMD. Examination of the young and old separately, however, revealed that significant relationships persisted in both groups only for the upright seated PLM response and BA FMD (young: r = 0.73 and r = 0.77; old: r = 0.35 and r = 0.45, ΔLBF and ΔLVC, respectively). Normalizing FMD for shear rate during PLM abrogated all significant relationships between the PLM and FMD response, suggesting a role for nitric oxide (NO) in these associations. Collectively, these data indicate that PLM, particularly upright seated PLM, likely provides an index of vascular health analogous to the traditional FMD test. Given the relative ease of PLM implementation, these data have important positive implications for PLM as a clinical vascular health assessment.
Exercise intensity modulates the appearance of circulating microvesicles with proangiogenic potential upon endothelial cells
Authors: Wilhelm Eurico N. , González-Alonso José , Parris Christopher , Rakobowchuk Mark
Published: September 2016

The effect of endurance exercise on circulating microvesicle dynamics and their impact on surrounding endothelial cells is unclear. Here we tested the hypothesis that exercise intensity modulates the time course of platelet (PMV) and endothelial-derived (EMV) microvesicle appearance in the circulation through hemodynamic and biochemical-related mechanisms, and that microvesicles formed during exercise would stimulate endothelial angiogenesis in vitro. Nine healthy young men had venous blood samples taken before, during, and throughout the recovery period after 1 h of moderate [46 ± 2% maximal oxygen uptake (V̇o2max)] or heavy (67 ± 2% V̇o2max) intensity semirecumbent cycling and a time-matched resting control trial. In vitro experiments were performed by incubating endothelial cells with rest and exercise-derived microvesicles to examine their effects on cell angiogenic capacities. PMVs (CD41+) increased from baseline only during heavy exercise (from 21 ± 1 × 103to 55 ± 8 × 103and 48 ± 6 × 103PMV/μl at 30 and 60 min, respectively; P < 0.05), returning to baseline early in postexercise recovery ( P > 0.05), whereas EMVs (CD62E+) were unchanged ( P > 0.05). PMVs were related to brachial artery shear rate ( r2= 0.43) and plasma norepinephrine concentrations ( r2= 0.21) during exercise ( P < 0.05). Exercise-derived microvesicles enhanced endothelial proliferation, migration, and tubule formation compared with rest microvesicles ( P < 0.05). These results demonstrate substantial increases in circulating PMVs during heavy exercise and that exercise-derived microvesicles stimulate human endothelial cells by enhancing angiogenesis and proliferation. This involvement of microvesicles may be considered a novel mechanism through which exercise mediates vascular healing and adaptation.
Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury
Authors: McHugh Walker M. , Russell William W. , Fleszar Andrew J. , Rodenhouse Paul E. , Rietberg Skyler P. , Sun Lei , Shanley Thomas P. , Cornell Timothy T.
Published: September 2016

Acute respiratory distress syndrome (ARDS) remains a leading cause of morbidity and mortality in both adult and pediatric intensive care units. A key event in the development of ARDS is neutrophil recruitment into the lungs leading to tissue damage and destruction. Interleukin-8 (IL-8) is the major human chemokine responsible for neutrophil recruitment into the lungs. Protein phosphatase 2A (PP2A) has been shown to be a key regulator of the mitogen-activated protein kinase (MAPK) cascades, which control the production of IL-8. Previously, our laboratory employed an in vitro model to show that inhibition of PP2A results in an increase in IL-8 production in human alveolar epithelial cells. The objective of this study was to determine whether PP2A regulated this response in vivo by investigating the impact of pharmacologic activation of PP2A on chemokine production and activation of the MAPK cascade and lung injury using endotoxin- and bacterial-challenge models of ARDS in mice. N6-cyclopentyladenosine ( N6-CPA) increased PP2A activity and inhibited endotoxin-induced cytokine production in a murine alveolar macrophage cell line. N6-CPA pretreatment in mice challenged with intratracheal endotoxin decreased chemokine production, reduced neutrophil infiltration, and attenuated lung injury. Following initiation of lung injury with live Pseudomonas aeruginosa, mice that received N6-CPA 4 h following bacterial challenge showed attenuated chemokine production and reduced neutrophil infiltration compared with control mice. Pharmacologic PP2A activation both limited and prevented inflammation and tissue injury in two direct injury models of ARDS. These results suggest modulation of PP2A activity as a therapeutic target in ARDS.
The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation
Authors: Nguyen Hang , Uhal Bruce D.
Published: September 2016

Recent work from this laboratory showed that endoplasmic reticulum (ER) stress-induced apoptosis of alveolar epithelial cells (AECs) is regulated by the autocrine angiotensin (ANG)II/ANG1-7 system. The proteasome inhibitor MG132 or surfactant protein C (SP-C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating the proapoptotic cathepsin D and reducing antiapoptotic angiotensin converting enzyme-2 (ACE-2). This study tested the hypothesis that ER stress-induced apoptosis of human AECs might be mediated by influence of the unfolded protein response (UPR) on the autocrine ANGII/ANG1-7 system. A549 cells were challenged with MG132 or SP-C BRICHOS domain mutant G100S to induce ER stress and activation of UPR pathways. The results showed that either MG132 or G100S SP-C mutation activated all three canonical pathways of the UPR (IRE1/XBP1, ATF6, and PERK/eIF2α), which led to a significant increase in cathepsin D or in TACE (an ACE-2 ectodomain shedding enzyme) and eventually caused AEC apoptosis. However, ER stress-induced AEC apoptosis could be prevented by chemical chaperone or by UPR blockers. It is also suggested that ATF6 and IRE1 pathways might play important role in regulation of angiotensin system. These data demonstrate that ER stress induces apoptosis in human AECs through mediation of UPR pathways, which in turn regulate the autocrine ANGII/ANG1-7 system. They also demonstrated that ER stress-induced AEC apoptosis can be blocked by inhibition of UPR signaling pathways.
Commentary on Almassalha et al., “The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer”
Authors: Lynch Henry T. , Rendell Marc , Shaw Trudy G. , Silberstein Peter , Ngo Binh T.
Published: September 2016

In this issue of Cancer Research, Almassalha and colleagues have proposed a new concept of the development of malignancy, that of the greater genomic landscape. They propose a stressor-related exploration of intracellular genomic sites as a response mechanism. This process can express sites with beneficial or deleterious effects, among them those that promote cell proliferation. They point out that their conception is broader, although certainly inclusive, of the process of gene induction. The authors view the physical process of chromatin reorganization as central to the exploration of the genomic landscape. Accordingly, they advocate the development of agents to limit chromatin structural modification as a chemotherapeutic approach in cancer. We found their theory relevant to understand the phenotypic heterogeneity of malignancy, particularly in familial cancer syndromes. For example, the familial atypical multiple mole melanoma (FAMMM) syndrome, related to a gene mutation, is characterized by a diversity of melanocytic lesions, only some of which become malignant melanoma. This new conceptualization can do much to increase understanding of the diversity of malignancy in families with hereditary cancer. Cancer Res; 76(19); 5602–4. ©2016 AACR.
Mutant p53 Together with TGFβ Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer
Authors: Zhong Yi , Macgregor-Das Anne , Saunders Tyler , Whittle Martin C. , Makohon-Moore Alvin , Kohutek Zachary A. , Poling Justin , Herbst Brian T. , Javier Breanna M. , Cope Leslie , Leach Steven D. , Hingorani Sunil R. , Iacobuzio-Donahue Christine A.
Published: September 2016

Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored.

Experimental Design: KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated, and the frequency and morphology of organ-specific hematogenous metastases compared with that seen in KPTC and KTC littermates (Tgfbr2+/−). Key findings were validated in primary cells from each genotype and samples of human pancreatic cancer liver metastases.

Results: The frequency of hematogenous metastasis in KPTC mice was significantly lower than for KPC mice (41% vs. 68%, P < 0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases, whereas liver metastases in KPTC mice showed a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. Secretome analyses of KPC cells revealed an abundance of secreted prometastatic mediators including Col6A1 and Lcn2 that promoted early steps of metastatic colonization. These mediators were overexpressed in primary tumors but not metastases, suggesting that the ability to colonize is, in part, developed within the primary site, a phenomenon we refer to as the “Cinderella effect.”

Conclusions: These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically. Clin Cancer Res; 23(6); 1607–20. ©2016 AACR.
The Human CD38 Monoclonal Antibody Daratumumab Shows Antitumor Activity and Hampers Leukemia–Microenvironment Interactions in Chronic Lymphocytic Leukemia
Authors: Matas-Céspedes Alba , Vidal-Crespo Anna , Rodriguez Vanina , Villamor Neus , Delgado Julio , Giné Eva , Roca-Ho Heleia , Menéndez Pablo , Campo Elías , López-Guillermo Armando , Colomer Dolors , Roué Gaël , Wiestner Adrian , Parren Paul W.H.I. , Doshi Parul , van Bueren Jeroen Lammerts , Pérez-Galán Patricia
Published: September 2016

Purpose: To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38+ chronic lymphocytic leukemia (CLL) subtype.

Experimental Design: The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blood mononuclear cells to analyze antibody-dependent cell cytotoxicity (ADCC), murine and human macrophages to study antibody-dependent cell phagocytosis (ADCP), or human serum to analyze complement-dependent cytotoxicity (CDC). The effect of daratumumab on CLL cell migration and adhesion to extracellular matrix was characterized. Daratumumab activity was validated in two in vivo models.

Results: Daratumumab demonstrated efficient lysis of patient-derived CLL cells and cell lines by ADCC in vitro and ADCP both in vitro and in vivo whereas exhibited negligible CDC in these cells. To demonstrate the therapeutic effect of daratumumab in CLL, we generated a disseminated CLL mouse model with the CD38+ MEC2 cell line and CLL patient–derived xenografts (CLL-PDX). Daratumumab significantly prolonged overall survival of MEC2 mice, completely eliminated cells from the infiltrated organs, and significantly reduced disease burden in the spleen of CLL-PDX. The effect of daratumumab on patient-derived CLL cell dissemination was demonstrated in vitro by its effect on CXCL12-induced migration and in vivo by interfering with CLL cell homing to spleen in NSG mice. Daratumumab also reduced adhesion of CLL cells to VCAM-1, accompanied by downregulation of the matrix metalloproteinase MMP9.

Conclusions: These unique and substantial effects of daratumumab on CLL viability and dissemination support the investigation of its use in a clinical setting of CLL. Clin Cancer Res; 23(6); 1493–505. ©2016 AACR.