bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Complete Genome Sequence of the Emerging Pathogen Mycobacterium haemophilum Explains Its Unique Culture Requirements
Authors: Tufariello JoAnn M. , Kerantzas Christopher A. , Vilchèze Catherine , Calder R. Brent , Nordberg Eric K. , Fischer Jack A. , Hartman Travis E. , Yang Eva , Driscoll Timothy , Cole Laura E. , Sebra Robert , Maqbool Shahina B. , Wattam Alice R. , Jacobs William R. 
Published: November 2015

ABSTRACT

Mycobacterium haemophilum
is an emerging pathogen associated with a variety of clinical syndromes, most commonly skin infections in immunocompromised individuals.
M. haemophilum
exhibits a unique requirement for iron supplementation to support its growth in culture, but the basis for this property and how it may shape pathogenesis is unclear. Using a combination of Illumina, PacBio, and Sanger sequencing, the complete genome sequence of
M. haemophilum
was determined. Guided by this sequence, experiments were performed to define the basis for the unique growth requirements of
M. haemophilum
. We found that
M. haemophilum
, unlike many other mycobacteria, is unable to synthesize iron-binding siderophores known as mycobactins or to utilize ferri-mycobactins to support growth. These differences correlate with the absence of genes associated with mycobactin synthesis, secretion, and uptake. In agreement with the ability of heme to promote growth, we identified genes encoding heme uptake machinery. Consistent with its propensity to infect the skin, we show at the whole-genome level the genetic closeness of
M. haemophilum
with
Mycobacterium leprae
, an organism which cannot be cultivated
in vitro
, and we identify genes uniquely shared by these organisms. Finally, we identify means to express foreign genes in
M. haemophilum
. These data explain the unique culture requirements for this important pathogen, provide a foundation upon which the genome sequence can be exploited to improve diagnostics and therapeutics, and suggest use of
M. haemophilum
as a tool to elucidate functions of genes shared with
M. leprae
.

IMPORTANCE
Mycobacterium haemophilum
is an emerging pathogen with an unknown natural reservoir that exhibits unique requirements for iron supplementation to grow
in vitro
. Understanding the basis for this iron requirement is important because it is fundamental to isolation of the organism from clinical samples and environmental sources. Defining the molecular basis for
M. haemophilium
's growth requirements will also shed new light on mycobacterial strategies to acquire iron and can be exploited to define how differences in such strategies influence pathogenesis. Here, through a combination of sequencing and experimental approaches, we explain the basis for the iron requirement. We further demonstrate the genetic closeness of
M. haemophilum
and
Mycobacterium leprae
, the causative agent of leprosy which cannot be cultured
in vitro
, and we demonstrate methods to genetically manipulate
M. haemophilum
. These findings pave the way for the use of
M. haemophilum
as a model to elucidate functions of genes shared with
M. leprae
.
Experimental Infection of Snakes with
Ophidiomyces ophiodiicola
Causes Pathological Changes That Typify Snake Fungal Disease
Authors: Lorch Jeffrey M. , Lankton Julia , Werner Katrien , Falendysz Elizabeth A. , McCurley Kevin , Blehert David S. 
Published: November 2015

ABSTRACT

Snake fungal disease (SFD) is an emerging skin infection of wild snakes in eastern North America. The fungus
Ophidiomyces ophiodiicola
is frequently associated with the skin lesions that are characteristic of SFD, but a causal relationship between the fungus and the disease has not been established. We experimentally infected captive-bred corn snakes (
Pantherophis guttatus
) in the laboratory with pure cultures of
O. ophiodiicola
. All snakes in the infected group (
n
= 8) developed gross and microscopic lesions identical to those observed in wild snakes with SFD; snakes in the control group (
n
= 7) did not develop skin infections. Furthermore, the same strain of
O. ophiodiicola
used to inoculate snakes was recovered from lesions of all animals in the infected group, but no fungi were isolated from individuals in the control group. Monitoring progression of lesions throughout the experiment captured a range of presentations of SFD that have been described in wild snakes. The host response to the infection included marked recruitment of granulocytes to sites of fungal invasion, increased frequency of molting, and abnormal behaviors, such as anorexia and resting in conspicuous areas of enclosures. While these responses may help snakes to fight infection, they could also impact host fitness and may contribute to mortality in wild snakes with chronic
O. ophiodiicola
infection. This work provides a basis for understanding the pathogenicity of
O. ophiodiicola
and the ecology of SFD by using a model system that incorporates a host species that is easy to procure and maintain in the laboratory.

IMPORTANCE
Skin infections in snakes, referred to as snake fungal disease (SFD), have been reported with increasing frequency in wild snakes in the eastern United States. While most of these infections are associated with the fungus
Ophidiomyces ophiodiicola
, there has been no conclusive evidence to implicate this fungus as a primary pathogen. Furthermore, it is not understood why the infections affect different host populations differently. Our experiment demonstrates that
O. ophiodiicola
is the causative agent of SFD and can elicit pathological changes that likely impact fitness of wild snakes. This information, and the laboratory model we describe, will be essential in addressing unresolved questions regarding disease ecology and outcomes of
O. ophiodiicola
infection and helping to conserve snake populations threatened by the disease. The SFD model of infection also offers utility for exploring larger concepts related to comparative fungal virulence, host response, and host-pathogen evolution.
Observational, longitudinal study of delirium in consecutive unselected acute medical admissions: age-specific rates and associated factors, mortality and re-admission
Authors: Pendlebury ST , Lovett NG , Smith SC , Dutta N , Bendon C , Lloyd-Lavery A , Mehta Z , Rothwell PM 
Published: November 2015

ObjectivesWe aimed to determine age-specific rates of delirium and associated factors in acute medicine, and the impact of delirium on mortality and re-admission on long-term follow-up.DesignObservational study. Consecutive patients over two 8-week periods (2010, 2012) were screened for delirium on admission, using the confusion assessment method (CAM), and reviewed daily thereafter. Delirium diagnosis was made using the Diagnostic and Statistical Manual Fourth Edition (DSM IV) criteria. For patients aged ≥65 years, potentially important covariables identified in previous studies were collected with follow-up for death and re-admission until January 2014.Participants503 consecutive patients (age median=72, range 16–99 years, 236 (48%) male).SettingAcute general medicine.ResultsDelirium occurred in 101/503 (20%) (71 on admission, 30 during admission, 17 both), with risk increasing from 3% (6/195) at <65 years to 14% (10/74) for 65–74 years and 36% (85/234) at ≥75 years (p<0.0001). Among 308 patients aged>65 years, after adjustment for age, delirium was associated with previous falls (OR=2.47, 95% CI 1.45 to 4.22, p=0.001), prior dementia (2.08, 1.10 to 3.93, p=0.024), dependency (2.58, 1.48 to 4.48, p=0.001), low cognitive score (5.00, 2.50 to 9.99, p<0.0001), dehydration (3.53, 1.91 to 6.53, p<0.0001), severe illness (1.98, 1.17 to 3.38, p=0.011), pressure sore risk (5.56, 2.60 to 11.88, p<0.0001) and infection (4.88, 2.85 to 8.36, p<0.0001). Patients with delirium were more likely to fall (OR=4.55, 1.47 to 14.05, p=0.008), be incontinent of urine (3.76, 2.15 to 6.58, p<0.0001) or faeces (3.49, 1.81–6.73, p=0.0002) and be catheterised (5.08, 2.44 to 10.54, p<0.0001); and delirium was associated with stay >7 days (2.82, 1.68 to 4.75, p<0.0001), death (4.56, 1.71 to 12.17, p=0.003) and an increase in dependency among survivors (2.56, 1.37 to 4.76, p=0.003) with excess mortality still evident at 2-year follow-up. Patients with delirium had fewer re-admissions within 30-days (OR=0.32, 95% CI 0.09 to 1.1, p=0.07) and in total (median, IQR total re-admissions=0, 0–1 vs 1, 0–2, p=0.01).ConclusionsDelirium affected a fifth of acute medical admissions and a third of those aged ≥75 years, and was associated with increased mortality, institutionalisation and dependency, but not with increased risk of re-admission on follow-up.
‘Klar bleiben’: a school-based alcohol prevention programme for German adolescents—study protocol for a cluster randomised controlled trial
Authors: Tomczyk Samuel , Hanewinkel Reiner , Isensee Barbara 
Published: November 2015

IntroductionThere is a noticeable increase in hazardous alcohol use during adolescence, which is significantly associated with adverse consequences. In Germany, up to 30% of adolescents report regular heavy episodic drinking. However, only a few German prevention programmes target adolescents of legal drinking age (16 years and above); thus, this trial aims to develop, implement and evaluate ‘Klar bleiben’ (‘Stay clearheaded’), a school-based prevention programme for grade 10 students.Methods and analysis‘Klar bleiben’ consists of a class commitment to drink responsibly and refrain from hazardous consumption patterns for 9 weeks. The commitment is accompanied by educational lessons on alcohol-related cognitions and consequences. It will be evaluated in a sample of approximately 3000 students (150 classes) from two German federal states (Schleswig-Holstein and Lower Saxony) via a two-armed cluster randomised controlled trial with baseline and postassessment 6 months apart. The intervention group (75 classes) will participate in ‘Klar bleiben’, whereas the control group (75 classes) will receive education as usual. ‘Klar bleiben’ addresses classes, individuals, teachers and parents. It is based on a social norms approach and aims to reduce hazardous drinking and drinking-related consequences in adolescents. Secondary outcomes include general drinking behaviour, use of other substances, alcohol-related cognitions and social factors. Covariates include sociodemographic characteristics, environmental and individual (vulnerability) factors.Ethics and dissemination‘Klar bleiben’ provides a multicomponent school-based programme that bridges a gap in alcohol prevention. Similar class-level and social norms-based prevention programmes have already been proven to be successful for other substances among adolescents. Thus, dissemination to other federal states as well as longer term follow-up testing of the robustness of effects is to be anticipated. The study was approved by the Ethics Committee of the German Psychological Society (RH_0620152), and study findings will be disseminated through peer-reviewed publications and conference contributions.Trial registration numberGerman Clinical Trials Register: DRKS00009424.
Low-Cost Real-Time 3D Reconstruction of Large-Scale Excavation Sites
Authors: Zollhöfer M. , Siegl C. , Vetter M. , Dreyer B. , Stamminger M. , Aybek Serdar , Bauer F. 
Published: November 2015

The 3D reconstruction of archeological sites is still an expensive and time-consuming task. In this article, we present a novel interactive, low-cost approach to 3D reconstruction and compare it to a standard photogrammetry pipeline based on high-resolution photographs.
Our novel real-time reconstruction pipeline is based on a low-cost, consumer-level hand-held RGB-D sensor. While scanning, the user sees a live view of the current reconstruction, allowing the user to intervene immediately and adapt the sensor path to the current scanning result. After a raw reconstruction has been acquired, the digital model is interactively warped to fit a geo-referenced map using a handle-based deformation paradigm. Even large sites can be scanned within a few minutes, and no costly postprocessing is required. The quality of the acquired digitized raw 3D models is evaluated by comparing them to actual imagery, a geo-referenced map of the excavation site, and a photogrammetry-based reconstruction.
We made extensive tests under real-world conditions on an archeological excavation in Metropolis, Ionia, Turkey. We found that the reconstruction quality of our approach is comparable to that of photogrammetry. Yet, both approaches have advantages and shortcomings in specific setups, which we analyze and discuss.
Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition
Authors: Herkert Barbara , Kauffmann Audrey , Mollé Sandra , Schnell Christian , Ferrat Thomas , Voshol Hans , Juengert Janina , Erasimus Hélène , Marszalek Grégory , Kazic-Legueux Malika , Billy Eric , Ruddy David , Stump Mark , Guthy Daniel , Ristov Mitko , Calkins Keith , Maira Sauveur-Michel , Sellers William R. , Hofmann Francesco , Hall Michael N. , Brachmann Saskia M. 
Published: November 2015

AbstractThe introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAFMUT) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTENLOF) occurs in approximately 40% of BRAFMUT melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTENLOF/BRAFMUT melanoma. Large-scale compound sensitivity profiling revealed that PTENLOF melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R–PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTENLOF/BRAFMUT melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTENLOF/BRAFMUT melanoma patients to achieve maximal response. Cancer Res; 76(2); 390–402. ©2015 AACR.
CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling
Authors: DeLeon-Pennell Kristine Y. , Tian Yuan , Zhang Bai , Cates Courtney A. , Iyer Rugmani Padmanabhan , Cannon Presley , Shah Punit , Aiyetan Paul , Halade Ganesh V. , Ma Yonggang , Flynn Elizabeth , Zhang Zhen , Jin Yu-Fang , Zhang Hui , Lindsey Merry L. 
Published: November 2015

Background—
After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling.

Methods and Results—

Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541
N
-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all
P
<0.05). Cartilage intermediate layer protein and platelet glycoprotein 4 (CD36) were identified as having the highest fold increase in MMP-9 null mice. By immunoblotting, CD36 but not cartilage intermediate layer protein decreased steadily during the time course post-myocardial infarction, which identified CD36 as a candidate MMP-9 substrate. MMP-9 was confirmed in vitro and in vivo to proteolytically degrade CD36. In vitro stimulation of day 7 post-myocardial infarction macrophages with MMP-9 or a CD36-blocking peptide reduced phagocytic capacity. Dual immunofluorescence revealed concomitant accumulation of apoptotic neutrophils in the MMP-9 null group compared with wild-type group. In vitro stimulation of isolated neutrophils with MMP-9 decreased neutrophil apoptosis, indicated by reduced caspase-9 expression.

Conclusions—
Our data reveal a new cell-signaling role for MMP-9 through CD36 degradation to regulate macrophage phagocytosis and neutrophil apoptosis.
Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: Chabriat Hugues , Hervé Dominique , Duering Marco , Godin Ophelia , Jouvent Eric , Opherk Christian , Alili Nassira , Reyes Sonia , Jabouley Aude , Zieren Nikola , Guichard Jean-Pierre , Pachai Chahin , Vicaut Eric , Dichgans Martin 
Published: November 2015

Background and Purpose—
Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy remain unknown. This study aims to identify demographic, clinical, and magnetic resonance imaging predictors of incident strokes, incident dementia, clinical deterioration, and death in patients with this genetically proven disease.

Methods—
Two hundred ninety subjects (mean age, 50.6±11.4 years) were assessed at baseline and followed up for 36 months. Incident clinical events were recorded, and clinical scores included the Mini Mental State Examination, Mattis Dementia Rating Scale, modified Rankin Scale, and Barthel index. The number of lacunes and microbleeds, the volume of white-matter hyperintensities, and brain parenchymal fraction were assessed on baseline magnetic resonance imaging. Data were analyzed by ANCOVA, multivariable logistic regression, and Cox proportional hazard models.

Results—
Incident stroke occurred in 55 of 278 patients (19.8%). Moderate or severe disability developed in 19 of 210 (9%) nondisabled individuals, incident dementia in 49 of 231 (20%) nondemented subjects, and 4.8% of patients died. Active smoking, the number of lacunes, and brain parenchymal fraction independently predicted incident stroke during follow-up. Gait disturbance, dementia, and brain parenchymal fraction predicted progression toward moderate or severe disability. Active smoking, disability, and brain parenchymal fraction predicted incident dementia. Age was the only significant predictor of death.

Conclusions—
Clinical assessment and brain magnetic resonance imaging aid in predicting incident clinical events and clinical deterioration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There is a bidirectional relationship between dementia and moderate or severe disability in predicting each other’s onset. Active smoking is a modifiable risk factor associated with clinical progression in Notch3 mutation carriers.
Death After Life or Life After Death?
Authors: Sim David C. 
Published: November 2015

The early Church Fathers accepted the notion of an intermediate state, the existence of the soul following death until its reunification with the body at the time of the final resurrection. This view is common in the modern Christian world, but it has been challenged as being unbiblical. This study reflects upon this question. Does the New Testament speak exclusively of death after life, complete lifelessness until the day of resurrection, or does it also contain the notion of life after life or immediate post-mortem existence? It will be argued that, while the doctrine of future resurrection is the most common Christian view, it was not the only one present in the Christian canon. There are hints, especially in the Gospel of Luke and the Revelation of John, that people do indeed live again immediately after death, although the doctrine of resurrection is also present. These two ideas are never coherently related to one another in the New Testament and it was the Church Fathers who first sought to systematise them.
A Lagrangian Study of Precipitation-Driven Downdrafts*
Authors: Torri Giuseppe , Kuang Zhiming 
Published: November 2015

Abstract
Precipitation-driven downdrafts are an important component of deep convective systems. They stabilize the atmosphere by injecting relatively cold and dry air into the boundary layer. They have also been invoked as responsible for balancing surface latent and sensible heat fluxes in the heat and moisture budget of tropical boundary layers. This study is focused on precipitation-driven downdrafts and basic aspects of their dynamics in a case of radiative–convective equilibrium. Using Lagrangian particle tracking, it is shown that such downdrafts have very low initial heights, with most parcels originating within 1.5 km from the surface. The tracking is also used to compute the contribution of downdrafts to the flux of moist static energy at the top of the boundary layer, and it is found that this is on the same order of magnitude as the contribution due to convective updrafts, but much smaller than that due to turbulent mixing across the boundary layer top in the environment. Furthermore, considering the mechanisms driving the downdrafts, it is shown that the work done by rain evaporation is less than half that done by condensate loading.
Variability, Instabilities, and Eddies in a Snowball Ocean
Authors: Ashkenazy Yosef , Tziperman Eli 
Published: November 2015

Abstract
Oceanic variability and eddy dynamics during snowball Earth events, under a kilometer of ice and driven by a very weak geothermal heat flux, are studied using a high-resolution sector model centered at the equator, where previous studies have shown the ocean circulation to be most prominent. The solution is characterized by an energetic eddy field, equatorward-propagating zonal jets, and a strongly variable equatorial meridional overturning circulation (EMOC), on the order of tens of Sverdrups (Sv; 1 Sv ≡ 106 m3 s−1), restricted to be very close to the equator. The ocean is well mixed vertically by convective mixing, and horizontal mixing rates by currents and eddies are similar to present-day values. There are two main opposite-sign zonal jets near the equator that are not eddy driven, together with multiple secondary eddy-driven jets off the equator. Barotropic stability analyses, the Lorenz energy cycle (LEC), and barotropic-to-baroclinic energy conversion rates together indicate that both baroclinic and barotropic instabilities serve as eddy-generating mechanisms. The LEC shows a dominant input into the mean available potential energy (APE) by geothermal heat flux and by surface ice melting and then transformation to eddy APE, to eddy kinetic energy, and finally to mean kinetic energy via eddy–jet interaction, similarly to the present-day atmosphere and unlike the present-day ocean. The EMOC variability is due to the interaction of warm plumes driven by geothermal heating that reach the ocean surface, leading to ice-melt events that change the stratification and, therefore, the EMOC. The results presented here may be relevant to the ocean dynamics of planetary ice-covered moons such as Europa and Enceladus.