bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in
Toxoplasma gondii
Authors: Fellows Justin D. , Cipriano Michael J. , Agrawal Swati , Striepen Boris 
Published: June 2017

ABSTRACT

Apicomplexan parasites cause a variety of important infectious diseases, including malaria, toxoplasma encephalitis, and severe diarrhea due to
Cryptosporidium
. Most apicomplexans depend on an organelle called the apicoplast which is derived from a red algal endosymbiont. The apicoplast is essential for the parasite as the compartment of fatty acid, heme, and isoprenoid biosynthesis. The majority of the approximate 500 apicoplast proteins are nucleus encoded and have to be imported across the four membranes that surround the apicoplast. Import across the second outermost membrane of the apicoplast, the periplastid membrane, depends on an apicoplast-specific endoplasmic reticulum-associated protein degradation (ERAD) complex and on enzymes of the associated ubiquitination cascade. However, identification of an apicoplast ubiquitin associated with this machinery has long been elusive. Here we identify a plastid ubiquitin-like protein (PUBL), an apicoplast protein that is derived from a ubiquitin ancestor but that has significantly changed in its primary sequence. PUBL is distinct from known ubiquitin-like proteins, and phylogenomic analyses suggest a clade specific to apicomplexans. We demonstrate that PUBL and the AAA ATPase CDC48
AP
both act to translocate apicoplast proteins across the periplastid membrane during protein import. Conditional null mutants and genetic complementation show that both proteins are critical for this process and for parasite survival. PUBL residues homologous to those that are required for ubiquitin conjugation onto target proteins are essential for this function, while those required for polyubiquitination and preprotein processing are dispensable. Our experiments provide a mechanistic understanding of the molecular machinery that drives protein import across the membranes of the apicoplast.

IMPORTANCE
Apicomplexan parasites are responsible for important human diseases. There are no effective vaccines for use in humans, and drug treatment faces multiple challenges, including emerging resistance, lack of efficacy across the lifecycle, and adverse drug effects. The apicoplast is a promising target for novel treatments: this chloroplast-like organelle is derived from an algal symbiont, is absent from the host, and is essential for parasite growth and pathogenesis. We use
Toxoplasma gondii
as a model to study the apicoplast due to its strong genetic tools and established functional assays. We identify a plastid ubiquitin-like protein (PUBL) which is a novel ubiquitin-like protein and demonstrate its importance and that of the motor protein CDC48
AP
for apicoplast protein import. These findings broaden our understanding of the evolution and mechanistic workings of a unique parasite organelle and may lead to new opportunities for treatments against important human pathogens.
Efficient Branch and Bound on FPGAs Using Work Stealing and Instance-Specific Designs
Authors: Riebler Heinrich , Lass Michael , Mittendorf Robert , Löcke Thomas , Plessl Christian 
Published: June 2017

Branch and bound (B8B) algorithms structure the search space as a tree and eliminate infeasible solutions early by pruning subtrees that cannot lead to a valid or optimal solution. Custom hardware designs significantly accelerate the execution of these algorithms. In this article, we demonstrate a high-performance B8B implementation on FPGAs. First, we identify general elements of B8B algorithms and describe their implementation as a finite state machine. Then, we introduce workers that autonomously cooperate using work stealing to allow parallel execution and full utilization of the target FPGA. Finally, we explore advantages of instance-specific designs that target a specific problem instance to improve performance.
We evaluate our concepts by applying them to a branch and bound problem, the reconstruction of corrupted AES keys obtained from cold-boot attacks. The evaluation shows that our work stealing approach is scalable with the available resources and provides speedups proportional to the number of workers. Instance-specific designs allow us to achieve an overall speedup of 47 × compared to the fastest implementation of AES key reconstruction so far. Finally, we demonstrate how instance-specific designs can be generated just-in-time such that the provided speedups outweigh the additional time required for design synthesis.
Intermuscular coherence reflects functional coordination
Authors: Laine Christopher M. , Valero-Cuevas Francisco J. 
Published: June 2017

Coherence analysis has the ability to identify the presence of common descending drive shared by motor unit pools and reveals its spectral properties. However, the link between spectral properties of shared neural drive and functional interactions among muscles remains unclear. We assessed shared neural drive between muscles of the thumb and index finger while participants executed two mechanically distinct precision pinch tasks, each requiring distinct functional coordination among muscles. We found that shared neural drive was systematically reduced or enhanced at specific frequencies of interest (~10 and ~40 Hz). While amplitude correlations between surface EMG signals also exhibited changes across tasks, only their coherence has strong physiological underpinnings indicative of neural binding. Our results support the use of intermuscular coherence as a tool to detect when coactivated muscles are members of a functional group or synergy of neural origin. Furthermore, our results demonstrate the advantages of considering neural binding at 10, ~20, and >30 Hz, as indicators of task-dependent neural coordination strategies. NEW & NOTEWORTHY It is often unclear whether correlated activity among muscles reflects their neural binding or simply reflects the constraints defining the task. Using the fact that high-frequency coherence between EMG signals (>6 Hz) is thought to reflect shared neural drive, we demonstrate that coherence analysis can reveal the neural origin of distinct muscle coordination patterns required by different tasks.
Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling
Authors: Donia Marco , Harbst Katja , van Buuren Marit , Kvistborg Pia , Lindberg Mattias F. , Andersen Rikke , Idorn Manja , Munir Ahmad Shamaila , Ellebæk Eva , Mueller Anja , Fagone Paolo , Nicoletti Ferdinando , Libra Massimo , Lauss Martin , Hadrup Sine Reker , Schmidt Henrik , Andersen Mads Hald , thor Straten Per , Nilsson Jonas A. , Schumacher Ton N. , Seliger Barbara , Jönsson Göran , Svane Inge Marie 
Published: June 2017

Abstract
Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8+ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted. Cancer Res; 77(17); 4562–6. ©2017 AACR.
Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity
Authors: Zheng Shunsheng , Koh Xin Yu , Goh Hui Chin , Rahmat Siti Aishah B. , Hwang Le-Ann , Lane David P. 
Published: June 2017

Abstract
Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed. Cancer Res; 77(16); 4342–54. ©2017 AACR.
Inhibition of Megakaryocyte Differentiation by Antibody–Drug Conjugates (ADCs) is Mediated by Macropinocytosis: Implications for ADC-induced Thrombocytopenia
Authors: Zhao Hui , Gulesserian Sara , Ganesan Sathish Kumar , Ou Jimmy , Morrison Karen , Zeng Zhilan , Robles Veronica , Snyder Josh , Do Lisa , Aviña Hector , Karki Sher , Stover David R. , Doñate Fernando 
Published: June 2017

Abstract
Thrombocytopenia is a common adverse event in cancer patients treated with antibody–drug conjugates (ADC), including AGS-16C3F, an ADC targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase-3) and trastuzumab emtansine (T-DM1). This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MK) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers. Effects of AGS-16C3F, T-DM1, and control ADCs on maturing megakaryocytes were evaluated in an in vitro system in which human hematopoietic stem cells (HSC) were differentiated into MKs. AGS-16C3F, like T-DM1, did not affect platelets directly, but inhibited MK differentiation by the activity of Cys-mcMMAF, its active metabolite. FcγRIIA did not appear to play an important role in ADC cytotoxicity to differentiating MKs. AGS-16C3F, cytotoxic to MKs, did not bind to FcγRIIA on MKs. Blocking the interaction of T-DM1 with FcγRIIA did not prevent the inhibition of MK differentiation and IgG1-mcMMAF was not as cytotoxic to MKs despite binding to FcγRIIA. Several lines of evidence suggest that internalization of AGS-16C3F into MKs is mediated by macropinocytosis. Macropinocytosis activity of differentiating HSCs correlated with cell sensitivity to AGS-16C3F. AGS-16C3F was colocalized with a macropinocytosis marker, dextran-Texas Red in differentiating MKs. Ethyl isopropyl amiloride (EIPA), a macropinocytosis inhibitor, blocked internalization of dextran-Texas Red and AGS-16C3F. These data support the notion that inhibition of MK differentiation via macropinocytosis-mediated internalization plays a role in ADC-induced thrombocytopenia. Mol Cancer Ther; 16(9); 1877–86. ©2017 AACR.
See related article by Zhao et al., p. 1866
Optimal Transport Destination for Ischemic Stroke Patients With Unknown Vessel Status
Authors: Schlemm Eckhard , Ebinger Martin , Nolte Christian H. , Endres Matthias , Schlemm Ludwig 
Published: June 2017

Background and Purpose—
Patients with acute ischemic stroke (AIS) and large vessel occlusion may benefit from direct transportation to an endovascular capable comprehensive stroke center (mothership approach) as opposed to direct transportation to the nearest stroke unit without endovascular therapy (drip and ship approach). The optimal transport strategy for patients with AIS and unknown vessel status is uncertain. The rapid arterial occlusion evaluation scale (RACE, scores ranging from 0 to 9, with higher scores indicating higher stroke severity) correlates with the National Institutes of Health Stroke Scale and was developed to identify patients with large vessel occlusion in a prehospital setting. We evaluate how the RACE scale can help to inform prehospital triage decisions for AIS patients.

Methods—
In a model-based approach, we estimate probabilities of good outcome (modified Rankin Scale score of ≤2 at 3 months) as a function of severity of stroke symptoms and transport times for the mothership approach and the drip and ship approach. We use these probabilities to obtain optimal RACE cutoff scores for different transfer time settings and combinations of treatment options (time-based eligibility for secondary transfer under the drip and ship approach, time-based eligibility for thrombolysis at the comprehensive stroke center under the mothership approach).

Results—
In our model, patients with AIS are more likely to benefit from direct transportation to the comprehensive stroke center if they have more severe strokes. Values of the optimal RACE cutoff scores range from 0 (mothership for all patients) to >9 (drip and ship for all patients). Shorter transfer times and longer door-to-needle and needle-to-transfer (door out) times are associated with lower optimal RACE cutoff scores.

Conclusions—
Use of RACE cutoff scores that take into account transport times to triage AIS patients to the nearest appropriate hospital may lead to improved outcomes. Further studies should examine the feasibility of translation into clinical practice.
The Igor’ Tale and the Origins of Conspiracy Theory
Authors: Ingham † Norman W. 
Published: June 2017

In his 2004 lecture delivered at Harvard, Norman W. Ingham critiques Edward L. Keenan’s controversial book Joseph Dobrovský and the Origins of the Igor’ Tale (Slovo o polku Igoreve) and argues that Keenan’s claims against the poem’s authenticity are not convincing.
Characteristics of Land–Air Exchange Parameters over Grassland in Southeast Tibet
Authors: Ma Shupo , Zhou Libo 
Published: June 2017

Abstract
Accurate parameters that describe land–air exchange processes are essential for studying and predicting atmospheric processes over the Tibetan Plateau. Radiation, atmospheric thermal and moisture conditions, and turbulent heat and momentum fluxes were measured in the Yarlung Zangbo River, southeast Tibet, in May–July 2013. Based on the data, land–air exchange parameters were derived over the grassland surface, including the aerodynamic roughness length z0m, thermal roughness length z0h, the excess resistance to heat transfer kB−1 (where k represents the von Kármán constant and B−1 represents the Stanton number), and momentum and heat transfer coefficients (CD and CH, respectively). The average z0m was 7.0 cm, with a standard deviation of 1.4 cm; these values are higher than those observed in the central and western plateau regions and may have been affected by the tall grass and bush surface covers that surrounded the observation site. The average kB−1 was 5.7 ± 1.8, which is higher than that in other plateau regions in the same season. The average CD during the observation period, (11.9 ± 1.6) × 10−3, is also higher than that of other plateau regions. The commonly used iterative scheme and three noniterative turbulent flux parameterization schemes were evaluated over southeast Tibet using the above observational data. Parameter CD was underestimated by most schemes, whereas CH was overestimated by all schemes. Additional studies suggested that the iterative scheme performed best in retrieving the land–air exchange parameters and can be applied over southeast Tibet.
Development of a Precipitation Climate Record from Spaceborne Precipitation Radar Data. Part I: Mitigation of the Effects of Switching to Redundancy Electronics in the TRMM Precipitation Radar
Authors: Kanemaru Kaya , Kubota Takuji , Iguchi Toshio , Takayabu Yukari N. , Oki Riko 
Published: June 2017

AbstractPrecipitation observation with the Tropical Rainfall Measuring Mission’s (TRMM’s) precipitation radar (PR) lasted for more than 17 years. To study the changes in the water and energy cycle related to interannual and decadal variabilities of climate, homogeneity of long-term PR data is essential. The aim of the study is to develop a precipitation climate record from the 17-yr PR observation. The focus was on mitigating the discontinuities associated with the switching to redundant electronics in the PR in June 2009. In version 7 of the level-1 PR product, a discontinuity in noise power is found at this timing, indicating a change in the signal-to-noise ratio. To mitigate the effect of this discontinuity on climate studies, the noise power of the B-side PR obtained after June 2009 is artificially increased to match that of the A-side PR. Simulation results show that the storm height and the precipitation frequency detected by the PR relatively decrease by 2.17% and 5.15% in the TRMM coverage area (35°S–35°N), respectively, and that the obvious discontinuity of the time series by the storm height and the precipitation fraction caused by the switching to the redundancy electronics is mitigated. Differences in the statistics of other precipitation parameters caused by the switching are also mitigated. The unconditional precipitation rate derived from the adjusted data obtained over the TRMM coverage area decreases by 0.90% as compared with that determined from the original data. This decrease is mainly caused by reductions in the detection of light precipitation.
Spontaneous Separation of Macular Epiretinal Membrane Without Peripheral Posterior Vitreous Detachment
Authors: Lin James , Chang Jonathan S. , Fuchs Wayne , Chang Stanley 
Published: June 2017

Purpose: To describe findings of a patient with spontaneous separation of macular epiretinal membrane (ERM) associated with a limited posterior vitreous detachment. Methods: Case report. Results: A 69-year-old woman presented with metamorphopsia and loss of vision (20/200) in the left eye (OS) secondary to ERM. One month later, the vision improved (20/40−) following spontaneous separation of the ERM. However, residual epiretinal fibrotic membranes were adherent along the vascular arcades, causing persistent disabling metamorphopsia. During vitrectomy, peeling of the membranes from the vascular arcades demonstrated that the peripheral vitreous cortex had not separated around the macula. The metamorphopsia subsequently improved. Conclusions: This case demonstrates a unique finding at the vitreomacular interface, where spontaneous ERM separation was not associated with a peripheral vitreous detachment. The peripheral cortical vitreous remained intact, serving as a scaffold for membrane proliferation along the vascular arcades.
Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study
Authors: DeAngelo Daniel J. , Stock Wendy , Stein Anthony S. , Shustov Andrei , Liedtke Michaela , Schiffer Charles A. , Vandendries Erik , Liau Katherine , Ananthakrishnan Revathi , Boni Joseph , Laird A. Douglas , Fostvedt Luke , Kantarjian Hagop M. , Advani Anjali S. 
Published: June 2017

Key Points
Weekly InO 1.8 mg/m2 per cycle is associated with manageable toxicities and encouraging activity in patients with relapsed/refractory ALL. Achievement of MRD negativity and disease burden was not correlated; InO may thus be effective regardless of baseline disease severity.
Migrating out of a crowded labor market: evidence from Egypt
Authors: David Anda , Jarreau Joachim 
Published: June 2017

AbstractWe analyze the determinants of emigration at the individual and household level, using three waves of the Egyptian labor market panel survey (ELMPS) covering the 1998–2012 period. Exploiting the panel structure of the data allows us to reduce the risk of reverse causality and to estimate the effect of migrant networks more accurately than in studies based on cross-sectional data. We confirm, in the Egyptian context, the non-linear relationship between household resources and migration propensity, due to migration costs; a larger network of past emigrants from the same community mitigates this selection on wealth, increasing the propensity to migrate among poorer households. We also show that unemployment and informal employment act as incentives to emigrate, suggesting that the scarcity of quality jobs, in particular on the skilled labor market, is one important driver of emigration flows in Egypt. However, these incentives turn into effective migration only in communities with a sufficiently large network of past migrants.
The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease
Authors: Finkelstein David I. , Billings Jessica L. , Adlard Paul A. , Ayton Scott , Sedjahtera Amelia , Masters Colin L. , Wilkins Simon , Shackleford David M. , Charman Susan A. , Bal Wojciech , Zawisza Izabela A , Kurowska Ewa , Gundlach Andrew L. , Ma Sheri , Bush Ashley I. , Hare Dominic J. , Doble Philip A. , Crawford Simon , Gautier Elisabeth CL. , Parsons Jack , Huggins Penny , Barnham Kevin J. , Cherny Robert A. 
Published: June 2017

AbstractElevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD.
A survey of diminished reality: Techniques for visually concealing, eliminating, and seeing through real objects
Authors: Mori Shohei , Ikeda Sei , Saito Hideo 
Published: June 2017

Abstract
In this paper, we review diminished reality (DR) studies that visually remove, hide, and see through real objects from the real world. We systematically analyze and classify publications and present a technology map as a reference for future research. We also discuss future directions, including multimodal diminished reality. We believe that this paper will be useful mainly for students who are interested in DR, beginning DR researchers, and teachers who introduce DR in their classes.