bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cone-Beam CT With Augmented Fluoroscopy Combined With Electromagnetic Navigation Bronchoscopy for Biopsy of Pulmonary Nodules
Authors: Pritchett Michael A. , Schampaert Stéphanie , de Groot Joris A.H. , Schirmer Charles C. , van der Bom Imramsjah 
Published: September 2018

Background:
Electromagnetic navigation bronchoscopy (ENB) has been widely adopted as a guidance technique for biopsy of peripheral lung nodules. However, ENB is limited by the lack of real-time confirmation of the biopsy devices. Intraprocedural cone-beam computed tomography (CBCT) imaging can be utilized to assess or confirm the location of biopsy devices. The aim of this study is to determine the safety and diagnostic yield (DY) of image fusion of intraprocedural CBCT data with live fluoroscopy (augmented fluoroscopy) during ENB-guided biopsy of peripheral lung nodules.

Methods:
Data from 75 consecutive patients who underwent biopsy with ENB was collected retrospectively. Patients underwent CBCT imaging while temporarily suspending mechanical ventilation. CBCT data were acquired and 3-dimensional segmentation of nodules was performed using commercially available software (OncoSuite). During ENB, the segmented lesions were projected and fused with live fluoroscopy enabling real-time 3-dimensional guidance.

Results:
A total of 93 lesions with a median size of 16.0 mm were biopsied in 75 consecutive patients. The overall DY by lesion was 83.7% (95% confidence interval, 74.8%-89.9%). Multivariate regression analysis showed no independent correlation between lesion size, lesion location, lesion visibility under standard fluoroscopy, and the presence of a bronchus sign with DY. Pneumothorax occurred in 3 patients (4%).

Conclusion:
Intraprocedural CBCT imaging with augmented fluoroscopy is feasible and effective and is associated with high DY during ENB-guided biopsies.
Greenhouse- and orbital-forced climate extremes during the early Eocene
Authors: Kiehl Jeffrey T. , Shields Christine A. , Snyder Mark A. , Zachos James C. , Rothstein Mathew 
Published: September 2018

The Palaeocene–Eocene Thermal Maximum (PETM) was a significant global warming event in Earth's deep past (56 Mya). The warming across the PETM boundary was driven by a rapid rise in greenhouse gases. The event also coincided with a time of maximum insolation in Northern Hemisphere summer. There is increased evidence that the mean warming was accompanied by enhanced seasonality and/or extremes in precipitation (and flooding) and drought. A high horizontal resolution (50 km) global climate model is used to explore changes in the seasonal cycle of surface temperature, precipitation, evaporation minus precipitation and river run-off for regions where proxy data are available. Comparison for the regions indicates the model accurately simulates the observed changes in these climatic characteristics with North American interior warming and drying, and warming and increased river run-off at other regions. The addition of maximum insolation in Northern Hemisphere summer leads to a drier North America, but wetter conditions at most other locations. Long-range transport of atmospheric moisture plays a critical role in explaining regional changes in the water cycle. Such high-frequency variations in precipitation might also help explain discrepancies or misinterpretation of some climate proxies from the same locations, especially where sampling is coarse, i.e. at or greater than the frequency of precession.
This article is part of a discussion meeting issue ‘Hyperthermals: rapid and extreme global warming in our geological past’.
Strategies in times of crisis—insights into the benthic foraminiferal record of the Palaeocene–Eocene Thermal Maximum
Authors: Schmidt Daniela N. , Thomas Ellen , Authier Elisabeth , Saunders David , Ridgwell Andy 
Published: September 2018

Climate change is predicted to alter temperature, carbonate chemistry and oxygen availability in the oceans, which will affect individuals, populations and ecosystems. We use the fossil record of benthic foraminifers to assess developmental impacts in response to environmental changes during the Palaeocene–Eocene Thermal Maximum (PETM). Using an unprecedented number of µ-computed tomography scans, we determine the size of the proloculus (first chamber), the number of chambers and the final size of two benthic foraminiferal species which survived the extinction at sites 690 (Atlantic sector, Southern Ocean, palaeodepth 1900 m), 1210 (central equatorial Pacific, palaeodepth 2100 m) and 1135 (Indian Ocean sector, Southern Ocean, palaeodepth 600–1000 m). The population at the shallowest site, 1135, does not show a clear response to the PETM, whereas those at the other sites record reductions in diameter or proloculus size. Temperature was similar at all sites, thus it is not likely to be the reason for differences between sites. At site 1210, small size coincided with higher chamber numbers during the peak event, and may have been caused by a combination of low carbonate ion concentrations and low food supply. Dwarfing at site 690 occurred at lower chamber numbers, and may have been caused by decreasing carbonate saturation at sufficient food levels to reproduce. Proloculus size varied strongly between sites and through time, suggesting a large influence of environment on both microspheric and megalospheric forms without clear bimodality. The effect of the environmental changes during the PETM was more pronounced at deeper sites, possibly implicating carbonate saturation.
This article is part of a discussion meeting issue ‘Hyperthermals: rapid and extreme global warming in our geological past’.
An essential role for dNTP homeostasis following CDK-induced replication stress
Authors: Pai Chen-Chun , Hsu Kuo-Feng , Durley Samuel. C. , Keszthelyi Andrea , Kearsey Stephen E. , Rallis Charalampos , Folkes Lisa K. , Deegan Rachel , Wilkins Sarah E. , Pfister Sophia X. , León Nagore De , Schofield Christopher J. , Bähler Jürg , Carr Antony M. , Humphrey Timothy C. 
Published: September 2018

AbstractReplication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here we show that CDK-induced replication stress is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, Mus81-dependent DNA damage, and to genome instability. Cells respond to this replication stress by increasing dNTP supply through Set2-dependent MBF-induced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through abrogating Set2-dependent H3K36 tri-methylation or DNA integrity checkpoint inactivation results in critically low dNTP levels, replication collapse and cell death, which can be rescued by increasing dNTP levels. These findings support a ‘dNTP supply and demand’ model in which maintaining dNTP homeostasis is essential to prevent replication catastrophe in response to CDK-induced replication stress.
Endopeptidase regulation as a novel function of the Zur-dependent zinc starvation response
Authors: Murphy Shannon G. , Alvarez Laura , Adams Myfanwy C. , Liu Shuning , Chappie Joshua S. , Cava Felipe , Dörr Tobias 
Published: September 2018

AbstractThe cell wall is a strong, yet flexible, meshwork of peptidoglycan (PG) that gives a bacterium structural integrity. To accommodate a growing cell, the wall is remodeled by both PG synthesis and degradation.Vibrio choleraeencodes a group of three nearly identical zinc-dependent endopeptidases (EPs) that hydrolyze PG to facilitate cell growth. Two of these (shyAandshyC) are housekeeping genes and form a synthetic lethal pair, while the third (shyB) is not expressed under standard laboratory conditions. To investigate the role of ShyB, we conducted a transposon screen to identify mutations that activateshyBtranscription. We found thatshyBis induced as part of the Zur-mediated zinc starvation response, a mode of regulation not previously reported for cell wall lytic enzymes.In vivo, ShyB alone was sufficient to sustain cell growth in low-zinc environments.In vitro, ShyB retained its D,D-endopeptidase activity against purified sacculi in the presence of the metal chelator EDTA at a concentration that inhibits ShyA and ShyC. This suggests that ShyB can substitute for the other EPs during zinc starvation, a condition that pathogens encounter while infecting a human host. Our survey of transcriptomic data from diverse bacteria identified other candidate Zur-regulated endopeptidases, suggesting that this adaptation to zinc starvation is conserved in other Gram-negative bacteria.ImportanceThe human host sequesters zinc and other essential metals in order to restrict growth of potentially harmful bacteria. In response, invading bacteria express a set of genes enabling them to cope with zinc starvation. InVibrio cholerae, the causative agent of the diarrheal disease cholera, we have identified a novel member of this zinc starvation response: a cell wall hydrolase that retains function in low-zinc environments and is conditionally essential for cell growth. Other human pathogens contain homologs that appear to be under similar regulatory control. These findings are significant because they represent, to our knowledge, the first evidence that zinc homeostasis influences cell wall turnover. Anti-infective therapies commonly target the bacterial cell wall and, therefore, an improved understanding of how the cell wall adapts to host-induced zinc starvation could lead to new antibiotic development. Such therapeutic interventions are required to combat the rising threat of drug resistant infections.
A sex-stratified genome-wide association study of tuberculosis using a multi-ethnic genotyping array
Authors: Schurz Haiko , Kinnear Craig J , Gignoux Chris , Wojcik Genevieve , van Helden Paul D , Tromp Gerard , Henn Brenna , Hoal Eileen G , Möller Marlo 
Published: September 2018

AbstractTuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males as in females. While socio-economic status, behaviour and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. Individuals from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome and X chromosome in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.
Heterochrony of puberty in the European Badger (Meles meles) can be explained by growth rate and group-size: Evidence for two endocrinological phenotypes
Authors: Sugianto Nadine Adrianna , Newman Chris , Macdonald David Whyte , Buesching Christina Dagmar 
Published: September 2018

AbstractPuberty is a key stage in mammalian ontogeny, involving endocrinological, physiological and behavioural changes, moderated by intrinsic and extrinsic factors. Thus, not all individuals within one population achieve sexual maturity simultaneously. Here, using the European badger (Meles meles) as a model, we describe male testosterone and female oestrone profiles (using Enzyme-immunoassays) from first capture (3 months, post-weaning) until 28 months (attaining sexual maturity and final body size), along with metrics of somatic growth, scent gland development and maturation of external reproductive organs as well as intra-specific competition. In both sexes, endocrinological puberty commenced at ca. 11 months. Thereafter, cub hormone levels followed adult seasonal hormone patterns but at lower levels, with the majority of cubs reaching sexual maturity during their second mating season (22-28 months). Interestingly, there was evidence for two endocrinological phenotypes among male cubs (less evident in females), with early developers reaching sexual maturity at 11 months (first mating season) and late developers reaching sexual maturity at 22-26 months (second mating season). Early developers also attained a greater proportion of their ultimate adult size by 11 months, exhibiting faster growth rates than late developers (despite having similar adult size). Male cubs born into larger social groups tended to follow the late developer phenotype. Our results support the hypothesis that a minimum body size is required to reach sexual maturity, which may be achieved at different ages, even within a single population, where early maturity can confer individual fitness advantages and enhance population growth rate.
Mutant screen for reproduction unveils depression-associated Piccolo’s control over reproductive behavior
Authors: Medrano Gerardo A. , Singh Manvendra , Plautz Erik J. , Good Levi B. , Chapman Karen M. , Chaudhary Jaideep , Jaichander Priscilla , Powell Heather M. , Pudasaini Ashutosh , Shelton John M. , Richardson James A. , Xie Xian-Jin , Ivics Zoltán , Braun Christine , Ackermann Frauke , Garner Craig C. , Izsvák Zsuzsanna , Hamra F. Kent 
Published: September 2018

AbstractSuccessful sexual reproduction involves complex, genetically encoded interplay between animal physiology and behavior. The rat provides a highly fecund mammalian model for studying how the brain impacts reproduction. Here, we report a forward genetics screen in rats to identify genes that affect reproduction. A panel of 18 distinct rat strains harboring Sleeping Beauty gene trap mutations were analyzed for the ability to reproduce. As expected, our mutant screen identified genes where reproductive failure was connected to gametogenesis (Btrc, Pan3, Spaca6, Ube2k) and embryogenesis (Alk3, Exoc6b, Slc1a3, Tmx4, Zmynd8). In addition, we identified Ata13 (longevity) and Pclo (neuronal disorders), previously not associated with an inability to conceive. Neurologically, Pclo is known to regulate the size of presynaptic vesicle pools. Here, dominant traits in Pclo mutant rats caused epileptiform activity and affected genes supporting GABAergic synaptic transmission (Gabra6, Gabrg3). Recessive traits in Pclo mutant rats transmitted altered reproductive behavior, as homozygous Pclo mutant rats produced gametes but neither sex would mate with wildtype rats. Pclo mutant rat behavior was linked to endophenotypes signifying compromised brain-gonad crosstalk via disturbed GnRH signaling and allelic markers for major depressive disorder in humans (Grm5, Htr2a, Sorcs3, Negr1, Drd2). Thus, by rat genetics, we identified Pclo as a candidate presynaptic factor required for reproduction.Author SummaryPiccolo gene mutations have previously been identified in human cohorts diagnosed with behavioral syndromes that impact one’s emotions, including depression and bipolar disorder. Although studies in human populations implicate changes to Piccolo’s DNA sequence to enhanced susceptibility for behavioral disorders, studies in mouse models have yet to link Piccolo mutations to altered behavior. Here, by a novel genetics approach, we report Piccolo mutation-dependent effects on reproductive behavior in rats, a finding that may turn out to be relevant to the behavioral effects that are associated with human Piccolo gene mutations. Thus, research aimed at understanding how Piccolo functions to regulate reproduction in rats could prove pivotal in our ability to understand neurological mechanisms that influence human emotions.
The ER chaperone PfGRP170 is essential for asexual development and is linked to stress response in malaria parasites
Authors: Kudyba Heather M. , Cobb David W. , Fierro Manuel A. , Florentin Anat , Ljolje Dragan , Singh Balwan , Lucchi Naomi W. , Muralidharan Vasant 
Published: September 2018

ABSTRACTThe vast majority of malaria mortality is attributed to one parasite species: Plasmodium falciparum. Asexual replication of the parasite within the red blood cell is responsible for the pathology of the disease. In Plasmodium, the endoplasmic reticulum (ER) is a central hub for protein folding and trafficking as well as stress response pathways. In this study, we tested the role of an uncharacterized ER protein, PfGRP170, in regulating these key functions by generating conditional mutants. Our data show that PfGRP170 localizes to the ER and is essential for asexual growth, specifically required for proper development of schizonts. PfGRP170 is essential for surviving heat shock, suggesting a critical role in cellular stress response. The data demonstrate that PfGRP170 interacts with the Plasmodium orthologue of the ER chaperone, BiP. Finally, we found that loss of PfGRP170 function leads to the activation of the Plasmodium eIF2α kinase, PK4, suggesting a specific role for this protein in this parasite stress response pathway.
Harnessing Avidity: Quantifying Entropic and Energetic Effects of Linker Length and Rigidity Required for Multivalent Binding of Antibodies to HIV-1 Spikes
Authors: Einav Tal , Yazdi Shahrzad , Coey Aaron , Bjorkman Pamela J. , Phillips Rob 
Published: September 2018

AbstractDue to the low density of envelope (Env) spikes on the surface of HIV-1, neutralizing IgG antibodies rarely bind bivalently using both antigen-binding arms (Fabs) to crosslink between spikes (inter-spike crosslinking), instead resorting to weaker monovalent binding that is more sensitive to Env mutations. Synthetic antibodies designed to bivalently bind a single Env trimer (intra-spike crosslinking) were previously shown to exhibit increased neutralization potencies. In initial work, diFabs joined by varying lengths of rigid double-stranded DNA (dsDNA) were considered. Anticipating future experiments to improve synthetic antibodies, we investigate whether linkers with different rigidities could enhance diFab potency by modeling DNA-Fabs containing different combinations of rigid dsDNA and flexible single-stranded DNA (ssDNA) and characterizing their neutralization potential. Model predictions suggest that while a long flexible polymer may be capable of bivalent binding, it exhibits weak neutralization due to the large loss in entropic degrees of freedom when both Fabs are bound. In contrast, the strongest neutralization potencies are predicted to require a rigid linker that optimally spans the distance between two Fab binding sites on an Env trimer, and avidity can be further boosted by incorporating more Fabs into these constructs. These results inform the design of multivalent anti-HIV-1 therapeutics that utilize avidity effects to remain potent against HIV-1 in the face of the rapid mutation of Env spikes.SignificanceIgG antibodies utilize avidity to increase their apparent affinities through simultaneous binding of two antigen-binding Fabs – if one Fab dissociates from an antigen, the other Fab can remain attached, allowing rebinding. HIV-1 foils this strategy by having few, and highly-separated, Envelope spike targets for antibodies, forcing most IgGs to bind monovalently. Here we develop a statistical mechanics model of synthetic diFabs joined by DNA linkers of different lengths and flexibilities. This framework enables us to translate the energetic and entropic effects of the linker into the neutralization potency of a diFab. We demonstrate that the avidity of multivalent binding is enhanced by using rigid linkers or including additional Fabs capable of simultaneous binding, providing the means to quantitatively predict the potencies of other antibody designs.
Fatigue induces long lasting detrimental changes in motor skill learning
Authors: Branscheidt Meret , Kassavetis Panagiotis , Rogers Davis , Lindquist Martin A. , Celnik Pablo 
Published: September 2018

ABSTRACTFatigue due to physical exertion is a ubiquitous phenomenon in everyday life and especially common in a range of neurological diseases. While the effect of fatigue on limiting skill execution are well known, its influence on learning new skills is unclear. This is of particular interest as it is common practice to train athletes, musicians or perform rehabilitation exercises up to and beyond a point of fatigue. In a series of experiments, we describe how fatigue impairs motor skill learning beyond its effects on task execution. The negative effects on learning are evidenced by impaired task acquisition on subsequent practice days even in the absence of fatigue. Further, we found that this effect is in part mediated centrally and can be alleviated by altering motor cortex function. Thus, the common practice of training while, or beyond, fatigue levels should be carefully reconsidered, since this affects overall long-term skill learning.
Species abundance information improves sequence taxonomy classification accuracy
Authors: Kaehler Benjamin D. , Bokulich Nicholas A. , McDonald Daniel , Knight Rob , Gregory Caporaso J. , Huttley Gavin A. 
Published: September 2018

AbstractPopular naive Bayes taxonomic classifiers for amplicon sequences assume that all species in the reference database are equally likely to be observed. We demonstrate that classification accuracy degrades linearly with the degree to which that assumption is violated, and in practice it is always violated. By incorporating environment-specific taxonomic abundance information, we demonstrate that species-level resolution is attainable.
Comprehensive analysis of human hookworm secreted proteins using a proteogenomic approach
Authors: Logan J , Manda SS , Choi YJ , Field M , Eichenberger RM , Mulvenna J , Nagaraj SH , Fujiwara RT , Gazzinelli-Guimaraes P , Bueno L , Mati V , Mitreva M , Sotillo J , Loukas A 
Published: September 2018

SummaryThe human hookworm Necator americanus infects more than 400 million people worldwide, contributing substantially to the poverty in these regions. Adult stage N. americanus live in the small intestine of the human host where they inject excretory/secretory (ES) products into the mucosa. ES products have been characterized at the proteome level for a number of animal hookworm species, but until now, the difficulty in obtaining sufficient live N. americanus has been an obstacle in characterizing the secretome of this important human pathogen. Herein we describe the ES proteome of N. americanus and utilize this information to conduct the first proteogenomic analysis of a parasitic helminth, significantly improving the available genome and thereby generating a robust description of the parasite secretome. The genome annotation resulted in a a revised prediction of 3,425 fewer genes than initially reported, accompanied by a significant increase in the number of exons and introns, total gene length and the percentage of the genome covered by genes. Almost 200 ES proteins were identified by LC-MS/MS with SCP/TAPS proteins, ‘hypothetical’ proteins and proteases among the most abundant families. These proteins were compared to commonly used model species of human parasitic infections, including Ancylostoma caninum, Nippostrongylus brasiliensis and Heligmosomoides polygyrus. Our findings provide valuable information on important families of proteins with both known and unknown functions that could be instrumental in host-parasite interactions, including protein families that might be key for parasite survival in the onslaught of robust immune responses, as well as vaccine and drug targets.