bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Measurement of Donor-Specific Cell-Free DNA Identifies Recipients With Biopsy-Proven Acute Rejection Requiring Treatment After Liver Transplantation
Authors: Goh Su Kah , Do Hongdo , Testro Adam , Pavlovic Julie , Vago Angela , Lokan Julie , Jones Robert M. , Christophi Christopher , Dobrovic Alexander , Muralidharan Vijayaragavan 
Published: June 2019

Background.
Assessment of donor-specific cell-free DNA (dscfDNA) in the recipient is emerging as a noninvasive biomarker of organ rejection after transplantation. We previously developed a digital polymerase chain reaction (PCR)-based approach that readily measures dscfDNA within clinically relevant turnaround times. Using this approach, we characterized the dynamics and evaluated the clinical utility of dscfDNA after liver transplantation (LT).

Methods.
Deletion/insertion polymorphisms were used to distinguish donor-specific DNA from recipient-specific DNA. Posttransplant dscfDNA was measured in the plasma of the recipients. In the longitudinal cohort, dscfDNA was serially measured at days 3, 7, 14, 28, and 42 in 20 recipients. In the cross-sectional cohort, dscfDNA was measured in 4 clinically stable recipients (>1-y posttransplant) and 16 recipients (>1-mo posttransplant) who were undergoing liver biopsies.

Results.
Recipients who underwent LT without complications demonstrated an exponential decline in dscfDNA. Median levels at days 3, 7, 14, 28, and 42 were 1936, 1015, 247, 90, and 66 copies/mL, respectively. dscfDNA was higher in recipients with treated biopsy-proven acute rejection (tBPAR) when compared to those without. The area under the receiver operator characteristic curve of dscfDNA was higher than that of routine liver function tests for tBPAR (dscfDNA: 98.8% with 95% confidence interval, 95.8%-100%; alanine aminotransferase: 85.7%; alkaline phosphatase: 66.4%; gamma-glutamyl transferase: 80.1%; and bilirubin: 35.4%).

Conclusions.
dscfDNA as measured by probe-free droplet digital PCR methodology was reflective of organ health after LT. Our findings demonstrate the potential utility of dscfDNA as a diagnostic tool of tBPAR.
Complement Markers in Blood and Urine: No Diagnostic Value in Late Silent Antibody-Mediated Rejection
Authors: Mező Blanka , Heilos Andreas , Böhmig Georg A. , Eskandary Farsad , Wahrmann Markus , Bond Gregor , Kozakowski Nicolas , Halloran Philip F. , Rusai Krisztina , Prohászka Zoltán 
Published: June 2019

Background.
Antibody-mediated rejection (AMR) is a major cause of kidney allograft failure. Its molecular mechanisms are multifaceted and may include a role of complement activation via the classical pathway. Here, we investigated whether noninvasive complement monitoring adds predictive power to the diagnosis of AMR in the setting of donor-specific antibody (DSA) positivity.

Methods.
In this cross-sectional study, 741 kidney transplant recipients with stable graft function ≥180 days posttransplantation were screened for the presence of human leukocyte antigen (HLA) alloantibodies. Eighty-three of 111 DSA-positive recipients underwent protocol biopsies and were tested for blood and urinary levels of complement proteins (C1q, C4, C3) and activation products (C4d, C3a, C5a, C5b-9).

Results.
Forty-seven recipients were diagnosed with AMR, and 21 were C4d-positive. While biopsy-confirmed AMR (and C4d) associated with DSA-binding strength (IgG mean fluorescence intensity of the immunodominant DSA versus AMR; area under the receiver operating characteristic curve: 0.76), tested complement markers did not have any predictive value for rejection (area under the receiver operating characteristic curve: 0.49–0.56). There were, however, tight correlations between complement activation products in urine and protein/creatinine ratio (ρ = 0.44–0.64; P < 0.001). Analysis of death-censored graft survival over a median of 60 months revealed no independent associations with levels of complement markers in blood or urine.

Conclusions.
Complement patterns in blood and urine failed to identify AMR in late biopsies and may have no relevant diagnostic value in this particular context.
Insights into human genetic variation and population history from 929 diverse genomes
Authors: Bergström Anders , McCarthy Shane A. , Hui Ruoyun , Almarri Mohamed A. , Ayub Qasim , Danecek Petr , Chen Yuan , Felkel Sabine , Hallast Pille , Kamm Jack , Blanché Hélène , Deleuze Jean-François , Cann Howard , Mallick Swapan , Reich David , Sandhu Manjinder S. , Skoglund Pontus , Scally Aylwyn , Xue Yali , Durbin Richard , Tyler-Smith Chris 
Published: June 2019

AbstractGenome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented private genetic variation in southern and central Africa and in Oceania and the Americas, but an absence of fixed, private variants between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the last 10,000 years, a potentially major population growth episode after the peopling of the Americas, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations. We also demonstrate benefits to the study of population relationships of genome sequences over ascertained array genotypes. These genome sequences are freely available as a resource with no access or analysis restrictions.
Cue-reactivity and approach bias to social alcohol cues and their association with drinking in a social setting in young adults
Authors: Groefsema Martine M. , Mies Gabry W. , Cousijn Janna , Engels Rutger C.M.E. , Sescousse Guillaume , Luijten Maartje 
Published: June 2019

ABSTRACTAlcohol is mainly consumed in social settings, in which people often adapt their drinking behavior to that of others, also called imitation of drinking. Yet, it remains unclear what drives this drinking in a social setting. In this study, we expected to see stronger brain and behavioral responses to social compared to non-social alcohol cues, that would be associated with actual drinking in a social setting. The sample consisted of 153 beer-drinking males, aged 18-25 years. Brain responses to social alcohol cues were measured during an alcohol cue exposure task in the scanner. Behavioral responses to social alcohol cues were measured using a stimulus-response compatibility task, providing an index of approach bias towards these cues. Drinking in a social setting was measured in a Bar-Lab setting. Specific brain responses to social alcohol cues were observed in the bilateral superior temporal sulcus and the left inferior parietal lobe. There was no approach bias towards social alcohol cues specifically, however, we did find an approach bias towards alcohol (versus soda) cues in general. Brain responses and approach bias towards social alcohol cues were unrelated and not associated with drinking, measured in the Bar-Lab. Thus, we found no support for a relation between drinking in a social setting on the one hand, and brain cue-reactivity or behavioral approach biases to social alcohol cues on the other hand. This suggests that, in contrast to our hypothesis, drinking in a social setting may not be driven by brain or behavioral responses to social alcohol cues.
Reflexive gaze following in common marmoset monkeys
Authors: Spadacenta Silvia , Dicke Peter W. , Thier Peter 
Published: June 2019

ABSTRACTThe ability to extract the direction of the other’s gaze allows us to shift our attention to an object of interest to the other and to establish joint attention. By mapping one’s own expectations, desires and intentions on the object of joint attention, humans develop a Theory of (the other’s) Mind (TOM), a functional sequence possibly disrupted in autism. Although old world monkeys probably do not possess a TOM, they follow the other’s gaze and they establish joint attention. Gaze following of both humans and old world monkeys fulfills Fodor’s criteria of a domain specific function and is orchestrated by very similar cortical architectures, strongly suggesting homology. Also new world monkeys, a primate suborder that split from the old world monkey line about 35 million years ago, have complex social structures. One member of this group, the common marmoset (Callithrix jacchus), has received increasing interest as a potential model in studies of normal and disturbed human social cognition. Marmosets are known to follow human head-gaze. However, the question is if they use gaze following to establish joint attention with conspecifics. Here we show that this is indeed the case. In a free choice task, head-restrained marmosets prefer objects gazed at by a conspecific and, moreover, they exhibit considerably shorter choice reaction times for the same objects. These findings support the assumption of an evolutionary old domain specific faculty shared within the primate order and they underline the potential value of marmosets in studies of normal and disturbed joint attention.HIGHLIGHTSCommon marmosets follow the head gaze of conspecifics in order to establish joint attention.Brief exposures to head gaze are sufficient to reallocate an animal’s attention.The tendency to follow the other’s gaze competes with the attractional binding of the conspecific’s face
Prism adaptation modulates connectivity of the intraparietal sulcus with multiple brain networks
Authors: Schintu Selene , Freedberg Michael , Gotts Stephen J. , Cunningham Catherine A. , Alam Zaynah M. , Shomstein Sarah , Wassermann Eric M. 
Published: June 2019

ABSTRACTPrism adaptation (PA) alters spatial cognition according to the direction of visual displacement by temporarily modifying sensorimotor mapping. Right-shifting prisms (right PA) improve neglect of left space in patients, possibly by decreasing activity in the left hemisphere and increasing it in the right. Left PA shifts attention to the right in healthy individuals by an opposite mechanism. However, functional imaging studies of PA are inconsistent, perhaps because of differing activation tasks. We measured resting-state functional connectivity (RSFC) in healthy individuals before and after PA. Right, vs. left, PA decreased RSFC in the navigation network defined by the right posterior parietal cortices (PPCs), hippocampus, and cerebellum. Right PA, relative to baseline, increased RSFC between regions within both PPCs and between the PPCs and the right middle frontal gyrus, whereas left PA decreased RSFC between these regions. These results show that right PA modulates connectivity within the right-hemisphere navigation network and shifts attention leftward by increasing connectivity in the right frontoparietal network and left PA produces essentially opposite effects, consistent with the interhemispheric competition model. These finding explain the action of PA on intact cognition and will help optimize interventions in neglect patients.
Two pathways for thiosulfate oxidation in the alphaproteobacterial chemolithotrophParacoccus thiocyanatusSST
Authors: Rameez Moidu Jameela , Pyne Prosenjit , Mandal Subhrangshu , Chatterjee Sumit , Alam Masrure , Bhattacharya Sabyasachi , Mondal Nibendu , Sarkar Jagannath , Ghosh Wriddhiman 
Published: June 2019

AbstractChemolithotrophic bacteria oxidize various sulfur species for energy and electrons, thereby operationalizing biogeochemical sulfur cycles in nature. The best-studied pathway of bacterial sulfur-chemolithotrophy, involving direct oxidation of thiosulfate to sulfate (without any free intermediate) by the SoxXAYZBCD multienzyme system, is apparently the exclusive mechanism of thiosulfate oxidation in facultatively chemolithotrophic alphaproteobacteria. Here we explore the molecular mechanisms of sulfur oxidation in the thiosulfate- and tetrathionate-oxidizing alphaproteobacteriumParacoccus thiocyanatusSST, and compare them with the prototypical Sox process characterized inParacoccus pantotrophus. Our results revealed the unique case where, an alphaproteobacterium has Sox as its secondary pathway of thiosulfate oxidation, converting ∼10% of the thiosulfate supplied whilst 90% of the substrate is oxidized via a Tetrathionate-Intermediate pathway. Knock-out mutation, followed by the study of sulfur oxidation kinetics, showed that thiosulfate-to-tetrathionate conversion, in SST, is catalyzed by a thiosulfate dehydrogenase (TsdA) homolog that has far-higher substrate-affinity than the Sox system of this bacterium, which, remarkably, is also less efficient than theP. pantotrophusSox.soxB-deletion in SST abolished sulfate-formation from thiosulfate/tetrathionate while thiosulfate-to-tetrathionate conversion remained unperturbed. Physiological studies revealed the involvement of glutathione in SST tetrathionate oxidation. However, zero impact of the knock-out of a thiol dehydrotransferase (thdT) homolog, together with no production of sulfite as an intermediate, indicated that tetrathionate oxidation in SST is mechanistically novel, and distinct from its betaproteobacterial counterpart mediated by glutathione, ThdT, SoxBCD and sulfite:acceptor oxidoreductase. All the present findings collectively highlight extensive functional diversification of sulfur-oxidizing enzymes across phylogenetically close, as well as distant, bacteria.
Actomyosin regulation by Eph receptor signaling couples boundary cell formation to border sharpness
Authors: Cayuso Jordi , Xu Qiling , Addison Megan , Wilkinson David G. 
Published: June 2019

SummaryThe segregation of cells with distinct regional identity underlies formation of a sharp border, which in some tissues serves to organise a boundary signaling centre. It is unclear whether or how border sharpness is coordinated with induction of boundary-specific gene expression. We show that forward signaling of EphA4 is required for border sharpening and induction of boundary cells in the zebrafish hindbrain, which we find both require kinase-dependent signaling, with a lesser input of PDZ domain-dependent signaling. We find that boundary-specific gene expression is regulated by myosin II phosphorylation, which increases actomyosin contraction downstream of EphA4 signaling. Myosin phosphorylation leads to nuclear translocation of Taz, which together with Tead1a is required for boundary marker expression. Since actomyosin contraction maintains sharp borders, there is direct coupling of border sharpness to boundary cell induction that ensures correct organisation of signaling centres.
Using a barcoded AAV capsid library to select for novel clinically relevant gene therapy vectors
Authors: Pekrun Katja , De Alencastro Gustavo , Luo Qing-Jun , Liu Jun , Kim Youngjin , Nygaard Sean , Galivo Feorillo , Zhang Feijie , Song Ren , Tiffany Matthew R. , Xu Jianpeng , Hebrok Matthias , Grompe Markus , Kay Mark A. 
Published: June 2019

ABSTRACT:While gene transfer using recombinant adeno-associated viral (rAAV) vectors have shown success in some clinical trials, there remain many tissues that are not well transduced. Because of the recent success in reprogramming islet derived cells into functional β-cells in animal models, we constructed two highly complex barcoded replication competent capsid shuffled libraries and selected for high transducing variants on primary human islets. We describe a chimeric capsid (AAV-KP1) that penetrated and transduced primary human islet cells and human embryonic stem cell derived β-cells with up to 10-fold higher efficiency compared to previously studied best in class AAV vectors. Remarkably, this chimeric capsid was also able to transduce both mouse and human hepatocytes at very high levels in a humanized-chimeric mouse model, thus providing a versatile vector which has the potential to be used in both preclinical testing and human clinical trials for both liver-based diseases and diabetes.
Restoring ancestral phenotypes by reduction of plasticity is a general pattern in gene expression during adaptation to different stressors in Tribolium castaneum
Authors: Koch Eva L. , Guillaume Frédéric 
Published: June 2019

AbstractPlasticity and evolution are two processes individuals to respond to environmental change, but how both are related and impact each other is still controversial. We studied plastic and evolutionary responses in gene expression of Tribolium castaneum after exposure to new environments that differed from ancestral conditions in temperature, humidity or both. Using experimental evolution with ten replicated lines per condition, we were able to demonstrate adaptation after 20 generations. We measured gene expression in each condition in adapted selection lines and control lines to infer evolutionary and plastic changes. We found more evidence for changes in mean expression (shift in the intercept of reaction norms) in adapted lines than for changes in plasticity (shifts in slopes). Plasticity was mainly preserved and was responsible for a large part of the phenotypic divergence in expression between ancestral and new conditions. However, we found that genes with the largest evolutionary changes in expression also evolved reduced plasticity and often showed expression levels closer to the ancestral stage. Results obtained in the three different conditions were similar suggesting that restoration of ancestral expression levels during adaptation is a general evolutionary pattern. We increased the sample size in the most stressful condition and were then able to detect a positive correlation between proportion of genes with reversion of the ancestral plastic response and mean fitness per selection line.
Exogenous Protein as an Environmental Stimuli of Biofilm Formation in Select Bacterial Strains
Authors: Ye Donna , Bapu Lekha , Cavalcante Mariane Mota , Kato Jesse , Sneideman Maggie Lauria , Scribner Kim , Loch Thomas , Marsh Terence L. 
Published: June 2019

ABSTRACTA screening of environmental conditions that would elicit robust biofilm in a collection ofSerratia marcescensisolated from soil revealed that exogenous milk protein increased biofilm productivity up to ten-fold. A select screening of fish pathogens, freshwater and human isolates identified several other species that responded similarly to exogenous protein. The optimal protein concentration was species specific;S. marcescensat 5% milk protein,Aeromonassp. at 2-3%,Flavobacterium columnareat 1% andPseudomonas aeruginosaat 0.1-0.4%. Media supplemented with milk protein also increased the cell counts in biofilm as well as the protein incorporated into the biofilm matrix. These data suggest that relatively high concentrations of exogenous protein may serve as an environmental trigger for biofilm formation, particularly for pathogenic bacteria exposed to relatively high concentrations of protein in bodily fluids and mucosal surfaces.
FMRFGene Expression in the Nervous System of the SquidDoryteuthis Pealei* Hatchling
Authors: Burbach J. Peter H. , Grant Philip , Senft Stephen , Kripke Lizzie , Hellemons Anita J.C.G.M. , Pant Harish C. 
Published: June 2019

AbstractFMRFamide is a neuropeptide that is widely distributed in invertebrates and known to be involved in many physiological functions. Previously we noted marked differences in expression of thefmrfgene in the stellate ganglion ofDoryteuthis pealei*compared to the central nervous system. In this study we aimed to examen the brain systems ofDoryteuthis pealei*for the presence and distribution offmrf-expressing cells and fiber networks. Late squid embryos and hatchlings were examined by in situ hybridization and immunohistochemistry in whole mounts and tissue sections. All central lobes contained limited numbers of scattered neurons expressingfmrf, but the FMRFamide-containing fiber systems were abundant and extensive, mostly present in the neuropil of lobes. Main clusters of neurons were located in the magnocellular and chromatophore lobes of the posterior subesophageal mass (PSM), and in dorsal aspects of the basal lobe (BL). Dense FMRFamide-immunoreactive fibers were particularly seen in the optic lobe (OL), medial and posterior supraesophageal masses (MSM and SPM) often with a commissural organization. The data show that the central lobes ofDoryteuthis pealeihatchlings have a matured FMRFamide system organized in a limited number of centers, but with widely distributed efferents. This suggests that FMRFamide neurons are already functionally engaged in the late embryo. The localization indicates that control of chromatophores and fin movement are amongst these functions.
The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+T cell activity and synergizes with immune check-point inhibitors
Authors: Puca Emanuele , Probst Philipp , Stringhini Marco , Murer Patrizia , Pellegrini Giovanni , Cazzamalli Samuele , Hutmacher Cornelia , Gouyou Baptiste , Wulhfard Sarah , Matasci Mattia , Villa Alessandra , Neri Dario 
Published: June 2019

ABSTRACTWe describe the cloning and characterization of a novel fusion protein (termed L19-mIL12), consisting of murine interleukin-12 in single-chain format, sequentially fused to the L19 anti-body in tandem diabody format. The fusion protein bound avidly to the cognate antigen (the alternatively-spliced EDB domain of fibronectin), retained the activity of the parental cyto-kine and was able to selectively localize to murine tumorsin vivo, as shown by quantitative biodistribution analysis. L19-mIL12 exhibited a potent anti-tumor activity in immunocompetent mice bearing CT26 carcinomas and WEHI-164 sarcomas, which could be boosted by combination with check-point blockade, leading to durable cancer eradication. L19-mIL12 also inhibited tumor growth in mice with Lewis lung carcinoma (LLC), but in this case cancer cures could not be obtained, both in monotherapy and in combination. A microscopic analysis and a depletion experiment of tumor-infiltrating leukocytes illustrated the contribution of NK cells and CD8+T cells for the anti-cancer activity observed in both tumor models. Upon L19-mIL12 treatment, the density of regulatory T cells (Tregs) was strongly increased in LLC, but not in CT26 tumors. A FACS analysis also revealed that the majority of CD8+T cells in CT26 tumors were specific to the retroviral AH1 antigen.NOVELTY AND IMPACT STATEMENTIn this study, we describe the generation of a novel fusion protein consisting of murine inter-leukin-12 fused to the L19 antibody (specific to the EDB domain of fibronectin). L19-mIL12 revealed favourable tumor to organ ratios 24h after intravenous administration and it was able to cure 60% of CT26 tumor-bearing mice. From a clinical perspective, the rapid clearance from circulation should ease the administration to patients as infusions could be stopped upon onset of side-effects.