bluuebunny/crossref_metadata_2025 huggingface dataset:
Adapting the Surgical Apgar Score for Perioperative Outcome Prediction in Liver Transplantation: A Retrospective Study
Authors: Pearson Amy C. S. , Subramanian Arun , Schroeder Darrell R. , Findlay James Y.
Published: October 2017

Background

The surgical Apgar score (SAS) is a 10-point scale using the lowest heart rate, lowest mean arterial pressure, and estimated blood loss (EBL) during surgery to predict postoperative outcomes. The SAS has not yet been validated in liver transplantation patients, because typical blood loss usually exceeds the highest EBL category. Our primary aim was to develop a modified SAS for liver transplant (SAS-LT) by replacing the EBL parameter with volume of red cells transfused. We hypothesized that the SAS-LT would predict death or severe complication within 30 days of transplant with similar accuracy to current scoring systems.

Methods

A retrospective cohort of consecutive liver transplantations from July 2007 to November 2013 was used to develop the SAS-LT. The predictive ability of SAS-LT for early postoperative outcomes was compared with Model for End-stage Liver Disease, Sequential Organ Failure Assessment, and Acute Physiology and Chronic Health Evaluation III scores using multivariable logistic regression and receiver operating characteristic analysis.

Results

Of 628 transplants, death or serious perioperative morbidity occurred in 105 (16.7%). The SAS-LT (receiver operating characteristic area under the curve [AUC], 0.57) had similar predictive ability to Acute Physiology and Chronic Health Evaluation III, model for end-stage liver disease, and Sequential Organ Failure Assessment scores (0.57, 0.56, and 0.61, respectively).

Seventy-nine (12.6%) patients were discharged from the ICU in 24 hours or less. These patients’ SAS-LT scores were significantly higher than those with a longer stay (7.0 vs 6.2, P < 0.01). The AUC on multivariable modeling remained predictive of early ICU discharge (AUC, 0.67).

Conclusions

The SAS-LT utilized simple intraoperative metrics to predict early morbidity and mortality after liver transplant with similar accuracy to other scoring systems at an earlier postoperative time point.
Five-Year-Old Boy With Behavioral Changes and Papilledema
Authors: Ram Radha , Jones Jeremy Y. , Mohila Carrie A. , Shah Veeral S.
Published: October 2017

A 5-year-old boy had initial symptoms of behavioral changes, nausea, vomiting, headache, weight loss, and progressive vision failure. Brain MRI revealed abnormal signal intensity in both optic nerves, the optic chiasm, the right medial temporal lobe, and tissues surrounding the right supraclinoid internal carotid artery with associated leptomeningeal and spinal cord enhancement. After nondiagnostic dural and spinal arachnoid biopsies, a temporal lobe biopsy was diagnostic for a rare malignant peripheral nerve sheath tumor.
Single-cell transcriptome analysis identifies distinct cell types and intercellular niche signaling in a primary gastric organoid model
Authors: Chen Jiamin , Lau Billy T , Andor Noemi , Grimes Sue M , Handy Christine , Wood-Bouwens Christina , Ji Hanlee P
Published: October 2017

The diverse cellular milieu of the gastric tissue microenvironment plays a critical role in normal tissue homeostasis and tumor development. However, few cell culture model can recapitulate the tissue microenvironment and intercellular signalingin vitro. Here we applied an air-liquid interface method to culture primary gastric organoids that contains epithelium with endogenous stroma. To characterize the microenvironment and intercellular signaling in this model, we analyzed the transcriptomes of over 5,000 individual cells from primary gastric organoids cultured at different time points. We identified epithelial cells, fibroblasts and macrophages at the early stage of organoid formation, and revealed that macrophages were polarized towards wound healing and tumor promotion. The organoids maintained both epithelial and fibroblast lineages during the course of time, and a subset of cells in both lineages expressed the stem cell markerLgr5. We identified thatRspo3was specifically expressed in the fibroblast lineage, providing an endogenous source of the R-spondin to activate Wnt signaling. Our studies demonstrate that air-liquid-interface-derived organoids provide a novel platform to study intercellular signaling and immune responsein vitro.
The impact of surveillance and control on highly pathogenic avian inuenza outbreaks in poultry in Dhaka division, Bangladesh
Authors: Hill Edward M. , House Thomas , Dhingra Madhur S. , Kalpravidh Wantanee , Morzaria Subhash , Osmani Muzaffar G. , Brum Eric , Yamage Mat , Kalam Md. A. , Prosser Diann J. , Takekawa John Y. , Xiao Xiangming , Gilbert Marius , Tildesley Michael J.
Published: October 2017

In Bangladesh, the poultry industry is an economically and socially important sector, but it is persistently threatened by the effects of H5N1 highly pathogenic avian influenza. Thus, identifying the optimal control policy in response to an emerging disease outbreak is a key challenge for policy-makers. To inform this aim, a common approach is to carry out simulation studies comparing plausible strategies, while accounting for known capacity restrictions. In this study we perform simulations of a previously developed H5N1 influenza transmission model framework, fitted to two separate historical outbreaks, to assess specific control objectives related to the burden or duration of H5N1 outbreaks among poultry farms in the Dhaka division of Bangladesh. In particular, we explore the optimal implementation of ring culling, ring vaccination and active surveillance measures when presuming disease transmission predominately occurs from premises-to-premises, versus a setting requiring the inclusion of external factors. Additionally, we determine the sensitivity of the management actions under consideration to differing levels of capacity constraints and outbreaks with disparate transmission dynamics. While we find that reactive culling and vaccination policies should pay close attention to these factors to ensure intervention targeting is optimised, across multiple settings the top performing control action amongst those under consideration were targeted proactive surveillance schemes. Our findings may advise the type of control measure, plus its intensity, that could potentially be applied in the event of a developing outbreak of H5N1 amongst originally H5N1 virus-free commercially-reared poultry in the Dhaka division of Bangladesh.
Dynamic evolution of the major transcription factor DNA binding domain, and protein-protein interaction families during the evolution of the avian lineage
Authors: Graham Allie M. , Presnell Jason S.
Published: October 2017

Transcription factors are characterized by their domain architecture, including DNA binding and protein-protein interaction domain combinations, which regulate their binding specificity, as well as their ability to effect a change on gene expression of their downstream targets. Transcription factors are central to organismal development, thus they potentially are instrumental in producing phenotypic diversity. Transcription factor abundance was estimated via 49 major DNA binding domain families, as well as 34 protein-protein interaction domain families, in 48 bird genomes, which were then compared with 6 available reptile genomes, in an effort to assess the degree to which these domains are potentially connected to increased phenotypic diversity in the avian lineage. We hypothesized that there would be increased abundance in multiple transcription factor domain families, as well as domains associated with protein-protein interactions, that would correlate with the increased phenotypic diversity found in birds; instead, this data shows a general loss/contraction of major domain families, with the largest losses in domain families associated with multiple developmental (feather, body-plan, immune) and metabolic processes. Ultimately, the results of this analyses represent a general characterization of domain family composition in birds, thus the specific domain composition of TF families should be probed further, especially those with the largest reductions seen in this study.
miR-128 inhibits telomerase activity by targeting TERT mRNA
Authors: Guzman Herlinda , Sanders Katie , Idica Adam , Bochnakian Aurore , Jury Douglas , Daugaard Iben , Zisoulis Dimitrios G , Pedersen Irene Munk
Published: October 2017

Telomerase is a unique cellular reverse transcriptase essential for maintaining telomere stability and required for the unlimited proliferation of cancer cells. The limiting determinant of telomerase activity is the catalytic component TERT, and TERT expression is closely correlated with telomerase activity and cancer initiation and disease progression. For this reason the regulation of TERT levels in the cell is of great importance. microRNAs (miRs) function as an additional regulatory level in cells, crucial for defining expression boundaries, proper cell fate decisions, cell cycle control, genome integrity, cell death and metastasis. We performed an anti-miR library screen to identity novel miRs, which participate in the control of telomerase. We identified the tumor suppressor miR (miR-128) as a novel endogenous telomerase inhibitor and determined that miR-128 significantly reduces the mRNA and protein levels of Tert in a panel of cancer cell lines. We further evaluated the mechanism by which miR-128 regulates TERT and demonstrated that miR-128 interacts directly with the coding sequence of TERT mRNA in both HeLa cells and teratoma cells. Interestingly, the functional miR-128 binding site in TERT mRNA, is conserved between TERT and the other cellular reverse transcriptase encoded by Long Interspaced Elements-1 (LINE-1 or L1), which can also contribute to the oncogenic phenotype of cancer. This finding supports the novel idea that miRs may function in parallel pathways to inhibit tumorigenesis, by regulating a group of enzymes (RT) by targeting conserved binding sites in the coding region of both enzymes.

NOVELTY AND IMPACT

Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and almost universally provides the molecular basis for unlimited proliferative potential. Expression of human telomerase alone is sufficient for the immortalization of diverse cell types. We have identified the tumor suppressor microRNA (miR-128) as a novel regulator of telomerase, which directly targets the coding sequence (CDS) of TERT mRNA and significantly represses Tert protein expression in a panel of cancer cell lines.
A 30-minute nucleic acid amplification point-of-care test for genitalChlamydia trachomatisinfection in women: a prospective, multi-centre study of diagnostic accuracy
Authors: Harding-Esch EM , Cousins EC , Chow S-LC , Phillips LT , Hall CL , Cooper N , Fuller SS , Nori AV , Patel R , Thomas-William S , Whitlock G , Edwards SJE , Green M , Clarkson J , Arlett B , Dunbar JK , Lowndes CM , Sadiq ST
Published: October 2017

Background

Rapid Point-Of-Care Tests (POCTs) forChlamydia trachomatis(CT) may reduce onward transmission and reproductive sexual health (RSH) sequelae by reducing turnaround times between diagnosis and treatment. The io®single module system (Atlas Genetics Ltd) runs clinical samples through a microfluidic CT cartridge, delivering results in 30 minutes. We evaluated its performance on female genital samples in four UK Genito-Urinary Medicine (GUM)/RSH clinics.

Methods

Prospective diagnostic accuracy study, using BD ProbeTec CT/GC assay as the routine clinic nucleic acid amplification test (NAAT) as the initial comparator test, and the QIAgen Artus CT assay to resolve discrepancies. In these instances, the reference standard was defined as the resolved result when two out of three assay results concurred. Female participants aged ≥16 provided additional-to-routine self-collected vulvovaginal swabs. Samples were tested fresh with the io®CT assay within 7 days of collection, or were frozen at −80°C for later testing. Participant clinical, demographic and behavioural characteristics were collected to assess risk factors associated with CT infection.

Results

Of 785 participants recruited, final analyses were conducted on 709 (90.3%). CT prevalence was 7.2% (51/709) overall. Sensitivity, specificity, positive and negative predictive values of the io®CT assay were, respectively, 96.1% (95% Confidence Interval (CI): 86.5-99.5), 97.7% (95%CI: 96.3-98.7), 76.6% (95%CI: 64.3-86.2) and 99.7% (95%CI: 98.9-100). There was no significant difference in performance measures between fresh and frozen samples, or between symptomatic and asymptomatic participants (p>0.05). The only risk factor associated with CT infection was being a sexual contact of an individual with CT.

Conclusions

The io®CT-assay is the only 30-minute, fully automated, high-performing NAAT currently CE-marked for CT diagnosis in women, making it a highly promising diagnostic to enable specific treatment, initiation of partner notification and appropriately intensive health promotion at the point of care. Future research is required to evaluate acceptability by clinicians and patients in GUM/RSH clinics, impact on clinical pathways and patient management, and cost-effectiveness.
Repurposing non-cancer Drugs in Oncology – How many drugs are out there?
Authors: Pantziarka Pan , Sukhatme Vidula , Meheus Lydie , Sukhatme Vikas , Bouche Gauthier
Published: October 2017

Background

Drug repurposing can speed up access to new therapeutic options for cancer patients. With more than 2000 drugs approved worldwide and 6 relevant targets per drug on average, the potential is quantitatively important. In this paper, we have attempted to quantify the number of non-cancer drugs supported by either preclinical or clinical cancer data.

Methods

A PubMed search was performed to identify non-cancer drugs which could be repurposed in one or more cancer types. Drugs needed at least one peer-reviewed article showing an anticancer effect in vitro, in vivo or in humans.

Results

A total of 235 eligible non-cancer drugs were identified (Table 1). Main charateirstics of the drugs are summarized in Table 2. 67 (29%) are on the WHO list of essential medicines and 176 (75%) are off-patent. 133 (57%) had human data in cancer patient(s). Four were listed in clinical guidelines, namely thalidomide, all-trans retinoic acid, zoledronic acid and non-steroidal anti-inflammatory drugs (NSAID). Several drugs have shown a survival benefit in randomized trials such as cimetidine (colorectal cancer), progesterone (breast cancer) or itraconazole (lung cancer). Several other drugs induced responses in rare tumours, like clarithromycin, timolol or propranolol.

Conclusion

We have found that the number of off-patent repurposing opportunities is large and increasing. Joint non-commercial clinical development (academics, governments, charities) may bring new therapeutic options to patients at low cost, especially in indications for which the industry has no incentive to invest in.
Simulations for Designing and Interpreting Intervention Trials in Infectious Diseases
Authors: Elizabeth Halloran M. , Auranen Kari , Baird Sarah , Basta Nicole E. , Bellan Steve , Brookmeyer Ron , Cooper Ben , DeGruttola Victor , Hughes James , Lessler Justin , Lofgren Eric T. , Longini Ira M. , Onnela Jukka-Pekka , Özler Berk , Seage George , Smith Thomas A. , Vespignani Alessandro , Vynnycky Emilia , Lipsitch Marc
Published: October 2017

Here we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly in emerging infectious disease, that more accurately reflects the dynamics of the transmission process. Interventions in infectious diseases can have indirect effects on those not receiving the intervention as well as direct effects on those receiving the intervention. Combinations of interventions can have complex interactions at the population level. These often cannot be adequately addressed with standard study designs and analytic methods. Simulations can help to accurately represent transmission dynamics in an increasingly complex world which is critical for proper trial design and interpretation. Some ethical aspects of a trial can also be quantified using simulations. After a trial has been conducted, simulations can be used to explore possible explanations for the observed effects. A great deal is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods and the conduct of clinical trials.
Melanoma proteomics unravels major differences related to mutational status
Authors: Trilla-Fuertes Lucía , Gámez-Pozo Angelo , Prado-Vázquez Guillermo , Zapater-Moros Andrea , Díaz-Almirón Mariana , Fortes Claudia , López-Vacas Rocío , Márquez-Rodas Iván , Soria Ainara , Fresno Vara Juan Ángel , Espinosa Enrique
Published: October 2017

The aim of the study was to explore the molecular differences between melanoma tumor subtypes, based on BRAF and NRAS mutational status. Fourteen formalin-fixed, paraffin- embedded melanoma samples were analyzed using a high-throughput proteomics approach, coupled with probabilistic graphical models and Flux Balance Analysis, to characterize these differences. Proteomics analyses showed differences in expression of proteins related with fatty acid metabolism, melanogenesis and extracellular space between BRAF mutated and BRAF non-mutated melanoma tumors. Additionally, probabilistic graphical models showed differences between melanoma subgroups at biological processes such as melanogenesis or metabolism. On the other hand, Flux Balance Analysis predicts a higher tumor growth rate in BRAF mutated melanoma samples. In conclusion, differential biological processes between melanomas showing a specific mutational status can be detected using combined proteomics and computational approaches.
Application of benchmark analysis for mixed contaminant exposures: Mutual adjustment of two perfluoroalkylate substances associated with immunotoxicity
Authors: Budtz-Jøergensen Esben , Grandjean, Philippe
Published: October 2017

Background

Developmental exposure to perfluorinated substances is associated with deficient IgG antibody responses to childhood vaccines as an indication of depressed immune system functions. As this outcome may represent a critical effect of these substances, calculation of benchmark dose (BMD) results would be useful for standards setting to protect exposed populations against adverse effects. However, in the mixed exposure setting of most epidemiological evidence, the two major and inter-related substances associated with this adverse effect have shown similar benchmark results that raise concerns about possible confounding.

Methods

With the aim of better characterizing the immunotoxicity impact of the two major perfluorinated substances in the mixed exposures, we carried out BMD calculations on prospective data from two prospective birth cohort studies from the Faroe Islands with a total of 1,146 children. Exposure data included serum concentrations of perfluorooctane sulfonate and perfluorooctanoate at birth and at age 5 years and, as outcome parameters, the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7. We calculated the BMDs and their lower confidence bounds (BMDLs) and included mutual adjustment for the two compounds.

Results

The BMDLs for the two immunotoxicants were of similar magnitude before and after adjustment. Both substances showed lower results for a logarithmic dose-response model, which also provided a slightly better fit than a linear dose model for both antibodies. We also used a broken curve shape that allowed a different slope below the median exposure. Postnatal exposure as represented by the age 5 serum concentration, showed a stronger association with the antibody outcomes than the prenatal exposure. Due to the correlation between the two immunotoxicants, the mutual adjustment resulted in elevated BMD results andpvalues. However, the BMDL values were virtually unchanged.

Conclusions

Adjustment for co-exposure to another immunotoxicant increased the variance and the BMD values, but affected the BMDL values only to a negligible extent. These calculations are in accordance with an interpretation that, when two toxicants appear to affect an outcome to an almost equal degree and none of them is known to be solely responsible, the exposures should both be considered responsible and attract equal regulatory attention until further evidence shows otherwise.
The VT GAL4, LexA, and split-GAL4 driver line collections for targeted expression in theDrosophilanervous system
Authors: Tirian Laszlo , Dickson Barry J.
Published: October 2017

In studying the cellular interactions within complex tissues, it is extremely valuable to be able to reproducibly and flexibly target transgene expression to restricted subsets of cells. This approach is particularly valuable in studying the nervous system, with its bewildering diversity of neuronal cell types. We report here the generation of over 18,000 driver lines (the VT collection) that exploit the GAL4, LexA, and split-GAL4 systems to express transgenes in distinct and highly specific cell types inDrosophila. We document the expression patterns of over 14,000 of these lines in the adult male brain.
Data mining of digitized health records in a resource-constrained setting reveals that timely immunophenotyping is associated with improved breast cancer outcomes
Authors: López-Pineda Arturo , Rodríguez-Moran Mario F. , Álvarez-Aguilar Cleto , Fuentes Valle Sarah M. , Acosta-Rosales Román , Bhatt Ami S. , Sheth Shruti N. , Bustamante Carlos D.
Published: October 2017

Background

Organizations that issue guidance on breast cancer recommend the use of immunohistochemistry (IHC) for providing appropriate and precise care. However, little focus has been directed to the identification of maximum allowable turnaround times for IHC, which is necessary given the diversity of hospital settings in the world. Much less effort has been committed to the development of digital tools that allow hospital administrators to monitor service utilization histories of their patients.

Methods

In this retrospective cohort study, we reviewed electronic and paper medical records of all suspected breast cancer patients treated at one secondary-care hospital of the Mexican Institute of Social Security (IMSS), located in western Mexico. We then followed three years of medical history of those patients with IHC testing.

Results

In 2014, there were 402 breast cancer patients, of which 30 were tested for some IHC biomarker (ER, PR, HER2). The subtyping allowed doctors to adjust (56.7 %) or confirm (43.3 %) the initial therapeutic regimen. The average turnaround time was 56 days. Opportune IHC testing was found to be beneficial when it was available before or during the first rounds of chemotherapy.

Conclusions

The use of data mining tools applied to health record data revealed that there is an association between timely immunohistochemistry and improved outcomes in breast cancer patients. Based on this finding, inclusion of turnaround time in clinical guidelines is recommended. As much of the health data in the country becomes digitized, our visualization tools allow a digital dashboard of the hospital service utilization histories.
In the Absence of Apoptosis, Myeloid Cells Arrest When Deprived of Growth Factor, But Remain Viable by Consuming Extracellular Glucose
Authors: Dong Li , Reljic Boris , Cheung Jen G. , Ng Elizabeth S. , Lindqvist Lisa M. , Elefanty Andrew G. , Vaux David L. , Tran Hoanh
Published: October 2017

Withdrawal of the growth factor interleukin 3 from IL3-dependent myeloid cells causes them to undergo Bax/Bak1-dependent apoptosis, whereas factor-deprivedBax-/-Bak1-/-cells remain viable, but arrest and shrink. It was reported that withdrawal of IL3 fromBax-/-Bak1-/-cells caused decreased expression of the glucose transporter Glut1, leading to reduced glucose uptake, so that arrested cells required Atg5-dependent autophagy for long-term survival. In other cell types, a decrease in Glut1 is mediated by the thioredoxin-interacting protein Txnip, which is induced in IL3-dependent myeloid cells when growth factor is removed. We mutatedAtg5andTxnipby CRISPR/Cas9 and found that Atg5-dependent autophagy was not necessary for the long-term viability of cycling or arrestedBax-/-Bak1-/-cells, and that Txnip was not required for the decrease in Glut1 expression in response to IL3 withdrawal. Surprisingly, Atg5-deficientBax/Bak1double mutant cells survived for several weeks in medium supplemented with 10% fetal bovine serum (FBS), without high concentrations of added glucose or glutamine. When serum was withdrawn, the provision of an equivalent amount of glucose present in 10% FBS (~0.5 mM) was sufficient to support cell survival for more than a week, in the presence or absence of IL3. Thus,Bax-/-Bak1-/-myeloid cells deprived of growth factor consume extracellular glucose to maintain long-term viability, without a requirement for Atg5-dependent autophagy.
Immunological tolerance, pregnancy and pre-eclampsia: the roles of semen microbes and the father1
Authors: Kenny Louise C. , Kell Douglas B.
Published: October 2017

Although it is widely recognised as involving two stages (poor placentation followed by oxidative stress/inflammation), the precise originating causes of pre-eclampsia (PE) remain elusive. We have previously brought together some of the considerable evidence that a (dormant) microbial component is commonly a significant part of its aetiology. However, apart from recognising, consistent with this view, that the many inflammatory markers of PE are also increased in infection, we had little to say about immunity, whether innate or adaptive. In addition, we focussed on the gut, oral and female urinary tract microbiomes as the main sources of the infection. We here marshall further evidence for an infectious component in PE, focussing on the immunological tolerance characteristic of pregnancy, and the well-established fact that increased exposure to the father’s semen assists this immunological tolerance. As well as these benefits, however, semen is not sterile, microbial tolerance mechanisms may exist, and we also review the evidence that semen may be responsible for inoculating the developing conceptus with microbes, not all of which are benign. It is suggested that when they are not, this may be a significant cause of preeclampsia. A variety of epidemiological and other evidence is entirely consistent with this, not least correlations between semen infection, infertility and PE. Our view also leads to a series of other, testable predictions. Overall, we argue for a significant paternal role in the development of PE through microbial infection of the mother via insemination.

“In one of the last articles which he wrote, the late Professor F J Browne (1958) expressed the opinion that all the essential facts about pregnancy toxaemia are now available and that all that is required to solve the problem is to fit them together in the right order, like the pieces of a jigsaw puzzle” [1]

“It appears astonishing how little attention has been given in reproductive medicine to the maternal immune system over the last few decades.” [2]
Epidemiology of the Zika virus outbreak in the Cabo Verde Islands, West Africa
Authors: Lourenço José , de Lourdes Monteiro Maria , Valdez Tomás , Rodrigues Júlio Monteiro , Pybus Oliver G. , Faria Nuno Rodrigues
Published: October 2017

Introduction

The Zika virus (ZIKV) outbreak in the island nation of Cabo Verde was of unprecedented magnitude in Africa and the first to be associated with microcephaly in the continent.

Methods

Using a simple mathematical framework we present a first epidemiological assessment of attack and observation rates from 7,580 ZIKV notified cases and 18 microcephaly reports between July 2015 and May 2016.

Results

In line with observations from the Americas and elsewhere, the single-wave Cabo Verdean ZIKV epidemic was characterized by a basic reproductive number of 1.85 (95% CI, 1.5 −2.2), with overall the attack rate of 51.1% (range 42.1 - 61.1) and observation rate of 2.7% (range 2.29 - 3.33).

Conclusion

Current herd-immunity may not be sufficient to prevent future small-to-medium epidemics in Cabo Verde. Together with a small observation rate, these results highlight the need for rapid and integrated epidemiological, molecular and genomic surveillance to tackle forthcoming outbreaks of ZIKV and other arboviruses.
Attending to what and where: Background connectivity integrates categorical and spatial attention
Authors: Tompary Alexa , Al-Aidroos Naseem , Turk-Browne Nicholas B.
Published: October 2017

Top-down attention prioritizes the processing of goal-relevant information throughout visual cortex, based on where that information is found in space and what it looks like. Whereas attentional goals often have both spatial and featural components, most research on the neural basis of attention has examined these components separately. This may reflect the fact that attention is typically studied in individual visual areas that preferentially code for either spatial locations or particular features. Here we investigated how these attentional components are integrated by examining the attentional modulation of functional connectivity between visual areas with different selectivity. Specifically, we used fMRI to measure temporal correlations between spatially-selective regions of early visual cortex and category-selective regions in ventral temporal cortex while participants performed a task that benefitted from both spatial and categorical attention. We found that categorical attention modulated the connectivity of category-selective areas, but only with retinotopic areas that coded for the spatially attended location. The reverse was not true, however, with spatial attention modulating the connectivity of retinotopic areas with category-selective areas coding for both attended and unattended features. This pattern of results suggests that attentional modulation of connectivity is dominated by spatial selection, which in turn gates featural biases. Combined with exploratory analyses of frontoparietal areas that track these changes in connectivity among visual areas, this study begins to shed light on how different components of attention are integrated in support of more complex behavioral goals.
Demonstration of the potential of environmental DNA as a tool for the detection of avian species
Authors: Ushio Masayuki , Murata Koichi , Sado Tetsuya , Nishiumi Isao , Takeshita Masamichi , Iwasaki Wataru , Miya Masaki
Published: October 2017

Birds play unique functional roles in the maintenance of ecosystems, such as pollina-tion and seed dispersal, and thus monitoring bird communities (e.g., monitoring bird species diversity) is a first step towards avoiding undesirable consequences of anthro-pogenic impacts on bird communities. In the present study, we hypothesized that birds, regardless of their main habitats, must have frequent contact with water and that tissues that contain their DNA that persists in the environment (environmental DNA; eDNA) could be used to detect the presence of avian species. To this end, we applied a set of universal PCR primers (MiBird, a modified version of fish/mammal universal primers) for metabarcoding avian eDNA. We confirmed the versatility of MiBird primers by performingin silicoanalyses and by amplifying DNAs extracted from bird tissues. Analyses of water samples from zoo cages of birds with known species composition suggested that the use of MiBird primers combined with the Il-lumina MiSeq platform could successfully detect avian species from water samples. Additionally, analysis of water samples collected from a natural pond detected five avian species common to the sampling areas. The present findings suggest that avian eDNA metabarcoding would be a complementary detection/identification tool in cases where visual detection and identification of bird species is difficult.
A low-level perceptual correlate of behavioral and clinical deficits in ADHD
Authors: Mihali Andra , Young Allison G , Adler Lenard A. , Halassa Michael M. , Ma Wei Ji
Published: October 2017

In many studies of attention-deficit hyperactivity disorder (ADHD), stimulus encoding and processing (per-ceptual function) and response selection (executive function) have been intertwined. To dissociate deficits in these functions, we introduced a task that parametrically varied low-level stimulus features (orientation and color) for fine-grained analysis of perceptual function. It also required participants to switch their attention between feature dimensions on a trial-by-trial basis, thus taxing executive processes. Furthermore, we used a response paradigm that captured task-irrelevant motor output (TIMO), reflecting failures to use the correct stimulus-response rule. ADHD participants had substantially higher perceptual variability than Controls, especially for orientation, as well as higher TIMO. In both ADHD and Controls, TIMO was strongly affected by the switch manipulation. Across participants, the perceptual variability parameter was correlated with TIMO, suggesting that perceptual deficits are associated with executive function deficits. Based on perceptual variability alone, we were able to classify participants into ADHD and Controls with a mean accuracy of about 77%. Participants’ self-reported General Executive Composite score correlated not only with TIMO but also with the perceptual variability parameter. Our results highlight the role of perceptual deficits in ADHD and the usefulness of computational modeling of behavior in dissociating perceptual from executive processes.
De novoassemblies of high-quality reference transcriptomes identifies Rosaceae-common andRosa-specific encoding genes
Authors: Li Shubin , Zhong Micai , Dong Xue , Jiang Xiaodong , Sun Yibo , Dezhu Li , Tang Kaixue , Hu Jin-Yong
Published: October 2017

Roses are important plants for human beings with important economical and biological traits like continuous flowering, flower architecture, color and scent, that current model plants do not feature, thus are becoming ideal models for studying these traits. Due to high heterozygosity of rose genomes likely caused by frequent inter-species hybridization, a high-quality and well-annotated genome forRosaplants is not available yet. Developing genetic and genomic tools with high quality has become necessary for further roses breeding and for disentangling the molecular genetic mechanisms underlying roses domestication. We here generated the high quality and comprehensive reference transcriptomes forRosa chinensis‘Old Blush’ (OB) andR. wichuriana‘Basyes’ Thornless’ (BT), two roses contrasting at several important traits. These reference transcriptomes showed transcripts N50 above 2000bp. The two species shared about 23310 transcripts (N50 = 2364bp), among which about 8975 orthologs were conserved within genera ofRosa.Rosaplants shared about 5049 transcripts (Rosaceae-common) with these fromMalus, Prunus, Rubus, andFragaria. Finally, a pool of 417 transcripts unique toRosaplants (Rosa-specific) was identified. These Rosaceae-common andRosa-specific transcripts should facilitate the phylogenetic analysis of Rosaceae plants and investigation ofRosa-specific traits. The data reported here should provide the fundamental genomic tools and knowledge critical for understanding the biology and domestication of roses.
Top-down expectation effects of food labels on motivation
Authors: Wegman Joost , Loon Ilke van , Smeets Paul A.M. , Cools Roshan , Aarts Esther
Published: October 2017

When we buy our food, the information on the package informs us about the properties of the product, such as its taste and healthiness. These beliefs can influence the processing of food rewards and impact decision making beyond objective sensory properties. However, no studies, within or beyond the food domain, have assessed how written information, such as food labels, affect implicit motivation to obtain rewards, even though choices in daily life might be strongly driven by implicit motivational biases. We investigated how written information affects implicit motivation to obtain food rewards. We used food labels (high- and low-calorie), associated with an identical lemonade, to study motivation for food rewards during fMRI. In a joystick task, hungry participants (N=31) were instructed to make fast approach or avoid movements to earn the cued drinks. Behaviorally, we found a general approach bias, which was stronger for the drink that was most preferred during a subsequent choice test, i.e. the one labeled as low-calorie. This behavioral effect was accompanied by increased BOLD signal in the sensorimotor cortex during the response phase of the task for the preferred, low-calorie drink compared with the non-preferred, high-calorie drink. During the anticipation phase, the non-preferred, high-calorie drink label elicited stronger fMRI signal in the right ventral anterior insula, a region associated with aversion and taste intensity, than the preferred, low-calorie label. Together, these data suggest that high-calorie labeling can increase avoidance of drinks and reduce neural activity in brain regions associated with motor control. In conclusion, we show effects of food labeling on fMRI responses during anticipation and subsequent motivated action and on behavior, in the absence of objective taste differences, demonstrating the influence of written information on implicit biases. These findings contribute to our understanding of implicit biases in real-life eating behavior.
Exploiting modal demultiplexing properties of tapered optical fibers for tailored optogenetic stimulation
Authors: Pisanello Marco , Pisano Filippo , Sileo Leonardo , Maglie Emanuela , Bellistri Elisa , Spagnolo Barbara , Mandelbaum Gil , Sabatini Bernardo L. , De Vittorio Massimo , Pisanello Ferruccio
Published: October 2017

Optogenetic control of neural activity in deep brain regions requires precise and flexible light delivery with non-invasive devices. To this end, Tapered Optical Fibers (TFs) represent a minimally-invasive tool that can deliver light over either large brain volumes or spatially confined subregions. This work links the emission properties of TFs with the modal content injected into the fiber, finding that the maximum transversal propagation constant (kt) and the total number of guided modes sustained by the waveguide are key parameters for engineering the mode demultiplexing properties of TFs. Intrinsic features of the optical fiber (numerical aperture and core/cladding diameter) define the optically active segment of the taper (up to ∼3mm), along which a linear relation between the propagating set of ktvalues and the emission position exists. These site-selective light-delivery properties are preserved at multiple wavelengths, further extending the range of applications expected for tapered fibers for optical control of neural activity.
Cross-task contributions of fronto-basal ganglia circuitry in response inhibition and conflict-induced slowing
Authors: Jahfari Sara , Ridderinkhof K Richard , Collins Anne GE , Knapen Tomas , Waldorp Lourens J , Frank Michael J
Published: October 2017

Why are we so slow in choosing the lesser of two evils? We considered whether such slowing relates to uncertainty about the value of these options, which arises from the tendency to avoid them during learning, and whether such slowing relates to fronto-subthalamic inhibitory control mechanisms. 49 participants performed a reinforcement-learning task and a stop-signal task while fMRI was recorded. A reinforcement-learning model was used to quantify learning strategies. Individual differences in lose-lose slowing related to information uncertainty due to sampling, and independently, to less efficient response inhibition in the stop-signal task. Neuroimaging analysis revealed an analogous dissociation: subthalamic nucleus (STN) BOLD activity related to variability in stopping latencies, whereas weaker fronto-subthalamic connectivity related to slowing and information sampling. Across tasks, fast inhibitors increased STN activity for successfully cancelled responses in the stop task, but decreased activity for lose-lose choices. These data support the notion that fronto-STN communication implements a rapid but transient brake on response execution, and that slowing due to decision uncertainty could result from an inefficient release of this “hold your horses” mechanism.
Pausing controls branching between productive and non-productive pathways during initial transcription
Authors: Dulin David , Bauer David L. V. , Malinen Anssi M. , Bakermans Jacob J. W. , Kaller Martin , Morichaud Zakia , Petushkov Ivan , Depken Martin , Brodolin Konstantin , Kulbachinskiy Andrey , Kapanidis Achillefs N.
Published: October 2017

Transcription in bacteria is controlled by multiple molecular mechanisms that precisely regulate gene expression. Recently, initial RNA synthesis by the bacterial RNA polymerase (RNAP) has been shown to be interrupted by pauses; however, the pausing determinants and the relationship of pausing with productive and abortive RNA synthesis remain poorly understood. Here, we employed single-molecule FRET and biochemical analysis to disentangle the pausing-related pathways of bacterial initial transcription. We present further evidence that region σ3.2constitutes a barrier after the initial transcribing complex synthesizes a 6-nt RNA (ITC6), halting transcription. We also show that the paused ITC6 state acts as a checkpoint that directs RNAP, in an NTP-dependent manner, to one of three competing pathways: productive transcription, abortive RNA release, or a new unscrunching/scrunching pathway that blocks transcription initiation. Our results show that abortive RNA release and DNA unscrunching are not as tightly coupled as previously thought.
VASC: dimension reduction and visualization of single cell RNA sequencing data by deep variational autoencoder
Authors: Wang Dongfang , Gu Jin
Published: October 2017

Single cell RNA sequencing (scRNA-seq) is a powerful technique to analyze the transcriptomic heterogeneities in single cell level. It is an important step for studying cell sub-populations and lineages based on scRNA-seq data by finding an effective low-dimensional representation and visualization of the original data. The scRNA-seq data are much noiser than traditional bulk RNA-Seq: in the single cell level, the transcriptional fluctuations are much larger than the average of a cell population and the low amount of RNA transcripts will increase the rate of technical dropout events. In this study, we proposed VASC (deep Variational Autoencoder for scRNA-seq data), a deep multi-layer generative model, for the unsupervised dimension reduction and visualization of scRNA-seq data. It can explicitly model the dropout events and find the nonlinear hierarchical feature representations of the original data. Tested on twenty datasets, VASC shows superior performances in most cases and broader dataset compatibility compared with four state-of-the-art dimension reduction methods. Then, for a case study of pre-implantation embryos, VASC successfully re-establishes the cell dynamics and identifies several candidate marker genes associated with the early embryo development.
The common origin of symmetry and structure in genetic sequences
Authors: Cristadoro G. , Degli Esposti M. , Altmann E.G.
Published: October 2017

When exploring statistical properties of genetic sequences two main features stand out: the existence of non-random structures at various scales (e.g., long-range correlations) and the presence of symmetries (e.g., Chargaff parity rules). In the last decades, numerous studies investigated the origin and significance of each of these features separately. Here we show that both symmetry and structure have to be considered as the outcome of the same biological processes, whose cumulative effect can be quantitatively measured on extant genomes. We present a novel analysis (based on a minimal model) that not only explains and reproduces previous observations but also predicts the existence of a nested hierarchy of symmetries emerging at different structural scales. Our genome-wide analysis of H. Sapiens confirms the theoretical predictions.
A novel zebrafish intestinal tumor model reveals a role forcyp7a1-dependent tumor-liver crosstalk in tumor's adverse effects on host
Authors: Enya Sora , Kawakami Koichi , Suzuki Yutaka , Kawaoka Shinpei
Published: October 2017

The nature of host organs and genes that underlie tumor-induced physiological disruption on host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is optimized for addressing this issue, and find that hepaticcyp7a1, the rate-limiting factor for synthesizing bile acids (BAs), is such a host gene. InducingkrasG12DbyGal4specifically expressed in the posterior intestine resulted in formation of an intestinal tumor classified as dysplasia. The local intestinal tumor caused systemic detrimental effects on host including liver inflammation, hepatomegaly, growth defects, and organismal death. Whole-organismal level gene expression analysis and metabolite measurements revealed that the intestinal tumor reduced total BAs levels via down-regulation of hepaticcyp7a1. Genetically rescuingcyp7a1expression in the liver restored the BAs synthesis and ameliorated tumor-induced liver inflammation, but not other tumor-dependent phenotypes. Thus, we found a previously unknown role ofcyp7a1as the host gene that links the intestinal tumor, hepatic cholesterol-BAs metabolism, and liver inflammation in tumor-bearing fish. Our model provides an important basis to discover host genes responsible for tumor-induced phenotypes and to uncover mechanisms underlying how tumors adversely affect host organisms.
Spatially segregated responses to visuo-tactile stimuli in mouse neocortex during active sensation
Authors: Couto J , Kandler S , Mao D , McNaughton BL , Arckens L , Bonin V
Published: October 2017

Multisensory integration is key for perception and animal survival yet how information from separate senses is integrated has been debated for decades. In the cortex, information from each sense is first processed in primary sensory areas and then combined in association areas. An alternative hypothesis to this hierarchical model is that primary sensory cortices partake in multisensory encoding. We probed tactile and visual responses in primary somatosensory and visual cortices in awake behaving animals using two-photon calcium imaging from layer 2/3 excitatory neurons. In support of an hierarchical model we found segregation of visual and tactile responses. Tactile stimuli evoked responses in S1 neurons. In striking contrast, V1 neurons failed to respond to tactile stimuli. This was true for passive whisker stimulation and for stimulation during active whisking. Furthermore, responses of V1 neurons to congruent visuo-tactile cues during active exploration, a condition where vision precedes touch, were completely abolished in darkness. The rostro-lateral area of the visual cortex responded to both visual and tactile aspects of the stimuli and may form a substrate for encoding multisensory signals during active exploration. Our results indicate that primary sensory areas mainly encode their primary sense and that the impact of other modalities may be restricted to modulatory effects.