bluuebunny/crossref_metadata_2025 huggingface dataset:
Suture Cruroplasty Versus Mesh Hiatal Herniorrhaphy for Large Hiatal Hernias (HHs): An Updated Meta-Analysis and Systematic Review of Randomized Controlled Trials
Authors: Memon Muhammed A. , Siddaiah-Subramanya Manjunath , Yunus Rossita M. , Memon Breda , Khan Shahjahan
Published: March 2019

Background:

To explore the clinical outcomes, safety and effectiveness of suture cruroplasty versus mesh repair for large hiatal hernias (HHs) by an updated meta-analysis.

Material and Methods:

Randomized controlled trials evaluating the effects of these 2 treatment modalities were searched from PubMed and other electronic databases between January 1991 and July 2018. The outcome variables analyzed included operating time, complications, recurrence of HH or wrap migration, reoperation, hospital stay and quality of life.

Results:

Five randomized controlled trials totaling 478 patients (suture=222, mesh=256) were analyzed. For reoperation variable, the odds ratio was significantly 3.26 times higher for the suture group. For recurrence of HH, the odds ratio for the suture group was nonsignificantly 1.65 times higher compared with the mesh group. Comparable effects were noted for all other variables.

Conclusions:

Mesh repair seems to be superior to suture cruroplasty for large HH repair. Therefore, the routine use of mesh may be advantageous in selected cases.
Complications After Endoscopic Stenting for Malignant Gastric Outlet Obstruction: A Cohort Study
Authors: Sterpetti Antonio V. , Fiori Enrico , Sapienza Paolo , Lamazza Antonietta
Published: March 2019

Background:

Gastric stenting has become a common place in clinical practice. The aim of our study was to evaluate the factors influencing the clinical outcome in patients who received endoscopic stenting for malignant gastric outlet obstruction (GOO).

Materials and Methods:

We prospectively evaluated the clinical course of 87 patients who presented to our attention with malignant GOO.

Results:

There was neither mortality nor major morbidity after endoscopic stenting. Survival was reduced (average, 2 mo) in patients with an obstruction due to no resectable pancreatic cancer. In patients with primary no resectable pyloric adenocarcinoma, the crude survival was >1 year. Almost half of the patients required a new endoscopy. Food obstruction was common after 6 months from stent placement, limiting the quality of life of the patients.

Conclusions:

Endoscopic stenting represents a valid treatment in patients with symptoms of GOO from metastatic cancer. Patients with metastatic pyloric adenocarcinoma and normal liver function tests have survival rates longer than 1 year. In this selected group of patients, laparoscopic surgical gastrojejunostomy can be a valid alternative to avoid a close and exhausting follow-up, with the possibility of a better quality of life (res Registry 808).
Pelvic Organ Prolapse Recurrence and Patient-Centered Outcomes Following Minimally Invasive Abdominal Uterosacral Ligament and Mesh-Augmented Sacrohysteropexy
Authors: Davidson Emily R.W. , Casas-Puig Viviana , Paraiso Marie Fidela R. , Ridgeway Beri , Ferrando Cecile A.
Published: March 2019

Objectives

The objective of this study was to compare outcomes after minimally invasive uterosacral ligament hysteropexy (USLH) and mesh-augmented sacrohysteropexy (MSH) for women with uterovaginal prolapse including prolapse recurrence and long-term patient satisfaction.

Methods

This was a retrospective cohort study with a cross-sectional survey component. The medical record was queried for perioperative data for patients undergoing USLH and MSH between 2004 and 2016. Pelvic organ prolapse (POP) recurrence was defined as bulge symptoms and/or retreatment with a pessary or surgery. A cross-sectional survey assessed for adverse events and used validated questionnaires to assess symptoms and improvement.

Results

Ninety-seven patients met the inclusion criteria: 42 MSH and 55 USLH. Mean age was 48 ± 14 years. Patients undergoing MSH were older, had more advanced POP, and were less likely to undergo concurrent procedures. There were no differences in perioperative complications between groups; 22.7% (n = 22) of patients experienced POP recurrence with 8.3% (n = 8) undergoing repeat surgery. After controlling for preoperative differences, there was no difference in POP recurrence between groups. The incidence of sacrohysteropexy mesh exposure was 7% (n = 3). Sixty-one percent (n = 59) of patients completed the survey; median follow-up time was 104 (46–164) months. Forty-one percent of respondents reported bothersome pelvic floor symptoms. Bulge symptoms were more common after MSH (41% vs 10%, P = 0.006). Ninety-three percent of all patients reported improvement after surgery, which was not different between groups.

Conclusions

One in 5 patients experienced POP recurrence with fewer than 10% undergoing repeat surgery for recurrence. There does not seem to be a significant difference in the incidence of recurrence between MSH and USLH.
Assessment of safety and bleeding risk in the use of extracorporeal membrane oxygenation for multitrauma patients: A multicenter review
Authors: Kruit Natalie , Prusak Michal , Miller Matthew , Barrett Nicholas , Richardson Carla , Vuylsteke Alain
Published: March 2019

BACKGROUND

Respiratory failure is the most common form of organ failure following traumatic injury. Previously, there have been concerns regarding extracorporeal membrane oxygenation (ECMO) use in the trauma setting because of the increased risk of bleeding and thrombotic complications. We sought to examine the management of trauma patients with ECMO and to assess the safety and outcome of its use.

METHODS

Data of all patients who experienced a traumatic injury and were supported with ECMO were collected from the five National Respiratory ECMO centers in the United Kingdom over the period from December 2011 to May 2017. Primary outcome variables included 30-day and 6-month mortality and exacerbation of underlying traumatic injury after ECMO commencement. Secondary outcome variables included duration of ECMO support, thrombotic complications, and worsening of intracranial injury.

RESULTS

Fifty-two patients were identified. The overall hospital mortality was 15%. The incidence of bleeding complications was 50%, the majority of these not requiring intervention. Forty patients underwent surgical management prior to ECMO commencement; only four patients required take-back to the operating theater. There was no significant difference between the bleeding and nonbleeding groups in time of injury to ECMO commencement (median difference, 4.5 days; 95% CI, −3 to 3 days; p = 0.75). There was no statistically significant difference between the bleeding and nonbleeding groups in regard to time to anticoagulation commencement after starting ECMO (median difference, − 1 hour; 95% CI, −48 to 2 hours; p = 0.29) or after trauma (median difference, − 1 day; 95% CI, −4 to 2 days; p = 0.41). Nineteen patients were diagnosed with significant neurological injury. Twelve of these patients were anticoagulated. Two patients died as a direct result of worsening neurological injury.

CONCLUSIONS

Our findings suggest that the use of ECMO in trauma patients does not exacerbate primary traumatic injury regardless of anticoagulation commencement and may confer a survival benefit. Neurological injury should not be seen as an absolute contraindication to ECMO.

LEVEL OF EVIDENCE

Therapeutic/Care Management, Level V.
Antibody-suppressor CD8+ T Cells Require CXCR5
Authors: Zimmerer Jason M. , Ringwald Bryce A. , Elzein Steven M. , Avila Christina L. , Warren Robert T. , Abdel-Rasoul Mahmoud , Bumgardner Ginny L.
Published: March 2019

Background.

We previously reported the novel activity of alloprimed CD8+ T cells that suppress posttransplant alloantibody production. The purpose of the study is to investigate the expression and role of CXCR5 on antibody-suppressor CD8+ T-cell function.

Methods.

C57BL/6 mice were transplanted with FVB/N hepatocytes. Alloprimed CD8+ T cells were retrieved on day 7 from hepatocyte transplant recipients. Unsorted or flow-sorted (CXCR5+CXCR3− and CXCR3+CXCR5−) alloprimed CD8+ T-cell subsets were analyzed for in vitro cytotoxicity and capacity to inhibit in vivo alloantibody production following adoptive transfer into C57BL/6 or high alloantibody-producing CD8 knock out (KO) hepatocyte transplant recipients. Alloantibody titer was assessed in CD8 KO mice reconstituted with naive CD8+ T cells retrieved from C57BL/6, CXCR5 KO, or CXCR3 KO mice. Antibody suppression by ovalbumin (OVA)-primed monoclonal OVA-specific t-cell receptor transgenic CD8+ T cells (OT-I) CXCR5+ or CXCR3+ CD8+ T-cell subsets was also investigated.

Results.

Alloprimed CXCR5+CXCR3−CD8+ T cells mediated in vitro cytotoxicity of alloprimed “self” B cells, while CXCR3+CXCR5−CD8+ T cells did not. Only flow-sorted alloprimed CXCR5+CXCR3−CD8+ T cells (not flow-sorted alloprimed CXCR3+CXCR5−CD8+ T cells) suppressed alloantibody production and enhanced graft survival when transferred into transplant recipients. Unlike CD8+ T cells from wild-type or CXCR3 KO mice, CD8+ T cells from CXCR5 KO mice do not develop alloantibody-suppressor function. Similarly, only flow-sorted CXCR5+CXCR3− (and not CXCR3+CXCR5−) OVA-primed OT-I CD8+ T cells mediated in vivo suppression of anti-OVA antibody production.

Conclusions.

These data support the conclusion that expression of CXCR5 by antigen-primed CD8+ T cells is critical for the function of antibody-suppressor CD8+ T cells.
APRIL/BLyS Blockade Reduces Donor-specific Antibodies in Allosensitized Mice
Authors: Wilson Nancy A. , Bath Natalie M. , Verhoven Bret M. , Ding Xiang , Boldt Brittney A. , Sukhwal Adarsh , Zhong Weixiong , Panzer Sarah E. , Redfield Robert R.
Published: March 2019

Background.

Highly sensitized candidates on the transplant waitlist remain a significant challenge, as current desensitization protocols have variable success rates of donor-specific antibody (DSA) reduction. Therefore, improved therapies are needed. A proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS) are critical survival factors for B-lymphocytes and plasma cells, which are the primary sources of alloantibody production. We examined the effect of APRIL/BLyS blockade on DSA in a murine kidney transplant model as a possible novel desensitization strategy.

Methods.

C57BL/6 mice were sensitized with intraperitoneal (IP) injections of 2 × 106 BALB/c splenocytes. Twenty-one days following sensitization, animals were treated with 100 μg of BLyS blockade (B-cell activating factor receptor-immunoglobulin) or APRIL/BLyS blockade (transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin), administered thrice weekly for an additional 21 days. Animals were then euthanized or randomized to kidney transplant with Control Ig, BLyS blockade, or APRIL/BLyS blockade. Animals were euthanized 7 days posttransplant. B-lymphocytes and DSA of BLyS blockade only or APRIL/BLyS blockade-treated mice were assessed by flow cytometry, immunohistochemistry, and enzyme-linked immunospot.

Results.

APRIL/BLyS inhibition resulted in a significant reduction of DSA by flow crossmatch compared with controls (P < 0.01). APRIL/BLyS blockade also significantly depleted IgM- and IgG-secreting cells and B-lymphocyte populations compared to controls (P < 0.0001). APRIL/BLyS blockade in transplanted mice also resulted in decreased B-lymphocyte populations; however, no difference in rejection rates were seen between groups.

Conclusions.

APRIL/BLyS blockade with transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin significantly depleted B-lymphocytes and reduced DSA in this sensitized murine model. APRIL/BLyS inhibition may be a clinically useful desensitization strategy for sensitized transplant candidates.
Enhancing rate of water absorption in seeds via a miniature surface acoustic wave device
Authors: Wong Kiing S. , Lee Lillian , Yeo Leslie Y. , Tan Ming K.
Published: March 2019

Seeds, which are high in protein and essential nutrients, must go through a hydration process before consumption. The ability to rapidly increase water absorption can significantly reduce the soaking time as well as the amount of energy needed for cooking seeds. Many studies in the literature employ high-power (10
2
W) low-frequency (10
4
Hz) ultrasound; although their results are very promising where more than 100% increase in water content can be obtained between the treated and untreated seeds, the high-power and low-frequency ultrasound often causes acoustic cavitation under high intensity, which can severely disrupt the cell walls and damage the seeds. In our study, however, we demonstrate that treating the seeds via a miniature surface acoustic wave device, which operates at low-power (10
0
W) and high-frequency (10
7
Hz) range, gives rise to a higher water absorption rate without the acoustic cavitations. By comparing the water content between the treated and untreated seeds, an increase of up to 2600% (for chickpeas) and 6350% (for mung bean) can be obtained after 60 min. A significantly higher water absorption in mung beans can be attributed to the larger pore size when compared with the acoustic wavelength in water, enabling an efficient transmission of acoustic wave inside the pores. Our results also indicate that the germination time can be reduced by half for treated seeds as compared to the untreated seeds.
Testing the unitary theory of language lateralization using functional transcranial Doppler sonography in adults
Authors: Woodhead Z. V. J. , Bradshaw A. R. , Wilson A. C. , Thompson P. A. , Bishop D. V. M.
Published: March 2019

Hemispheric dominance for language can vary from task to task, but it is unclear if this reflects error of measurement or independent lateralization of different language systems. We used functional transcranial Doppler sonography to assess language lateralization within the middle cerebral artery territory in 37 adults (seven left-handers) on six tasks, each given on two occasions. Tasks taxed different aspects of language function. A pre-registered structural equation analysis was used to compare models of means and covariances. For most people, a single lateralized factor explained most of the covariance between tasks. A minority, however, showed dissociation of asymmetry, giving a second factor. This was mostly derived from a receptive task, which was highly reliable but not lateralized. The results suggest that variation in the strength of language lateralization reflects true individual differences and not just error of measurement. The inclusion of several tasks in a laterality battery makes it easier to detect cases of atypical asymmetry.
Dispersive dynamics in the characteristic moving frame
Authors: Ratliff D. J.
Published: March 2019

A mechanism for dispersion to automatically arise from the dispersionless Whitham Modulation equations (WMEs) is presented, relying on the use of a moving frame. The speed of this is chosen to be one of the characteristics which emerge from the linearization of the Whitham system, and assuming these are real (and thus the WMEs are hyperbolic) morphs the WMEs into the Korteweg-de Vries (KdV) equation in the boosted coordinate. Strikingly, the coefficients of the KdV equation are universal, in the sense that they are determined by abstract properties of the original Lagrangian density. Two illustrative examples of the theory are given to illustrate how the KdV may be constructed in practice. The first being a revisitation of the derivation of the KdV equation from shallow water flows, to highlight how the theory of this paper fits into the existing literature. The second is a complex Klein–Gordon system, providing a case where the KdV equation may only arise with the use of a moving frame.
Thermodynamics of heating
Authors: Bejan Adrian
Published: March 2019

Heat transfer is a mature science, and so is thermodynamics. They are almost 200 years old having developed largely independently until the 1980s. Maturity comes from the usefulness and success of the thermal sciences. This review uses the thermodynamics of heat transfer to focus on aspects that are usually not discussed in physics: performance, purpose, function, objective and direction of evolutionary design. The article illustrates the unity of the thermal sciences discipline (heat transfer +thermodynamics + constructal law), and uses the opportunity to correct a few recent interpretations of the thermodynamics of heat transfer regarding dissipative engines and energy storage.
Bed particle saltation in turbulent wall-shear flow: a review
Authors: Zeeshan Ali Sk , Dey Subhasish
Published: March 2019

Bed particle saltation in turbulent wall-shear flow remains an intriguing phenomenon in applied hydro-dynamics. In this review, we report the current state of the art of bed particle saltation in turbulent wall-shear flow, highlighting the physical characteristics of bed particle saltation and its mathematical modelling. A critical appraisal of the mechanics of bed particle saltation is presented thorough ample experimental evidence. The salient features of bed particle saltation, encompassing the saltation height, saltation length, particle velocity, saltation duration, particle collision with the bed, particle rotation, particle resting time and particle re-entrainment, are thoroughly discussed. Both the deterministic and computational fluid dynamics approaches in modelling bed particle saltation are summarized, and the subtle role of the hydrodynamic forces is elaborated. The estimation of bedload flux in a fluvial environment, emanating from the mathematical modelling of bed particle saltation, is delineated using different modelling approaches. Finally, the challenges in modelling bed particle saltation are highlighted, and a new look at bed particle saltation is furnished.
Climate is a strong predictor of near-infrared reflectance but a poor predictor of colour in butterflies
Authors: Munro Joshua T. , Medina Iliana , Walker Ken , Moussalli Adnan , Kearney Michael R. , Dyer Adrian G. , Garcia Jair , Rankin Katrina J. , Stuart-Fox Devi
Published: March 2019

Colour variation across climatic gradients is a common ecogeographical pattern; yet there is long-standing contention over underlying causes, particularly selection for thermal benefits. We tested the evolutionary association between climate gradients and reflectance of near-infrared (NIR) wavelengths, which influence heat gain but are not visible to animals. We measured ultraviolet (UVA), visible (Vis) and NIR reflectance from calibrated images of 372 butterfly specimens from 60 populations (49 species, five families) spanning the Australian continent. Consistent with selection for thermal benefits, the association between climate and reflectance was stronger for NIR than UVA–Vis wavelengths. Furthermore, climate predicted reflectance of the thorax and basal wing, which are critical to thermoregulation; but it did not predict reflectance of the entire wing, which has a variable role in thermoregulation depending on basking behaviour. These results provide evidence that selection for thermal benefits has shaped the reflectance properties of butterflies.
Tactile sensory channels over-ruled by frequency decoding system that utilizes spike pattern regardless of receptor type
Authors: Birznieks Ingvars , McIntyre Sarah , Nilsson Hanna M , Nagi Saad S , Macefield Vaughan G , Mahns David A , Vickery Richard M
Published: March 2019

The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies < 60 Hz) and vibratory hum (frequencies > 60 Hz), subserved by two distinct receptor types (Meissner’s and Pacinian corpuscle, respectively) which may engage different neural processing pathways or channels and fulfill quite different biological roles. In psychological and physiological literature those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types.
Determining the Minimal Background Area for Species Distribution Models: MinBar PACKAGE
Authors: Rotllan-Puig Xavier , Traveset Anna
Published: March 2019

One of the crucial choices when modelling species distributions using pseudo-absences approaches is the delineation of the background area to fit the model. We hypothesise that there is a minimum background area around the centre of the species distribution that characterizes well enough the range of environmental conditions needed by the species to survive. Thus, fitting the model within this area should be the optimal solution in terms of both quality of the model and execution time.

MinBAR is an R package that calculates the optimal background area. The version 1.0.0 is implemented for MaxEnt and uses Boyce Index as a metric to assess models performance.

Two case studies are presented to assess the hypothesis and to illustrate the package.

Partial models trained with part of the species distribution often perform better than those fitted on the entire extension. MinBAR is a versatile tool that helps modellers to objectively define the optimal solution.
Automated and Manual Quantification of Tumour Cellularity in Digital Slides for Tumour Burden Assessment
Authors: Akbar Shazia , Peikari Mohammad , Salama Sherine , Panah Azadeh Y. , Nofech-Mozes Sharon , Martel Anne L.
Published: March 2019

Aims

The residual cancer burden index is an important quantitative measure used for assessing treatment response following neoadjuvant therapy for breast cancer. It has shown to be predictive of overall survival and is composed of two key metrics: qualitative assessment of lymph nodes and the percentage of invasive or in-situ tumour cellularity (TC) in the tumour bed (TB). Currently, TC is assessed through eye-balling of routine histopathology slides estimating the proportion of tumour cells within the TB. With the advances in production of digitized slides and increasing availability of slide scanners in pathology laboratories, there is potential to measure TC using automated algorithms with greater precision and accuracy.

Methods

We describe two methods for automated TC scoring: 1) a traditional approach to image analysis development whereby we mimic the pathologists’ workflow, and 2) a recent development in artificial intelligence in which features are learned automatically in deep neural networks using image data alone.

Results

We show strong agreements between automated and manual analysis of digital slides. Agreements between our trained deep neural networks and experts in this study (0.82) approach the inter-rater agreements between pathologists (0.89). We also reveal properties that are captured when we apply deep neural network to whole slide images, and discuss the potential of using such visualisations to improve upon TC assessment in the future.

Conclusions

TC scoring can be successfully automated by leveraging recent advancements in artificial intelligence, thereby alleviating the burden of manual analysis.
Time-course of population activity along the dorsoventral extent of the superior colliculus during delayed saccade tasks
Authors: Massot Corentin , Jagadisan Uday K. , Gandhi Neeraj J.
Published: March 2019

The superior colliculus (SC) is an excellent substrate to study functional organization of sensorimotor transformations. We used linear multi-contact array recordings to analyze the spatial and temporal properties of population activity along the SC dorsoventral axis during delayed saccade tasks. During the visual epoch, information appeared first in dorsal layers and systematically later in ventral layers. In the ensuing delay period, the laminar organization of low-spiking rate activity matched that of the visual epoch. During the pre-saccadic epoch, spiking activity emerged first in a more ventral layer, ∼100ms before saccade onset. This buildup of activity appeared later on nearby neurons situated both dorsally and ventrally, culminating in a synchronous burst across the dorsoventral axis, ∼28ms before saccade onset. Stimulation of individual contacts on the laminar probe produced saccades of similar vectors. Collectively, the results reveal a principled spatiotemporal organization of SC population activity underlying sensorimotor transformation for the control of gaze.
Event segmentation reveals working memory forgetting rate
Authors: Jafarpour Anna , Buffalo Elizabeth A , Knight Robert T , Collins Anne GE
Published: March 2019

We encounter the world as a continuous flow and effortlessly segment sequences of events into episodes. This process of event segmentation engages working memory (WM) for tracking the flow of events and impacts subsequent memory accuracy. WM is limited in how much information is retained (i.e., WM capacity) and for how long the information is retained (i.e., forgetting rate). It is unclear which aspect of WM limitations affects event segmentation. In two separate experiments with multiple tasks, we estimated participants’ WM capacity and forgetting rate in a dynamic context and evaluated their relationship to event segmentation. The results across tasks show that individuals who reported more movie segments than others (fine-segmenters) have a faster decaying WM. A separate task assessing long-term memory retrieval reveals that the coarse-segmenters have better recognition of temporal order of events in contrast to the fine-segmenters who performed better at free recall. The findings show that event segmentation employs dissociable memory strategies and depends on how long information is retained in WM.
Recent and rapid colonization of the Lesser Sundas Archipelago from adjacent Sundaland by seven amphibian and reptile species
Authors: Reilly Sean B. , Stubbs Alexander L. , Karin Benjamin R. , Arida Evy , Iskandar Djoko T. , Mcguire Jimmy A.
Published: March 2019

The Lesser Sundas Archipelago is comprised of two parallel chains of islands that extend between the Asian continental shelf (Sundaland) and Australo-Papuan continental shelf (Sahul). These islands have served as stepping-stones for taxa dispersing between the Asian and Australo-Papuan biogeographic realms. While the oceanic barriers have prevented many species from colonizing the archipelago, a number of terrestrial vertebrate species have colonized the islands either by rafting/swimming or human introduction. Here we examine phylogeographic structure within the Lesser Sundas for three snake, two lizard, and two frog species that each have a Sunda Shelf origin. These species are suspected to have recently colonized the archipelago, though all have inhabited the Lesser Sundas for over 100 years. We sequenced mtDNA from 230 samples to test whether there is sufficiently deep genetic structure within any of these taxa to reject human-mediated introduction. Additionally, we tested for genetic signatures of population expansion consistent with recent introduction, and estimated the ages of Lesser Sundas clades, if any exist. Our results show little to no genetic structure between populations on different islands in five species, and moderate structure in two species. Nucleotide diversity is low for all species, and the ages of the most recent common ancestor for species with monophyletic Lesser Sundas lineages date to the Holocene or late Pleistocene. These results support the hypothesis that these species entered the archipelago relatively recently and either naturally colonized or were introduced by humans to most of the islands within the archipelago within a short time span.
Intercellular positive-feedback loops promote the evolutionary stability of microbial cooperative behaviors
Authors: Ben-Zion Ishay , Eldar Avigdor
Published: March 2019

Microbial cooperation enables groups of conspecific cells to perform tasks that cannot be performed efficiently by individual cells, such as utilization of various secreted ‘public-good’ molecules, communication via quorum-sensing, or the formation of multicellular structures. Cooperation is often costly and therefore susceptible to exploitation by ‘cheater’ cells, which enjoy the benefit of cooperation without investing in it. While population structure is key to the maintenance of cooperation, it remains unclear whether other mechanisms help in stabilizing microbial cooperation. Like other microbial traits, cooperation is often governed by complex regulatory networks, and one reoccurring motif is an ‘intercellular positive-feedback loop’, where a secreted molecule, e.g. a public-good or a quorum-sensing signaling molecule, activates its own production in all surrounding cells. Here we investigate the role of intercellular feedbacks in the maintenance of bacterial cooperation. We combine theory with a synthetic-biology approach, using swarming motility ofBacillus subtilisengineered variants, to compare the response of ‘open-loop’ and feedback cooperators to the presence of cheaters. We find that positive feedbacks on cooperative behaviors – either directly or through a feedback on quorum-sensing – maintain cooperation in a broader range of environments, relieving the requirement for a strong population structure. Our results directly demonstrate the stabilizing effect of intercellular positive feedbacks on cooperative behaviors, and suggests an explanation for their abundance in regulatory networks of bacterial cooperation.
Active Efficient Coding Explains the Development of Binocular Vision and its Failure in Amblyopia
Authors: Eckmann Samuel , Klimmasch Lukas , Shi Bertram E. , Triesch Jochen
Published: March 2019

The development of vision during the first months of life is an active process that comprises the learning of appropriate neural representations and the learning of accurate eye movements. While it has long been suspected that the two learning processes are coupled, there is still no widely accepted theoretical framework describing this joint development. Here we propose a computational model of the development of active binocular vision to fill this gap. The model is based on a new formulation of the Active Efficient Coding theory, which proposes that eye movements, as well as stimulus encoding, are jointly adapted to maximize the overall coding efficiency. Under healthy conditions, the model self-calibrates to perform accurate vergence and accommodation eye movements. It exploits disparity cues to deduce the direction of defocus, which leads to co-ordinated vergence and accommodation responses. In a simulated anisometropic case, where the refraction power of the two eyes differs, an amblyopia-like state develops, in which the foveal region of one eye is suppressed due to inputs from the other eye. After correcting for refractive errors, the model can only reach healthy performance levels if receptive fields are still plastic, in line with findings on a critical period for binocular vision development. Overall, our model offers a unifying conceptual framework for understanding the development of binocular vision.

Significance Statement

Brains must operate in an energy-efficient manner. The efficient coding hypothesis states that sensory systems achieve this by adapting neural representations to the statistics of sensory input signals. Importantly, however, these statistics are shaped by the organism’s behavior and how it samples information from the environment. Therefore, optimal performance requires jointly optimizing neural representations and behavior, a theory called Active Efficient Coding. Here we test the plausibility of this theory by proposing a computational model of the development of binocular vision. The model explains the development of accurate binocular vision under healthy conditions. In the case of refractive errors, however, the model develops an amblyopia-like state and suggests conditions for successful treatment.
Using deep learning algorithm to surmount drawbacks of statistical method in the procession of identify related genes with cancer
Authors: Zou Bohao
Published: March 2019

Finding key genes which are relative with cancer is the first essential step to understand what has taken place in the tumor cell. At present, the most methods which can discover key genes make a contrast between normal samples and tumor samples and base on the statistical test. However, those methods face on some problems like the insufficient of statistical test in unbalanced samples, defect of only using single data that can not display the holistic situation in tumor cell. For solving those issues, i proposed a innovation method that uses semi-supervised and unsupervised algorithm to discover key genes which are linked with cancer. The genes in the final result list are not only in the double category but with distinct hierarchy and those genes are all detected from diversity data like methylation, gene expression RNA-Seq, exon expression RNA-Seq and so on. At last, for comparing the result of this method and traditional statistical method, i used the conception of information gain ratio to prove the advantage of this deep learning method in mathematical.
Oncogenic signaling alters cell shape and mechanics to facilitate cell division under confinement
Authors: Matthews Helen K. , Ganguli Sushila , Plak Katarzyna , Taubenberger Anna V. , Piel Matthieu , Guck Jochen , Baum Buzz
Published: March 2019

When cells enter mitosis, they become spherical and mechanically stiffen. We used MCF10A cell lines as a model system in which to investigate the effect of induced oncogene expression on mitotic entry. We find that activation of oncogenic RasV12, for as little as five hours, changes the way cells divide. RasV12-dependent activation of the MEK-ERK signalling cascade alters acto-myosin contractility to enhance mitotic rounding. RasV12also affects cell mechanics, so that RasV12expressing cells are softer in interphase but stiffen more upon entry into mitosis. As a consequence, RasV12expression augments the ability of cells to round up and divide faithfully when confined underneath a stiff hydrogel. Conversely, inhibition of the Ras-ERK pathway reduces mitotic rounding under confinement, resulting in chromosome segregation defects. These data suggest a novel mechanism by which oncogenic Ras-ERK signalling can aid division in stiff environments like those found in tumours.
CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake
Authors: McEwan Andrew R. , Davidson Connor , Hay Elizabeth , Turnbull Yvonne , Erickson Johanna Celene , Marini Pietro , Wilson Dana , McIntosh Andrew M. , Adams Mark J. , Murgatroyd Chris , Barrett Perry , Delibegovic Mirela , Clarke Toni-Kim , MacKenzie Alasdair
Published: March 2019

Excessive alcohol intake is associated with 5.9% of global deaths. However, this figure is especially acute in men such that 7.6% of deaths can be attributed to alcohol intake. Previous studies identified a significant interaction between genotypes of the galanin (GAL) gene with anxiety and alcohol abuse in different male populations but were unable to define a mechanism. To address these issues the current study analysed the human UK Biobank cohort and identified a significant interaction (n=115,865; p=0.0007) between allelic variation (GG or CA genotypes) in the highly conserved human GAL5.1 enhancer, alcohol intake (AUDIT questionnaire scores) and anxiety in men that was consistent with these previous studies. Critically, disruption of GAL5.1 in mice using CRISPR genome editing significantly reduced GAL expression in the amygdala and hypothalamus whilst producing a corresponding reduction in ethanol intake in KO mice. Intriguingly, we also found evidence of reduced anxiety-like behaviour in male GAL5.1KO animals mirroring that seen in humans. Using bioinformatic analysis and co-transfection studies we further identified the EGR1 transcription factor, that is co expressed with GAL in amygdala and hypothalamus, as being important in the protein kinase C (PKC) supported activity of the GG genotype of GAL5.1 but less so in the CA genotype. Our unique study uses a novel combination of human association analysis, CRISPR genome editing in mice, animal behavioural analysis and cell culture studies to identify a highly conserved regulatory mechanism linking anxiety and alcohol intake that might contribute to increased susceptibility to anxiety and alcohol abuse in men.
3D spatially-resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression
Authors: Segovia-Miranda Fabián , Morales-Navarrete Hernán , Kücken Michael , Moser Vincent , Seifert Sarah , Repnik Urska , Rost Fabian , Hendriks Alexander , Hinz Sebastian , Röcken Christoph , Lüthjohann Dieter , Kalaidzidis Yannis , Schafmayer Clemens , Brusch Lutz , Hampe Jochen , Zerial Marino
Published: March 2019

Early disease diagnosis is key for the effective treatment of diseases. It relies on the identification of biomarkers and morphological inspection of organs and tissues. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D structural changes that are consequence of functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially-resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of new morphometric cellular parameters correlated with disease progression. Moreover, we found profound topological defects in the 3D bile canaliculi (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and zonated cholestasis, consistent with elevated cholestatic biomarkers in patients’ sera. Our spatially-resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multi-parametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.
A General Statistic to Test an Optimally Weighted Combination of Common and/or Rare Variants
Authors: Zhang Jianjun , Wu Baolin , Sha Qiuying , Zhang Shuanglin , Wang Xuexia
Published: March 2019

Both genome-wide association study and next generation sequencing data analyses are widely employed in order to identify disease susceptible common and/or rare genetic variants in many large scale genetic studies. Rare variants generally have large effects though they are hard to detect due to their low frequency. Currently, many existing statistical methods for rare variants association studies employ a weighted combination scheme, which usually puts subjective weights or suboptimal weights based on some ad hoc assumptions (e.g. ignoring dependence between rare variants). In this study, we analytically derive optimal weights for both common and rare variants and propose a General and novel approach to Test association between an Optimally Weighted combination of variants (G-TOW) in a gene or pathway for a continuous or dichotomous trait while easily adjusting for covariates. We conduct extensive simulation studies to evaluate the performance of G-TOW. Results of the simulation studies show that G-TOW has properly controlled type I error rates and it is the most powerful test among the methods we compared, when testing effects of either both rare and common variants or rare variants only. We also illustrate the effectiveness of G-TOW using the Genetic Analysis Workshop 17 (GAW17) data. In addition, we applied G-TOW and other competitive methods to test association for schizophrenia. The G-TOW have successfully verified genes FYN and VPS39 which are associated with schizophrenia reported in existing publications. Both of these genes are missed by the weighted sum statistic (WSS) and the sequence kernel association test (SKAT). G-TOW also showed much stronger significance (p-value=0.0037) than our previously developed method named Testing the effect of an Optimally Weighted combination of variants (TOW) (p-value=0.0143) on gene FYN. FYN is a member of the protein-tyrosine kinase oncogene family that phosphorylates glutamate metabotropic receptors and ionotropic N-methyl-d-aspartate (NMDA) receptors. NMDA modulates trafficking, subcellular distribution and function. It is involved in neuronal apoptosis, brain development and synaptic transmission and lower expression, which has been observed in the platelets of schizophrenic patients compared with controls. The application for schizophrenia indicates that G-TOW is a powerful tool in genome-wide association studies.
Bid as a novel interacting partner of IRE1 differentially regulating its RNAse activity
Authors: Bashir Samirul , Pal Debnath , Banday Mariam , Qadri Ozaira , Bashir Arif , Hazari Younis Mohammad , Hilal Nazia , Altaf Mohammad , Fazili Khalid Majid
Published: March 2019

Unfolded protein response is a dynamic signalling pathway, which is involved in the maintenance of proteostasis and cellular homeostasis. IRE1, a transmembrane signalling protein represents the start point of a highly conserved UPR signalling cascade. IRE1 is endowed with kinase and endoribonuclease activities. The activation of the kinase domain of IRE1 by trans-autophosphorylation leads to the activation of its RNAse domain. RNAse domain performs atypical splicing of Xbp1 mRNA and degradation of mRNAs by an effector function known as Regulated IRE1 Dependent Decay (RIDD). The regulation of the distinctive nature of the IRE1 ribonuclease function is potentially mediated by a dynamic protein structure UPRosome that is an assembly of a huge number of proteins on IRE1. Here, we reported that Bid is a novel recruit to UPRosome, which directly interacts with the cytoplasmic domain of IRE1. Bid controls the auto-phosphorylation of IRE1 in a negative manner where Bid overexpression conditions displayed reduced phosphorylation levels of IRE1 and Bid knockdown cells showed slightly enhanced IRE1 phosphorylation. This effect was reciprocated with JNK, a downstream target of IRE1. Our Insilico analysis revealed that Bid binding to IRE1 dimer averts its structural flexibility and thereby preventing its trans-autophosphorylation activity. We found that the effect of Bid is specific to the IRE1 branch of UPR signalling and competitive in nature. The highlighting observation of the study was that Bid stimulated a differential activity of the IRE1 RNAse domain towards Xbp1 splicing and RIDD. These results together establish that Bid is a part of the UPRosome and modulates IRE1 in a way to differentially regulate its RNAse outputs.
Aberrant Visual Population Receptive Fields in Human Albinism
Authors: Duwell Ethan J. , Woertz Erica N. , Mathis Jedidiah , Carroll Joseph , DeYoe Edgar A.
Published: March 2019

Retinotopic organization is a fundamental feature of visual cortex thought to play a vital role in encoding spatial information. One important aspect of normal retinotopy is the representation of the right and left hemifields in contralateral visual cortex. However, in human albinism, many temporal retinal afferents decussate pathologically at the optic chiasm resulting in partially superimposed representations of opposite hemifields in each hemisphere of visual cortex. Previous fMRI studies in human albinism suggest that the right and left hemifield representations are superimposed in a mirror-symmetric manner. This should produce imaging voxels which respond to two separate regions in visual space mirrored across the vertical meridian. However, it is not yet clear how retino-cortical miswiring in albinism manifests at the level of single voxel population receptive fields. Here we used fMRI retinotopic mapping in conjunction with population receptive field (pRF) modeling to fit both single and dual pRF models to the visual responses of voxels in visual areas V1-V3 of five subjects with albinism. We found that subjects with albinism (but not controls) have sizable clusters of voxels with dual pRFs consistently corresponding to, but not fully coextensive with regions of hemifield overlap. These dual pRFs were typically positioned at roughly mirror image locations across the vertical meridian but were uniquely clustered within the visual field for each subject. We also found that single pRFs are larger in albinism than controls, and that single pRF sizes in the central visual field were anti-correlated with subjects’ foveal cone densities. Finally, dual pRF and aberrant hemifield representation characteristics varied significantly across subjects with albinism suggesting more central heterogeneity than previously appreciated.
Revealing new therapeutic opportunities through drug target prediction via class imbalance-tolerant machine learning
Authors: Liang Siqi , Yu Haiyuan
Published: March 2019

In silicodrug target prediction provides valuable information for drug repurposing, understanding of side effects as well as expansion of the druggable genome. In particular, discovery of actionable drug targets is critical to developing targeted therapies for diseases. Here, we develop a robust method for drug target prediction by leveraging a class imbalance-tolerant machine learning framework with a novel training scheme. We incorporate novel features, including drug-gene phenotype similarity and gene expression profile similarity, that capture information orthogonal to other features. We show that our classifier achieves robust performance and is able to predict gene targets for new drugs as well as drugs that target unexplored genes. By providing newly predicted drug-target associations, we uncover novel opportunities of drug repurposing that may benefit cancer treatment through action on either known drug targets or currently undrugged genes.
ExpansionHunter: A sequence-graph based tool to analyze variation in short tandem repeat regions
Authors: Dolzhenko Egor , Deshpande Viraj , Schlesinger Felix , Krusche Peter , Petrovski Roman , Chen Sai , Emig-Agius Dorothea , Gross Andrew , Narzisi Giuseppe , Bowman Brett , Scheffler Konrad , van Vugt Joke J.F.A. , French Courtney , Sanchis-Juan Alba , Ibáñez Kristina , Tucci Arianna , Lajoie Bryan , Veldink Jan H. , Raymond Lucy , Taft Ryan J. , Bentley David R. , Eberle Michael A.
Published: March 2019

We describe a novel computational method for genotyping repeats using sequence graphs. This method addresses the long-standing need to accurately genotype medically important loci containing repeats adjacent to other variants or imperfect DNA repeats such as polyalanine repeats. Here we introduce a new version of our repeat genotyping software, ExpansionHunter, that uses this method to perform targeted genotyping of a broad class of such loci.

Availability and implementation

ExpansionHunter is implemented in C++ and is available under the Apache License Version 2.0. The source code, documentation, and Linux/macOS binaries are available at https://github.com/Illumina/ExpansionHunter/.

Contact

meberle@illumina.com