bluuebunny/crossref_metadata_2025 huggingface dataset:
Welfare Checks for Suicide Risk Management: Risks and Benefits
Authors: WORTZEL HAL S. , BARNES SEAN M. , CANNIZZARO KAILY A. , VILLARREAL EDGAR J. , ALLEN MICHAEL H. , MATARAZZO BRIDGET B.
Published: November 2019

In clinical practice, welfare checks have become a fairly common aspect of suicide prevention. At the same time, there is almost no guidance in the medical literature to inform clinicians under what circumstances welfare checks should be requested, how best to go about placing those requests, or how to document decision-making around this important subject. Literature searches spanning both PubMed and Google Scholar fail to yield any applicable results. Performed correctly, welfare checks have the potential to be life-saving interventions for persons in suicidal crises. Performed incorrectly, the welfare check may become an overly defensive practice that damages therapeutic relationships, violates patients’ rights, and consumes important and limited community resources. The need for thoughtful guidance to assist clinicians in navigating these difficult clinical scenarios is long overdue. This article, the first in a 2-part series, will describe welfare checks and explore their potential risks and benefits.
Metastatic Prostate Adenocarcinoma of the Mandible Diagnosed With Oral Manifestations
Authors: Ayranci Ferhat , Omezli Mehmet Melih , Torul Damla , Ay Mustafa
Published: November 2019

Metastasis from the prostate gland to the mandible is rarely encountered and commonly present with non-specific features like unexplained pain, swelling, and numb chin syndrome. Here we present a case with metastatic prostate adenocarcinoma detected secondary to oral manifestations. Patients present with unexplained facial pain and numbness should alert clinicians to the presence of malignant disease, and appropriate hematological, radiological and or histological investigations should be performed. Thereby, clinicians can prevent the overlook of the first signs of metastasis, accelerate the early diagnosis and positively orientate the prognosis of the disease, especially in a patient without known malignancy.
Analysis of the Pterygomaxillary Fissure for Surgical Approach to Sphenopalatine Ganglion by Radiological Examination of Cone Beam Computed Tomography
Authors: Lentzen Max-Philipp , Safi Ali-Farid , Riekert Maximilian , Visser-Vandewalle Veerle , Grandoch Andrea , Zirk Matthias , Zöller Joachim E. , Kreppel Matthias
Published: November 2019

The pterygopalatine fossa (PPF) is a complex and paired anatomical structure located at the skull base. A clinically and surgically relevant structure located in the pterygopalatine fossa is the sphenopalatine ganglion. Electrical stimulation of the sphenopalatine ganglion is one possible method of treating cluster headache. The pterygomaxillary fissure (PMF) defines the pterygopalatine fossa laterally and determines the surgical approach. As part of preoperative surgical planning, each patient undergoes a preoperative head computed tomography or a cone beam computed tomography. In our study cone beam computed tomography images of 90 male and 110 female PMF were analyzed. Generally, males have a wider fissure than females. Moreover, a significant inter-subject difference could be shown between males and females. The analysis of the right and left PMF according to gender and age does not show any significant intra-subject differences. Following an established protocol for high-resolution CT images the measurements were classified into four fissure types and also analyzed according to gender and age. Fissure type I is significantly more often present in males, whereas the smaller fissure types (II, III, and IV) are significantly more often found in females. Older patients presented statistically significant more often with type I, whereas the younger patients showed more often the narrower types II and IV. Due to the fact that narrow fissures smaller than 2 mm could limit the insertion of neurostimulator implants in the PPF, special attention should be paid to females and younger patients during preoperative planning.
Navigation-Assisted Treatment of Giant Cysts in the Pterygopalatine Fossa With Endoscopy Method
Authors: Liu Tiancong , Sun Yang , Li Jinxing , Bai Weiliang
Published: November 2019

A couple of cysts lying in the pterygopalatine fossa are rare. The authors report a case of a 28-year-old woman who was admitted to the authors’ hospital with a 1-month history of headache and numbness on the left head. Three-dimensional computed tomography revealed a large soft mass in the pterygopalatine fossa. Magnetic resonance imaging showed that there were a couple of cysts in the pterygopalatine fossa. One cyst measured 41 × 38 × 34 mm and the other 23 × 19 × 19 mm. A transpterygoid transnasal endoscopic approach and resection of the lesion was performed. The authors opened the cyst with coblation and the lesion showed a lot of transparent thick yellow liquid. The authors located the posterior wall the other cyst with ENT image navigation. The puncture was conducted and a lot of yellow liquid flowed out of the lesion. The patient recovered rapidly. The headache and numbness were alleviated and disappeared after 1 month. The patient currently has no evidence of recurrence at 1 year postoperatively. The coblation and ENT image navigation make the surgeon more easily to achieve risk-free surgery under endoscopy.
Percutaneous Lower Blepharoplasty: A Novel Technique in Lower Eyelid Aesthetics
Authors: Guner Huseyin
Published: November 2019

Background:

More preservative approaches are being adopted in periorbital surgery each day. To avoid the possible complications of transcutaneous and transconjunctival blepharoplasty, the author has developed the safe and simple “Percutaneous Lower Blepharoplasty” technique, which he has been performing since 2008. The technique consists of the removal and transfer of lower orbital fat pads through 4-mm skin incisions with minimal dissection.

Patients and Methods:

The study is designed as a retrospective analysis of the operations done by the author from 2008 to 2018. The author performed 297 percutaneous lower blepharoplasty operations alone or in combination with tear-trough deformity correction, pinch skin excision, and/or carbon dioxide laser application. The video of the technique is demonstrated in the supplemental digital content.

Results:

The patients were followed for an average of 58.8 months. All the patients were satisfied with the result. There were no retractions or scleral show seen. The only complication was chemosis in 1 patient that subsided with steroid ointment. Conclusion: Percutaneous lower blepharoplasty is a novel technique that has the following advantages: Simple and fast, low complication rates, good cosmetic outcomes, tear trough deformity correction, better estimation of fat amount to be removed, and minimal dissection and avoidance of violation of lamellar structures. It can be performed safely alone or in combination with pinch excision and/or fractional laser resurfacing.
A corepressor participates in LexA-independent regulation of error-prone polymerases in Acinetobacter
Authors: Peterson Megan A. , Grice Alison N. , Hare Janelle M.
Published: November 2019

The DNA damage response of the multidrug-resistant pathogen

Acinetobacter baumannii

, which induces mutagenic UmuD′2C error-prone polymerases, differs from that of many bacteria.

Acinetobacter

species lack a LexA repressor, but induce gene transcription after DNA damage. One regulator, UmuDAb, binds to and represses the promoters of the multiple

A. baumannii

ATCC 17978 umuDC alleles and the divergently transcribed umuDAb and ddrR genes. ddrR is unique to the genus

Acinetobacter

and of unknown function. 5' RACE (rapid amplification of cDNA ends) PCR mapping of the umuDAb and ddrR transcriptional start sites revealed that their −35 promoter elements overlapped the UmuDAb binding site, suggesting that UmuDAb simultaneously repressed expression of both genes by blocking polymerase access. This coordinated control of ddrR and umuDAb suggested that ddrR might also regulate DNA damage-inducible gene transcription. RNA-sequencing experiments in 17 978 ddrR
− cells showed that ddrR regulated approximately 25 % (n=39) of the mitomycin C-induced regulon, with umuDAb coregulating 17 of these ddrR-regulated genes. Eight genes (the umuDC polymerases, umuDAb and ddrR) were de-repressed in the absence of DNA damage, and nine genes were uninduced in the presence of DNA damage, in both ddrR and umuDAb mutant strains. These data suggest ddrR has multiple roles, both as a co-repressor and as a positive regulator of DNA damage-inducible gene transcription. Additionally, 57 genes were induced by mitomycin C in the ddrR mutant but not in wild-type cells. This regulon contained multiple genes for DNA replication, recombination and repair, transcriptional regulators, RND efflux, and transport. This study uncovered another regulator of the atypical DNA damage response of this genus, to help describe how this pathogen acquires drug resistance through its expression of the error-prone polymerases under DdrR and UmuDAb control.
The unique genome architecture of the devastating West African cacao black pod pathogen Phytophthora megakarya
Authors: Morales-Cruz Abraham , Ali Shahin S. , Minio Andrea , Figueroa-Balderas Rosa , García Jadran F. , Kasuga Takao , Puig Alina S. , Marelli Jean-Philippe , Bailey Bryan A. , Cantu Dario
Published: November 2019

Phytophthora megakarya (Pmeg) and P. palmivora (Ppal) are oomycete pathogens that cause black pod rot of cacao (Theobroma cacao), the most economically important disease on cacao globally. While Ppal is a cosmopolitan pathogen, Pmeg, which is more aggressive on cacao than Ppal, has been reported only in West and Central Africa where it has been spreading and devastating cacao farms since the 1950s. In this study, we reconstructed the complete diploid genomes of multiple isolates of both species using single-molecule sequencing. Thirty-one additional genotypes were sequenced to analyze inter- and intra-species genomic diversity. These resources make it possible to better understand the molecular basis of virulence differences in closely related and consequential pathogens and study their evolutionary history. The Pmeg genome is exceptionally large (222 Mbp) and nearly twice the size Ppal (135 Mbp) and most known Phytophthora species (∼100 Mbp on average). We show that the genomes of both species recently expanded by independent whole-genome duplications (WGD). WGD and the dramatic transposable element associated expansion of a few gene families led to the exceptionally large genome and transcriptome of Pmeg and the diversification of virulence-related genes including secreted RxLR effectors. Finally, this study provides evidence of adaptive evolution among well-known effectors and discusses the implications of effector expansion and diversification.
MapCell: Learning a comparative cell type distance metric with Siamese neural nets with applications towards cell-types identification across experimental datasets
Authors: Koh Winston , Hoon Shawn
Published: November 2019

Large collections of annotated single-cell RNA sequencing (scRNA-seq) experiments are being generated across different organs, conditions and organisms on different platforms. Transferring annotations from this growing database of single cell expression data to a new unannotated experimental dataset can accelerate insights into the underlying biology. There have been many approaches towards aligning and unifying such heterogeneous datasets. In our work, we recognized the need for a robust data driven distance metric to map annotation across datasets. Towards this aim, we applied a one-shot training approach, Siamese Neural Networks (SNN), to learn a distance metric that can differentiate between known annotated single cell types. Requiring only a small training set, we demonstrated that the SNN can perform predictions across different scRNA-seq platforms, identify novel cell types and transfer annotations across samples.
LIMD1 phase separation contributes to cellular mechanics and durotaxis by regulating focal adhesion dynamics in response to force
Authors: Wang Yuan , Zhang Chunlei , Shao Shipeng , Sun Yujie , Liang Ling , Wu Congying
Published: November 2019

The mechanical environement affects cell morphology, differentiation and motility. The ability of cells to follow gradients of extracellular matrix stiffness-durotaxis has been implicated in development, fibrosis, and cancer. Cells sense and respond to extra-cellular mechanical cues through cell-matrix adhesions. Interestingly, the maturation of focal adhesions (FAs) is reciprocally force-dependent. How biomechanical cues dictate the status of cell motility and how FAs coordinate force sensing and self-organization remain enigmatic. LIMD1, a member of the LIM domain proteins, localizes to the FAs and has been reported to negatively regulate the Hippo-YAP pathway in response to tension. Here we identify the force sensitive recruitment of LIMD1 to the FAs. We discover that LIMD1 regulates cell spreading, maintains FA dynamics and cellular force, and is critical for durotaxis. Intriguingly, LIMD1 selectively recruits late but not early FA proteins through phase separation at the FAs under force. We suggest a model in which localization of LIMD1 to the FAs, triggered by mechanical force, serves as a phase separation hub for assembling and organizing late FA proteins, allowing for effective FA maturation and efficient cellular mechano-transduction.
Selective carbon sources influence the end-products of microbial nitrate respiration
Authors: Carlson Hans K. , Lui Lauren M. , Price Morgan N. , Kazakov Alexey E. , Carr Alex V. , Kuehl Jennifer V. , Owens Trenton K. , Nielsen Torben , Arkin Adam P. , Deutschbauer Adam M.
Published: November 2019

Respiratory and catabolic pathways are differentially distributed in microbial genomes. Thus, specific carbon sources may favor different respiratory processes. We profiled the influence of 94 carbon sources on the end-products of nitrate respiration in microbial enrichment cultures from diverse terrestrial environments. We found that some carbon sources consistently favor dissimilatory nitrate reduction to ammonium (DNRA/nitrate ammonification) while other carbon sources favor nitrite accumulation or denitrification. For an enrichment culture from aquatic sediment, we sequenced the genomes of the most abundant strains, matched these genomes to 16S rDNA exact sequence variants (ESVs), and used 16S rDNA amplicon sequencing to track the differential enrichment of functionally distinct ESVs on different carbon sources. We found that changes in the abundances of strains with different genetic potentials for nitrite accumulation, DNRA or denitrification were correlated with the nitrite or ammonium concentrations in the enrichment cultures recovered on different carbon sources. Specifically, we found that either L-sorbose or D-cellobiose enriched for aKlebsiellanitrite accumulator, other sugars enriched for anEscherichianitrate ammonifier, and citrate or formate enriched for aPseudomonasdenitrifier and aSulfurospirillumnitrate ammonifier. Our results add important nuance to the current paradigm that higher concentrations of carbon will always favor DNRA over denitrification or nitrite accumulation, and we propose that, in some cases, carbon composition can be as important as carbon concentration in determining nitrate respiratory end-products. Furthermore, our approach can be extended to other environments and metabolisms to characterize how selective parameters influence microbial community composition, gene content and function.
Individual and concurrent effects of drought and chilling stresses on morpho-physiological characteristics and oxidative metabolism of maize cultivars
Authors: Hussain Hafiz Athar , Men Shengnan , Hussain Saddam , Ashraf Umair , Zhang Qingwen , Anjum Shakeel Ahmad , Ali Iftikhar , Wang Longchang
Published: November 2019

Maize belongs to tropical environment and is extremely sensitive to drought and chilling stress, particularly at early developmental stages. The present study investigated the individual and combine effects of drought (15% PEG-Solution) and chilling stress (15°C/12°C) on the morpho-physiological growth, osmolyte accumulation, production and regulations of reactive oxygen species (ROS) and the activities of antioxidants in two maize hybrids i.e., ‘XD889’ and ‘XD319’ and two inbred cultivars i.e., ‘Yu13’ and ‘Yu37’. Individual and combined drought and chilling stresses stimulated the production of O2□, H2O2, OH□ and enhanced malondialdehyde (MDA) contents which led to reduced photosynthetic pigments and morphological growth. Drought, chilling and drought + chilling stress conditions induced the compatible osmolytes, ROS detoxifying proteins and antioxidants to counterbalanced the oxidative damage. It was found that the concurrent occurrence of drought + chilling stress was more lethal for maize seedling growth than the drought and chilling individual stresses. However, the performance of hybrid maize cultivars (XD889 and XD319) was better than the inbred maize cultivars (Yu13 and Yu37). For improving tolerance to individual and concurrent drought and chilling stress in maize, future research focus should be on developing genetically engineer plants that have the ability to generate specific response against sub-optimal temperature and water deficit conditions.
Comparative analysis of chemically and biologically synthesized iron oxide nanoparticles against Leishmania tropica
Authors: Ain Qurat ul , Islam Arshad , Nadhman Akhtar , Yasinzai Masoom
Published: November 2019

The current study was carried out to compare the antileishmanial potential of the characterized chemically and plant mediated (Trigonella foenum-graecum) FeO-NPs (FeO-NPs) against L.tropica KWH23. The promastigotes and amastigotes mortality, ROS generation, and biocompatibility assessment were estimated in time-dose dependent manner by PDT. LED exposed bio-inspired FeO-NPs after 72 hours, express significant suppressive effects by exhibiting 50% inhibitory concentration (IC50) 0.001572±0.02μg/ml and 0.011408±0.02μg/ml for promastigotes and amastigotes, respectively. Leishmanial DNA damage and membrane integrity caused by FeO-NPs were owe to high production of reactive oxygen species (ROS). By applying different ROS scavengers (mannitol and sodium azide) hydroxyl radical and singlet oxygen were found as main moieties for cell death by giving quantum yield 0.15 and 0.28 through chemically and green synthesized FeO-NPs, respectively. The light exposed green synthesized nanoparticles were found biocompatible on human red blood cells (RBCs), by exhibiting LD50 value 2659μg/mL. From these findings, it can be concluded that plant mediated FeO-NPs can be used as promising antiprotozoal agent.
AtacWorks: A deep convolutional neural network toolkit for epigenomics
Authors: Lal Avantika , Chiang Zachary D. , Yakovenko Nikolai , Duarte Fabiana M. , Israeli Johnny , Buenrostro Jason D.
Published: November 2019

We introduce AtacWorks (https://github.com/clara-genomics/AtacWorks), a method to denoise and identify accessible chromatin regions from low-coverage or low-quality ATAC-seq data. AtacWorks uses a deep neural network to learn a mapping between noisy ATAC-seq data and corresponding higher-coverage or higher-quality data. To demonstrate the utility of AtacWorks, we train a model on data from four human blood cell types and show that this model accurately denoises chromatin accessibility at base-pair resolution and identifies peaks from low-coverage bulk sequencing of unseen cell types and experimental conditions. We use the same framework to obtain high-quality results from as few as 50 aggregate single-cell ATAC-seq profiles, and also from data with a low signal-to-noise ratio. We further show that AtacWorks can be adapted for cross-modality prediction of transcription factor footprints and ChIP-seq peaks from low input ATAC-seq. Finally, we demonstrate the applications of our approach to single-cell genomics by using AtacWorks to identify regulatory regions that are differentially-accessible between rare lineage-primed subpopulations of hematopoietic stem cells.
Toward One-Shot Learning in Neuroscience-Inspired Deep Spiking Neural Networks
Authors: Faghihi Faramarz , Molhem Hossein , Moustafa Ahmed A.
Published: November 2019

Conventional deep neural networks capture essential information processing stages in perception. Deep neural networks often require very large volume of training examples, whereas children can learn concepts such as hand-written digits with few examples. The goal of this project is to develop a deep spiking neural network that can learn from few training trials. Using known neuronal mechanisms, a spiking neural network model is developed and trained to recognize hand-written digits with presenting one to four training examples for each digit taken from the MNIST database. The model detects and learns geometric features of the images from MNIST database. In this work, a novel biological back-propagation based learning rule is developed and used to a train the network to detect basic features of different digits. For this purpose, randomly initialized synaptic weights between the layers are being updated. By using a neuroscience inspired mechanism named ‘synaptic pruning’ and a predefined threshold, some of the synapses through the training are deleted. Hence, information channels are constructed that are highly specific for each digit as matrix of synaptic connections between two layers of spiking neural networks. These connection matrixes named ‘information channels’ are used in the test phase to assign a digit class to each test image. As similar to humans’ abilities to learn from small training trials, the developed spiking neural network needs a very small dataset for training, compared to conventional deep learning methods checked on MNIST dataset.
Foreign body reaction is triggeredin vivoby cellular mechanosensing of implants stiffer than host tissue
Authors: Carnicer-Lombarte Alejandro , Barone Damiano G. , Dimov Ivan B. , Hamilton Russell S. , Prater Malwina , Zhao Xiaohui , Rutz Alexandra L. , Malliaras George G. , Lacour Stephanie P. , Bryant Clare E. , Fawcett James W. , Franze Kristian
Published: November 2019

Medical implants offer a unique and powerful therapeutic approach in many areas of medicine. However, their lifetime is often limited as they may cause a foreign body reaction (FBR) leading to their encapsulation by scar tissue1–4. Despite the importance of this process, how cells recognise implanted materials is still poorly understood5, 6.

Here, we show how the mechanical mismatch between implants and host tissue leads to FBR. Fibroblasts and macrophages, which are both crucially involved in mediating FBR, became activated when cultured on materials just above the stiffness of healthy tissue. Coating stiff implants with a thin layer of hydrogel or silicone with a tissue-like elastic modulus (∼20 kPa in subcutaneous and ∼2 kPa in peripheral nerve implants) or softer significantly reduced inflammation and fibrosis three months after implantation. Materials stiffer than the host tissue led to nuclear localisation of the mechanosensitive transcriptional regulator YAP in neighbouring cellsin vivo, confirming mechanotransduction. The alleviation of FBR by soft coatings not exceeding the stiffness of the host tissue provides a strategy to achieve long-term implant stability without extensive modification of current implant manufacturing techniques, facilitating clinical translation.
Semi-supervised machine learning facilitates cell colocalization and tracking in intravital microscopy
Authors: Pizzagalli Diego Ulisse , Thelen Marcus , Gonzalez Santiago Fernandez , Krause Rolf
Published: November 2019

2-photon intravital microscopy (2P-IVM) is a key technique to investigate cell migration and cell-to-cell interactions in organs and tissues of living organisms. Focusing on immunology, 2P-IVM allowed recording videos of leukocytes during the immune response, highlighting unprecedented mechanisms of the immune system. However, the automatic analysis of the acquired videos remains challenging and poorly reproducible. In fact, both manual curation of results and tuning of bioimaging software parameters among different experiments, are required. One of the most difficult tasks for a user is transferring to a computer the knowledge on what a cell is and how it should appear with respect to the background, other objects, or other cell types. This is possibly due to the low specificity of acquisition channels which may include multiple cell populations and the presence of similar objects in the background.

In this work, we propose a method based on semi-supervised machine learning to facilitate colocalization. In line with recently proposed approaches for pixel classification, the method requires the user to draw some lines on the cells of interest and some line on the other objects/background. These lines embed knowledge, not only on which pixel belongs to a class or which pixel belongs to another class but also on how pixels in the same object are connected. Hence, the proposed method exploits the information from the lines to create an additional imaging channel that is specific for the cells fo interest. The usage of this method increased tracking accuracy on a dataset of challenging 2P-IVM videos of leukocytes. Additionally, it allowed processing multiple samples of the same experiment keeping the same mathematical model.
Development of Dynamic Functional Architecture during Early Infancy
Authors: Wen Xuyun , Wang Rifeng , Lin Weili , Zhang Han , Shen Dinggang
Published: November 2019

Understanding the moment-to-moment dynamics of functional connectivity (FC) in the human brain during early development is crucial for uncovering neuro-mechanisms of the emerging complex cognitive functions and behaviors. Instead of calculating FC in a static perspective, we leveraged a longitudinal resting-state functional magnetic resonances imaging dataset from fifty-one typically developing infants and, for the first time, thoroughly investigated how the temporal variability of the FC architecture develops at theglobal(entire brain),meso- (functional system) andlocal(brain region) levels in the first two years of age. Our results revealed that, in such a pivotal stage,1)the whole-brain FC dynamics is linearly increased;2)the high-order functional systems display increased FC dynamics for both within- and between-network connections, while the primary systems show the opposite trajectories;3)many frontal regions have increasing FC dynamics despite large heterogeneity in developmental trajectories and velocities. All these findings indicate that the brain is gradually reconfigured towards a more flexible, dynamic, and adaptive system with globally increasing but locally heterogeneous trajectories in the first two postnatal years, explaining why infants have emerging and rapidly developing high-order cognitive functions and complex behaviors.
Expansion Microscopy of Lipid Membranes
Authors: Karagiannis Emmanouil D. , Kang Jeong Seuk , Shin Tay Won , Emenari Amauche , Asano Shoh , Lin Leanne , Costa Emma K. ,   IMAXT Grand Challenge Consortium, Marblestone Adam H. , Kasthuri Narayanan , Boyden Edward S.
Published: November 2019

Lipids are fundamental building blocks of cells and their organelles, yet nanoscale resolution imaging of lipids has been largely limited to electron microscopy techniques. We introduce and validate a chemical tag that enables lipid membranes to be imaged optically at nanoscale resolution via a lipid-optimized form of expansion microscopy, which we call membrane expansion microscopy (mExM). mExM, via a novel post-expansion antibody labeling protocol, enables protein-lipid relationships to be imaged in organelles such as mitochondria, the endoplasmic reticulum, the nuclear membrane, and the Golgi apparatus. mExM may be of use in a variety of biological contexts, including the study of cell-cell interactions, intracellular transport, and neural connectomics.
Parallel Bimodal Single-cell Sequencing of Transcriptome and Chromatin Accessibility
Authors: Xing Qiao Rui , Farran Chadi EL , Yi Yao , Warrier Tushar , Gautam Pradeep , Collins James J. , Xu Jian , Li Hu , Zhang Li-Feng , Loh Yuin-Han
Published: November 2019

We developed ASTAR-Seq (Assay for Single-cell Transcriptome and Accessibility Regions) integrated with automated microfluidic chips, which allows for parallel sequencing of transcriptome and chromatin accessibility within the same single-cell. Using ASTAR-Seq, we profiled 192 mESCs cultured in serum+LIF and 2i medium, 424 human cell lines including BJ, K562, JK1, and Jurkat, and 480 primary cells undergoing erythroblast differentiation. Integrative analysis using Coupled NMF identified the distinct sub-populations and uncovered sets of regulatory regions and the respective target genes determining their distinctions. Analysis of epigenetic regulomes further unravelled the key transcription factors responsible for the heterogeneity observed.
Genetic structure at national and regional scale in a long-distance dispersing pest organism, the bird cherry–oat aphidRhopalosiphum padi
Authors: Morales-Hojas Ramiro , Gonzalez-Uriarte Asier , Iraizoz Fernando Alvira , Jenkins Todd , Alderson Lynda , Kruger Tracey , Hall Mike J. , Greenslade Alex , Shortall Chris R. , Bell James R.
Published: November 2019

Genetic diversity is determinant for pest species’ success and vector competence. Understanding the ecological and evolutionary processes that determine the genetic diversity is fundamental to help identify the spatial scale at which pest populations are best managed. In the present study, we present the first comprehensive analysis of the genetic diversity and evolution ofRhopalosiphum padi, a major pest of cereals and a main vector of the barley yellow dwarf virus (BYDV), in Great Britain. We have used a genotype by sequencing approach to study whether i) there is any underlying population genetic structure in this long distant disperser pest at a national and regional scale; ii) the populations evolve as a response to environmental change and selective pressures, and; iii) the populations comprise anholocyclic lineages. IndividualR. padiwere collected using the Rothamsted Insect Survey’s suction-trap network at several sites across England between 2004 and 2016 as part of the RIS long-term nationwide surveillance. Results identified two genetic clusters in Great Britain that mostly paralleled a North – South division, although gene flow is ongoing between the two subpopulations. These different groups do not correspond to sexual and asexual types, sexual reproduction being predominant in Great Britain, and could correspond to ecotypes. Results also show that there is migration with gene flow across Great Britain, although there is a reduction between the northern and southern sites with the Southwestern population being the most genetically differentiated. There is no evidence for isolation-by-distance and other factors like primary host distribution could influence the migration patterns. Finally, results also show no evidence for the evolution of theR. padipopulation, and it is demographically stable despite the ongoing environmental change. These results are discussed in view of their relevance to pest management and the transmission of BYDV.
Reduction of auditory input improves performance on the heartbeat tracking task, but does not necessarily enhance interoception
Authors: Todd Jennifer , Hina Farah , Aspell Jane E
Published: November 2019

Previous research utilising a between-subjects design has indicated that the use of noise-dampening ear-protectors might enhance interoceptive accuracy (IAcc). In the present study, we further examined this effect using a repeated-measures, within-participants design, and investigated potential mechanisms that might explain the effect. 50 participants completed the heartbeat tracking task (HTT) with and without the use of industrial ear-protectors, in a counter-balanced order. Participants were asked to count the number of heartbeats occurring in five discrete time intervals of 25, 35, 45, 55 and 95 seconds, without feeling for a manual pulse. HTT scores were significantly higher when ear-protectors were worn, and the improvement in performance was greatest for participants with lower baseline IAcc. The ear-protectors were associated with significantly increased self-reported heartbeat audibility, task-related confidence and concentration, and decreased levels of distractibility. Heartbeat audibility was also correlated with HTT performance when the ear-protectors were worn. Because the use of industrial ear defenders resulted in increased heartbeat audibility, this manipulation should not be used to assess causal hypotheses related to changes in IAcc. However, it may serve as a simple, non-invasive manipulation to assess the effects of externalised interoceptive signals.
Dentate gyrus somatostatin cells are required for contextual discrimination during episodic memory encoding
Authors: Morales Cristian , Morici Juan Facundo , Espinosa Nelson , Sacson Agostina , Lara-Vasquez Ariel , Garcia-Perez M. Alexandra , Bekinschtein Pedro , Weisstaub Noelia V. , Fuentealba Pablo
Published: November 2019

Episodic memory establishes and stores relations among the different elements of an experience, which are often similar and difficult to distinguish. Pattern separation, implemented by the dentate gyrus, is a neural mechanism that allows the discrimination of similar experiences by orthogonalizing synaptic inputs. Granule cells support such disambiguation by sparse rate coding, a process tightly controlled by highly diversified GABAergic neuronal populations, such as somatostatin-expressing cells which directly target the dendritic arbor of granule cells, massively innervated by entorhinal inputs reaching the molecular layer and conveying contextual information. Here, we tested the hypothesis that somatostatin neurons regulate the excitability of the dentate gyrus, thus controlling the efficacy of pattern separation during memory encoding in mice. Indeed, optogenetic suppression of dentate gyrus somatostatin neurons increased spiking activity in putative excitatory neurons and triggered dentate spikes. Moreover, optical inhibition of somatostatin neurons impaired both contextual and spatial discrimination of overlapping episodic-like memories during task acquisition. Importantly, effects were specific for similar environments, suggesting that pattern separation was selectively engaged when overlapping conditions ought to be distinguished. Overall, our results suggest that somatostatin cells regulate excitability in the dentate gyrus and are required for effective pattern separation during episodic memory encoding.

Significance statement

Memory systems must be able to discriminate stored representations of similar experiences in order to efficiently guide future decisions. This is solved by pattern separation, implemented in the dentate gyrus by granule cells to support episodic memory formation. The tonic inhibitory bombardment produced by multiple GABAergic cell populations maintains low activity levels in granule cells, permitting the process of pattern separation. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the dentate gyrus. Hence, somatostatin cells constitute an ideal candidate to regulate pattern separation. Here, by using optogenetic stimulation in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.
Natural naphthoquinones isolated from Lithospermum erythrorhizon suppress dextran sulfate sodium-induced murine experimental colitis
Authors: Sun Wenxue , Han Hongwei , Wang Zhaoyue , Wen Zhongling , Yang Minkai , Wang Yinsong , Fu Jiangyan , Feng Lu , Xu Xinhong , Yin Tongming , Wang Xiaoming , Lu Guihua , Qi Jinliang , Lin Hongyan , Yang Yonghua
Published: November 2019

The purpose of this study was to explore the effects of natural shikonin and its derivatives on mice experimental colitis induced by dextran sulfate sodium, and to investigate the underlying mechanisms in vivo. Our results suggested that, intragastric administration of single compound like shikonin and its derivatives contributed to attenuating symptoms of malignant induced by DSS. Meanwhile, shikonin or its derivatives could also remarkably reduce the disease activity index and histopathological scores, suppress the levels of pro-inflammatory cytokines (including IL-6, IL-1β and TNF-α), while increase that of inflammatory cytokine IL-10 in serum. Additionally, both shikonin and alkanin were found to restrain the levels of COX-2, MPO and iNOS in serum and colonic tissues. Moreover, western blotting results demonstrated that shikonin and its derivatives could inhibit the activation of the NLRP3 inflammasome and the NF-κB signaling pathway, relieve the DSS-induced disruption of colonic epithelial tight junction (TJ) in colonic tissues. Further, docking simulation had been performed to prove that shikonin and its derivatives could bind to the active sites of NLRP3 inflammasome and the NF-κB to generate an effective inflammatory effect. Taken together, our experimental data can provide some evidence for the potential use of shikonin and its derivatives to treat the inflammatory bowel disease (IBD).
Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage
Authors: Li Zhi , Rotival Maxime , Patin Etienne , Michel Frédérique , Pellegrini Sandra
Published: November 2019

TYK2 belongs to the JAK protein tyrosine kinase family and mediates signaling of numerous antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) in immune and non-immune cells. After many years of genetic association studies, TYK2 is recognized as a susceptibility gene for some inflammatory and autoimmune diseases (AID). Seven TYK2 variants have been associated with AIDs in Europeans, and establishing their causality remains challenging. Previous work showed that a protective variant (P1104A) is hypomorphic and also a risk allele for mycobacterial infection. Here, we have studied two AID-associated common TYK2 variants: rs12720270 located in intron 7 and rs2304256, a non-synonymous variant in exon 8 that causes a valine to phenylalanine substitution (c.1084 G > T, Val362Phe). We found that this amino acid substitution does not alter TYK2 expression, catalytic activity or ability to relay signaling in EBV-B cell lines or in reconstituted TYK2-null cells. Based on in silico predictions that these variants may impact splicing of exon 8, we: i) analyzed TYK2 transcripts in genotyped EBV-B cells and in CRISPR/Cas9-edited cells, ii) measured splicing using minigene assays, and iii) performed eQTL (expression quantitative trait locus) analysis of TYK2 transcripts in primary monocytes and whole blood cells. Our results reveal that the two variants promote the inclusion of exon 8, which, we demonstrate, is essential for TYK2 binding to cognate receptors. In addition and in line with GTEx (Genetic Tissue Expression) data, our eQTL results show that rs2304256 mildly enhances TYK2 expression in whole blood. In all, these findings suggest that these TYK2 variants are not neutral but instead have a potential impact in AID.
In silico analysis of Missense Variants in Human MPL Gene Associated with Essential Thrombocythemia
Authors: Elbager Sahar G. , Makkawi Abier A. , Mohamed Hadeel A. , Abdelrahman Fauzia A. , Osman Lamia H. , Hameed Moroj F. , Elrashid Asia M. , Basher Mohamed Y. , Khalil Safinaz I. , Bayoumi Magdi
Published: November 2019

Introduction

The proto-oncogene (MPL) gen encodes the receptor for thrombopoietin (TPO-R), a member of hematopoietic receptor superfamily. Thrombopoietin (TPO), the primary cytokine regulating self-renewal of hematopoietic stem cells, thrombopoiesis and megakaryocytopoiesis. TPO binding to TPO-R induces activation of Janus Kinase 2 (JAK2). Activated JAK2 triggers the activation of downstream positive signaling pathways, leading to the survival, proliferation, and differentiation of hematopoietic cells. Mutations in MPL gene possibly will alter the normal regulatory mechanisms. Numerous MPL mutations have been observed in various hematopoietic cancers such as essential thrombocythemia and primary myelofibrosis and leukemias. In this study, we performed a comprehensive in silico analysis of the functional and structural impact of non-synonymous (nsSNP) that are deleterious to TPO-R structure and function.

Methodology

The data on human MPL gene was retrieved from dbSNP/NCBI. Nine prediction algorithms; SIFT, Polyphen, PROVEAN, SNAP2, Condel, PhD-SNP, I-Mutant, Mutpred. RaptorX and Chimera were used to analyzing the effect of nsSNPs on functions and structure of the TPO-R. STRING and KEGG database were used for TPO-R protein-protein interaction.

Results and Discussion

As per dbSNP database, the human MPL gene contained 445 missense mutations. A total 5 nsSNPs (D295G, R257C, Y252H, R537W and D128Y) were predicted to have the most damaging effects on TPO-R structure and function. STRING and KEGG revealed that MPL had strong interactions with proteins that involved in cell growth, apoptosis, signal transduction pathway, some cancers pathways such as colorectal cancer, lung cancer, pancreas cancers, and skin cancer. A literature search revealed that Y252H has contribute to the development of essential thrombocythemia.

Conclusion

These in silico predictions will provide useful information in selecting the target SNPs that are likely to have functional impact on the TPO-R and moreover could act as potential targets in genetic association studies. Keywords: In Silico analyses; JAK2; Missense Variants; MPL gene; Thrombopoietin (TPO); Single nucleotide polymorphism (SNP).
Decoding and encoding models reveal the role of mental simulation in the brain representation of meaning
Authors: Soto David , Sheikh Usman Ayub , Mei Ning , Santana Roberto
Published: November 2019

How the brain representation of conceptual knowledge vary as a function of processing goals, strategies and task-factors remains a key unresolved question in cognitive neuroscience. Here we asked how the brain representation of semantic categories is shaped by the depth of processing during mental simulation. Participants were presented with visual words during functional magnetic resonance imaging (fMRI). During shallow processing, participants had to read the items. During deep processing, they had to mentally simulate the features associated with the words. Multivariate classification, informational connectivity and encoding models were used to reveal how the depth of processing determines the brain representation of word meaning. Decoding accuracy in putative substrates of the semantic network was enhanced when the depth processing was high, and the brain representations were more generalizable in semantic space relative to shallow processing contexts. This pattern was observed even in association areas in inferior frontal and parietal cortex. Deep information processing during mental simulation also increased the informational connectivity within key substrates of the semantic network. To further examine the properties of the words encoded in brain activity, we compared computer vision models - associated with the image referents of the words - and word embedding. Computer vision models explained more variance of the brain responses across multiple areas of the semantic network. These results indicate that the brain representation of word meaning is highly malleable by the depth of processing imposed by the task, relies on access to visual representations and is highly distributed, including prefrontal areas previously implicated in semantic control.
Clofarabine commandeers the RNR-α—ZRANB3 nuclear signaling axis
Authors: Long Marcus J. C. , Zhao Yi , Aye Yimon
Published: November 2019

Ribonucleotide reductase (RNR) is an essential enzyme in DNA-biogenesis and a target of several chemotherapeutics. Here we investigate how anti-leukemic drugs [e.g., clofarabine (ClF)] that target one of the two subunits of RNR, RNR-α, affect non-canonical RNR-α functions. We discovered that these clinically-approved RNR-inhibiting dATP-analogs inhibit growth by also targeting ZRANB3—a newly-identified DNA-synthesis promoter and nuclear-localized interactor of RNR-α. Remarkably, in early time points following drug treatment, ZRANB3-targeting accounted for most of the drug-induced DNA-synthesis suppression and multiple cell types featuring ZRANB3-knockout/knockdown were resistant to these drugs. Additionally, ZRANB3 plays a major role in regulating tumor-invasion and H-rasG12V-promoted transformation in a manner dependent on the recently-discovered interactome of RNR-α involving select cytosolic-/nuclear-localized protein-players. The H-rasG12V-promoted transformation—which we show requires ZRANB3-supported DNA-synthesis—was efficiently suppressed by ClF. Such overlooked mechanisms-of-action of approved drugs and a new example of non-oncogene addiction, which is suppressed by RNR-α, may advance cancer interventions.
Low Carbohydrate and Low Fat Diets with Equal Protein Content Lead to Similar Improvements in Body Composition and Glucose Tolerance in Obese Mice subjected to Caloric Restriction
Authors: Minderis Petras , Fokin Andrej , Dirmontas Mantas , Ratkevicius Aivaras
Published: November 2019

Background

Reported differences in effects of low and high carbohydrate diets on weight control and metabolic health are controversial. We aimed to examine if such diets induce different improvements in body composition and glucose tolerance under conditions of caloric restriction (CR) in obese mice.

Methods

Male C57BL/6J mice (n = 20) were fed obesogenic diet (45 and 17.5% kcal from fat and sugar)ad libitumfor 18 weeks and then subjected to 6-week CR which progressively increased up to 40% using either Low Fat diet (20, 60, 20% kcal from fat, carbohydrate, protein, n = 10) or Low Carb diet (20, 60, 20% kcal from carbohydrate, fat, protein, n = 10). Mice fed regular chow dietad libitumserved as controls (n = 10). Body mass, hind limb muscle mass, fat mass, energy expenditure and glucose tolerance were compared between the groups.

Results

Low Fat and Low Carb groups had similar body mass (p> 0.05) prior to CR which was 30% greater compared to control group (p< 0.001). CR resulted in weight loss with no differences between Low Fat and Low Carb groups (30.0 ± 5.6 and 23.8 ± 7.5%,p> 0.05). Weight loss was mainly due to fat loss in both groups. Energy expenditure of freely moving mice did not differ between the groups (p> 0.05). Intraperitoneal glucose tolerance test improved compared to control group (p< 0.05) and values before CR (p< 0.01) but without differences between Low Fat and Low Carb groups (p> 0.05).

Conclusions

Dietary carbohydrate or fat content when protein is equated does not play a significant role for body composition and metabolic health benefits of caloric restriction in obese mice.