bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric Parenteral Nutrition-Associated Liver Disease
Authors: Israelite Jill C.
Published: January 2020

Pediatric parenteral nutrition-associated liver disease (PNALD) is typically defined as a decrease in bile flow that is independent of a mechanical obstruction and of any other underlying liver disease. It is most often seen in pediatric patients receiving parenteral nutrition support. Up to 50% to 66% of children receiving long-term parenteral nutrition are reported to be diagnosed with PNALD. The goal of treatment for PNALD is advancement to full enteral nutrition and elimination of dependence on parenteral nutrition support. Achieving this goal is not always possible, especially in patients with short bowel syndrome. The following review article highlights some of the current treatment strategies focused on prevention or correction of PNALD as noted in current American Society for Parenteral and Enteral Nutrition guidelines.
An Experiential Learning Approach to Primary Palliative Care Nursing Education
Authors: Glover Toni L. , Horgas Ann L. , Castleman Joan , Turpening Paula , Kittelson Sheri
Published: January 2020

The need for palliative care is growing along with a rapidly aging population. To meet this need, the American Association of Colleges of Nursing developed palliative care competencies that all nurses should achieve before graduation. Many of these competencies rely on direct experience in caring for patients facing serious illness, leading to an increased emphasis on experiential learning in nursing curricula. Experiential learning is the process of creating knowledge through transformative experiences outside the traditional classroom setting. The Comfort Shawl Project is a service learning project that provides senior nursing students with a yearlong immersion in palliative care. Experiential learning activities include attending the interdisciplinary palliative care team meeting, gifting handcrafted shawls to patients, writing reflections, participating in extracurricular events, and sharing the impact of the project through written papers and presentations. The project has been successful in helping nursing students achieve palliative care competencies, including communicating effectively and compassionately with patients and families and recognizing one’s own beliefs about serious illness and death. This project addresses the need to achieve primary palliative care competencies for nursing students. Clinical experiences in palliative care are vital to supplementing didactic learning, and this project could be replicated in a variety of academic settings.
Justice in America
Authors: Paice Judith A. , Coyne Patrick
Published: January 2020

Pain is common in those with a life-threatening illness, yet barriers to adequate treatment persist. New challenges add to the well-known barriers of limited education, lack of time, and impaired access to expert treatment. The opioid abuse epidemic and the rising rate of deaths related to misuse of opioids present new obstacles to cancer pain relief. Although many of the efforts to reduce the impact of the opioid epidemic are important to the community, there are unintended consequences. When facing these challenges, ethical principles serve as a guide to the provision of safe and effective pain control in hospice and palliative care. The ethical principle most challenged during our current state is justice, the equal and fair distribution of resources. There are numerous examples of unfair distribution of cancer pain treatment, notably limited access to pharmacologic and nonpharmacologic therapies. Hospice and palliative nurses who are dedicated to the provision of excellent cancer pain care can ensure equitable distribution of resources, including opioids. Solutions to the challenge of fair access include individual professional development, interventions by health care organizations, and action by professional organizations.
Empowering Nurses Through Translating the End-of-Life Nursing Education Consortium
Authors: Takenouchi Sayaka , Sasahara Tomoyo , Miyashita Mitsunori , Kawa Masako , Umeda Megumi , Kuwata Miyoko , Arahata Tomoko , Kizawa Yoshiyuki , Tamura Keiko
Published: January 2020

The End-of-Life Nursing Education Consortium–Core Curriculum was translated in 2005 and has made a significant contribution to Japanese nurses. In this article, we describe our experience with curriculum revision to reflect on the cultural background inherent in Japan and evaluate the effect that it brought to the trainers. The main focus of this major revision was to (1) make the content relevant to the Japanese health care system, (2) add unique cultural considerations to each module, (3) replace case studies and role play scenarios, (4) add a new module “End-of-Life Care for Geriatric,” and (5) set clear rules for trainers. One thousand one hundred twenty evaluations were collected from participants of the End-of-Life Nursing Education Consortium–Japan Core train-the-trainer programs from 2011 to 2016. Course evaluations were highly positive, with all questions having mean scores greater than 4.1 of 5 across all 6 years of study. Comparative statistical analysis showed that refinement of the course not only helped nursing educators gain knowledge but also assisted them with developing a clear picture of how to plan and organize their training course. This course could be a valuable model to nursing educators seeking to develop their own leadership training seminar or introducing End-of-Life Nursing Education Consortium curricula.
Improving Long-Term Care Residents’ Outcomes by Educating Nursing Staff on End-of-Life Communication
Authors: Kunte Vera , Johansen Mary L. , Isenberg-Cohen Shari
Published: January 2020

This project aimed to examine whether improvement in end-of-life knowledge of long-term care nursing staff, especially nursing assistants, increases the rate of long-term care residents with advance directives and decreases the rate of their hospital transfers.

Nurses and nursing assistants in long-term care facilities are inadequately prepared to provide quality end-of-life (EOL) care. Few studies focus on improving EOL education of nursing assistants who are closest to the residents, providing most of their care. Eleven nurses and 18 nursing assistants from 1 urban and 1 suburban long-term care facilities received education based on the End-of-Life Nursing Education Consortium Geriatric curriculum separately and together. Pre-education and posteducation, knowledge of nursing staff was assessed and records of 139 residents were examined for advance directives and hospital transfers.

Posteducation, EOL knowledge of nursing assistants showed greater improvement than that of nurses; all nursing staff rated their knowledge higher. Documentation of resident EOL preferences improved minimally, but the rate of transfers to the hospitals was dramatically reduced.

Nursing staff education on EOL care reduces the number of long-term care residents’ hospital transfers leading to improved quality of EOL care. Nursing assistants benefit from combined education sessions with the nurses.
The Need for a Shared Understanding
Authors: Rost Michael , De Clercq Eva , Wangmo Tenzin , Elger Bernice S.
Published: January 2020

Conceptual confusion is a primary barrier to providing quality palliative care. This study aimed to analyze pediatric palliative care (PPC) guidelines from a conceptual perspective to facilitate a shared understanding of palliative care in pediatrics. Five online databases were searched systematically, in addition to a Google search. Analysis focused on the language used to determine the domains of PPC and on the composition of the PPC team. Guidelines express consensus on 4 core domains: physical, psychological, social, and spiritual care. However, conceptual vagueness exists with respect to the latter 3 because terminology is used inconsistently both within and across guidelines. An inconsistent use of terminology affects the quality of PPC nursing in various ways. Therefore, a shared understanding and unambiguous language must be envisaged. Furthermore, although guidelines agree on the most prominent team members, they do not clearly indicate how these occupational groups should collaborate.
Art Making From the HEART
Authors: Bultas Margaret W. , Saini Shermini , Marty Justine , Hendricks-Ferguson Verna L.
Published: January 2020

Diagnosis and treatment of childhood cancers are a potentially traumatic time of both emotional and physical distress for affected children and parents. Psychosocial palliative care interventions are needed to assist children to cope with unpleasant adverse effects during oncology treatments. Positive distraction techniques, such as art making, have shown evidence to reduce perceived pain and anxiety responses during cancer treatments. This exemplar case study highlights benefits of implementing an art-making project with an 11-year-old girl undergoing treatment for neuroblastoma, using an innovative and developmentally appropriate activity called the heirloom art-making (HEART) intervention. In the HEART intervention, the child and parent choose a meaningful photograph or picture that is transformed into a paint-by-number canvas, providing a fun activity for the parent and child to focus on together. The completed painting can be kept as a cherished family keepsake. Art-making projects, such as the HEART, can potentially be used by nurses to foster developmentally appropriate, nonpharmacological, palliative care interventions to help children focus on secondary-control coping strategies (ie, distraction) during oncology treatments. Art-making projects also provide a fun mechanism to foster positive interactions between nurses and patients, an opportunity for parent involvement, and a sense of normalcy for child and parents during oncology treatments.
Physical Therapists’ Contribution to the Hospice and Palliative Care Interdisciplinary Team
Authors: Wilson Christopher M. , Mueller Karen , Briggs Richard
Published: January 2020

There is mounting evidence of the physical therapist’s role in hospice and palliative care (HPC) for optimizing quality of life and engagement in remaining life activities. The purpose of this clinical summary is to describe the variety of roles and clinical approaches that physical therapists are able to contribute to the care of patients with a life-threatening or terminal illness. In addition, culture, religion, and individual patient/family preferences tend to be contributing factors as they relate to physical therapy (PT) in HPC. Physical therapists have multiple practice patterns that they can use in HPC for a variety of clinical signs and symptoms, patient situations, and disease trajectories. Access to PT services is inconsistent and often depends on the understanding of the role of PT within HPC. In addition, providers must acknowledge varying levels of acceptance and integration of PT and HPC based on individual and contextual factors. In order to optimize remaining quality of life and optimize care and safety, PT and HPC should be integrated in a collaborative, prospective manner, and PT should be closely integrated with the entire interdisciplinary HPC care team.
Rationale for Spiritually Oriented Cognitive Processing Therapy for Moral Injury in Active Duty Military and Veterans With Posttraumatic Stress Disorder
Authors: Koenig Harold G. , Boucher Nathan A. , Oliver Rev. John P. , Youssef Nagy , Mooney Scott R. , Currier Joseph M. , Pearce Michelle
Published: January 2020

Wartime experiences have long been known to cause ethical conflict, guilt, self-condemnation, difficulty forgiving, loss of trust, lack of meaning and purpose, and spiritual struggles. “Moral injury” (MI) (also sometimes called “inner conflict”) is the term used to capture this emotional, cognitive, and behavioral state. In this article, we provide rationale for developing and testing Spiritually Oriented Cognitive Processing Therapy, a version of standard cognitive processing therapy for the treatment of MI in active duty and veteran service members (SMs) with posttraumatic stress disorder symptoms who are spiritual or religious (S/R). Many SMs have S/R beliefs that could increase vulnerability to MI. Because the injury is to deeply held moral standards and ethical values and often adversely affects spiritual beliefs and worldview, we believe that those who are S/R will respond more favorably to a therapy that directly targets this injury from a spiritually oriented perspective. An evidence-based treatment for MI in posttraumatic stress disorder that not only respects but also utilizes SMs’ spiritual beliefs/behaviors may open the door to treatment for many S/R military personnel.
Longitudinal characterization of Plasmodium inter-species interactions during a period of increasing prevalence of Plasmodium ovale
Authors: Akala Hoseah M. , Watson Oliver , Mitei Kenneth K. , Juma Dennis W. , Verity Robert , Ingasia Luiser A. , Opot Benjamin H. , Okoth Raphael O. , Chemwor Gladys C. , Juma Jackline A. , Mwakio Edwin W. , Brazeau Nicholas , Cheruiyot Agnes C. , Yeda Redemptah A. , Maraka Maureen N. , Okello Charles O. , Kateete David P. , Managbanag Jim Ray , Andagalu Ben , Ogutu Bernhards R. , Kamau Edwin
Published: January 2020

Background

The epidemiology and severity of non-falciparum malaria in endemic settings has garnered limited attention. We aimed to characterize the prevalence, interaction, clinical risk factors and temporal trends of non-falciparum malaria in endemic settings of Kenya.

Methods

We diagnosed and analyzed infecting malaria species via PCR in 2027 clinical samples collected between 2008 and 2016. Descriptive statistics were used to describe the prevalence and distribution of Plasmodium species. A statistical model was designed and used for estimating the frequency of Plasmodium species and assessing inter-species interactions. Mixed effect linear regression models with random intercepts for each location was used to test for change in prevalence over time.

Findings

72•5% of the samples were P. falciparum single species infections, 25·8% were mixed infections and only 1•7% occurred as single non-falciparum species infections. 23•1% were mixed infections containing P. ovale. A likelihood-based model calculation of the population frequency of each species estimated a significant within-host interference between P. falciparum and P. ovale curtisi. Mixed-effect logistic regression models identified a significant increase of P. ovale wallikeri and P. ovale curtisi species over time with reciprocal decrease in P. falciparum single species and P. malariae. The risk of P. falciparum infections presenting with fever was 0•43 times less likely if co-infected with P. malariae.

Interpretation

Findings show higher prevalence of non-falciparum malaria than expected. The proportion of infections that were positive for infection by P. ovale wallikeri and P. ovale curtisi was observed to significantly increase over the period of study which could be due to attenuated responsiveness to malaria drug treatment on these species. The increase in frequency of P. ovale spp in Kenya could threaten malaria control effort in Kenya and pose increased risk of malaria to travelers.

Funding

AFHSB and its GEIS Section
A Preoperative Estimate of Central Venous Pressure Is Associated with Early Fontan Failure
Authors: Quail Michael A. , Chan Ignatius , Sarna Shiv , Hughes Marina , Muthurangu Vivek
Published: January 2020

Objective

Early Fontan Failure (EFF) is a serious complication following total cavopulmonary connection (TCPC), characterised by high central venous pressure (CVP), low cardiac output and resistance to medical therapy. This study aimed to estimate post-operative CVP in TCPC patients (CVPTCPC) using data routinely collected during pre-operative assessment. We sought to determine if this metric correlated with measured post-operative CVP and if it was associated with EFF.

Methods

In this retrospective study, CVPTCPC was estimated in 131 patients undergoing pre-TCPC assessment by cardiac magnetic resonance imaging and CVP measurement under general anaesthesia. Post-operative CVP during the first 24hours in ICU was collected from electronic patient records in a subset of patients. EFF was defined as death, transplantation, TCPC takedown or emergency fenestration within the first 30days.

Results

Estimated CVPTCPC correlated significantly with CVPICU (r=0.26, p=0.03), particularly in patients without a fenestration (r=0.45, p=0.01). CVPTCPC was significantly associated with EFF (Odds Ratio [OR] 1.12 (1.02-1.24), p=0.02). A threshold of CVPTCPC ≥33mmHg was found to have the highest specificity (90%) and sensitivity (67%) for identifying EFF (area under receiver operating curve, AUC = 0.79), OR 18.8 (3.1-114), p=0.001. This association was stronger in patients with single SVCs.

Conclusions

Estimated CVPTCPC is an easily calculated metric combining pre-operative pressure and flow data. Higher CVPTCPC is associated with an increased risk of EFF and is correlated with directly measured post-TCPC pressure. Identification of patients at risk of EFF has the potential to guide risk mitigation strategies.
Brucellasuppress innate immunity by down-regulating STING expression in macrophages
Authors: Khan Mike , Harms Jerome S. , Liu Yiping , Eickhoff Jens , Tan Jin Wen , Hu Tony , Cai Fengwei , Guimaraes Erika , Oliveira Sergio C. , Dahl Richard , Gutman Delia , Barber Glen , Splitter Gary A. , Smith Judith A.
Published: January 2020

Brucellosis, caused byBrucellabacteria species, remains the most prevalent zoonotic disease worldwide.Brucellaestablish chronic infections within host macrophages despite triggering cytosolic innate immune sensors, including Stimulator of Interferon Genes (STING), which potentially limit infection. In this study, STING was required for control of chronicBrucellainfectionin vivo. However, early during infection,Brucelladown-regulated STING mRNA and protein. Down-regulation occurred post-transcriptionally, required live bacteria, theBrucellatype IV secretion system, and was independent of host IRE1-RNase activity. Rather,Brucellainduced a STING-targeting microRNA, miR-24-2. Furthermore, STING downregulation was inhibited by miR-24 anti-miRs and inmirn23alocus-deficient macrophages. Failure to suppress STING expression inmirn23a−/−macrophages correlated with diminishedBrucellareplication, and was rescued by exogenous miR-24. Anti-miR-24 potently suppressed replication in wild type, but much less in STING−/−macrophages, suggesting most of the impact of miR-24 induction on replication occurred via STING suppression. In summary,Brucellasabotages innate immunity by miR-24-dependent suppression of STING expression; post-STING activation “damage control” via targeted STING destruction may enable establishment of chronic infection.

Author summary

Cytosolic pattern recognition receptors, such as the nucleotide-activated STING molecule, play a critical role in the innate immune system by detecting the presence of intracellular invaders.Brucellabacterial species establish chronic infections in macrophages despite initially activating STING. STING does participate in the control ofBrucellainfection, as mice or cells lacking STING show a higher burden ofBrucellainfection. However, we have found that early following infection,Brucellaupregulates a microRNA, miR-24, that targets the STING messenger RNA, resulting in lower STING levels. Dead bacteria or bacteria lacking a functional type IV secretion system were defective at upregulating miR-24 and STING suppression, suggesting an active bacteria-driven process. Failure to upregulate miR-24 and suppress STING greatly compromised the capacity forBrucellato replicate inside macrophages. Thus, althoughBrucellainitially activate STING during infection, the ensuing STING downregulation serves as a “damage control” mechanism, enabling intracellular infection. Viruses have long been known to target immune sensors such as STING. Our results indicate that intracellular bacterial pathogens also directly target innate immune receptors to enhance their infectious success.
Identification of human CD4+T cell populations with distinct antitumor activity
Authors: Nelson Michelle H. , Knochelmann Hannah M. , Bailey Stefanie R. , Huff Logan W. , Bowers Jacob S. , Majchrzak Kinga , Wyatt Megan M. , Rubinstein Mark P. , Mehrotra Shikhar , Nishimura Michael I. , Armeson Kent E. , Giresi Paul G. , Zilliox Michael J. , Broxmeyer Hal E. , Paulos Chrystal M.
Published: January 2020

How naturally arising human CD4+T helper subsets impact tumor immunity is unknown. We reported that human CD4+CD26highT cells elicit potent immunity against solid tumor malignancies. As CD26highT cells secrete type-17 cytokines and have been categorized as Th17 cells, we posited these helper populations would possess similar molecular properties. Herein, we reveal that CD26highT cells are epigenetically and transcriptionally distinct from Th17 cells. Of clinical significance, CD26highT cells engineered with a chimeric antigen receptor (CAR) ablated large human tumors to a greater extent than enriched Th17, Th1, or Th2 cells. Moreover, CD26highT cells mediated curative responses in mice, even when redirected with a suboptimal CAR and without the aid of CD8+CAR T cells. CD26highT cells co-secreted effector cytokines at heightened levels and robustly persisted. Collectively, our work reveals the potential of human CD4+T cell populations to improve durability of solid tumor therapies.
Acute Stress Desensitizes Hypothalamic CRH Neurons to Norepinephrine and Physiological Stress
Authors: Jiang Zhiying , Chen Chun , Weiss Grant L. , Fu Xin , Fisher Marc O. , Begley John C. , Stevens Carly R. , Harrison Laura M. , Tasker Jeffrey G.
Published: January 2020

Noradrenergic afferents to corticotropin releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN) provide a major excitatory drive to the hypothalamic-pituitary-adrenal (HPA) axis via α1 adrenoreceptor activation. The ascending noradrenergic afferents are recruited preferentially by physiological, rather than psychological, stress modalities.

Glucocorticoids secreted in response to HPA activation feed back onto the hypothalamus to negatively regulate the HPA axis, providing a critical autoregulatory constraint that prevents glucocorticoid overexposure. Whether differential negative feedback mechanisms target stress modality-specific HPA activation is not known. Here, we reveal a desensitization of the α1 adrenoreceptor activation of the HPA axis following acute stress that is mediated by rapid glucocorticoid regulation of adrenoreceptor trafficking. Prior stress desensitized the HPA axis to subsequent physiological, but not psychological, stress. Our findings demonstrate rapid glucocorticoid suppression of adrenoreceptor signaling in CRH neurons that is specific to physiological stress activation, and reveal, therefore, a rapid, modality-selective glucocorticoid feedback mechanism.
The rebound response plays a role in the motion mechanisms and perception
Authors: Cohen-Duwek Hadar , Spitzer Hedva
Published: January 2020

abstract

Motion estimation is an essential ability for sighted animals to survive in their natural environment. Many anatomical and electrophysiological studies on low visual levels have been based on the classic pioneering HRC (Hassenstein & Reichaedt Correlator) computational model. The accumulated experimental findings, which have given rise to a debate in the current computational models regarding the interaction between the On and Off pathways. The previous algorithms were challenged to correctly predict physiological experiment results and the two types of motion: a) Phi motion, also termed apparent motion. b) Reverse-phi motion that is perceived when the image contrast flips during the rapid succession. We have developed a computational model supported by simulations, which for the first time leads to correct predictions of the behavioral motions (phi and reverse-phi), while considering separated On and Off pathways and is also in agreement with the relevant electrophysiological findings. This has been achieved through the well-known neuronal response: the rebound response or “Off response”. We suggest that the rebound response, which has not been taken into account in the previous models, is a key player in the motion mechanism, and its existence requires separation between the On and the Off pathways for correct motion interpretation. We furthermore suggest that the criterial reverse-phi effect is only an epiphenomenon of the rebound response for the visual system. The theoretical predictions are confirmed by a psychophysical experiment on human subjects. Our findings shed new light on the comprehensive role of the rebound response as a parsimonious spatiotemporal detector for motion and additional memory tasks, such as for stabilization and navigation.
Heritability in friendship networks
Authors: Neugart Michael , Yildirim Selen
Published: January 2020

Friendship networks account for a large part of an individual’s economic success or failure in life. Using data from the German TwinLife study, we explore, within a classical twin design, to which extent friendship networks are related to genes. We find a substantial heritability component in twins’ network sizes and network homophily, but not in twins’ network closeness. Addressing indirect ways in which genes could influence network characteristics, we do not find evidence that shared hobbies affects networks.
Frequency switching between oscillatory homeostats and the regulation of p53
Authors: Ruoff Peter , Nishiyama Nobuaki
Published: January 2020

Homeostasis is an essential concept to understand the stability of organisms and their adaptive behaviors when coping with external and internal assaults. Many hormones that take part in homeostatic control come in antagonistic pairs, such as glucagon and insulin reflecting the inflow and outflow compensatory mechanisms to control a certain internal variable, such as blood sugar levels. By including negative feedback loops homeostatic controllers can exhibit oscillations with characteristic frequencies. In this paper we demonstrate the associated frequency changes in homeostatic systems when individual controllers in a set of interlocked feedback loops gain control in response to environmental changes. Taking p53 as an example, we show how the Per2, ATM and Mdm2 feedback loops -interlocked with p53-gain individual control in dependence to DNA damage and how each of these controllers provide certain functionalities in their regulation of p53. In unstressed cells, the circadian regulator Per2 ensures a basic p53 level to allow its rapid up-regulation in case of DNA damage. When DNA damage occurs the ATM controller increases the level of p53 and defends it towards uncontrolled degradation, which despite DNA damage, would drive p53 to lower values and p53 dysfunction. Mdm2 on its side keeps p53 at a maximum level to avoid premature apoptosis. However, with on-going DNA damage the Mdm2 set-point is increased by HSP90 and other p53 stabilizers leading finally to apoptosis. An essential aspect in p53 regulation at occurring cell stress is the coordinated inhibition of ubiquitin-independent and ubiquitin-dependent degradation reactions and the increasing stabilizing mechanisms of p53. Whether oscillations serve a function or are merely a by-product of the controllers are discussed in view of the finding that homeostatic control of p53, as indicated above, does in principle not require oscillatory homeostats.
Chaperonin Abundance Boosts Bacterial Fitness
Authors: Kumar C. M. Santosh , Chugh Kritika , Dutta Anirban , Mahamkali Vishnuvardhan , Bose Tungadri , Mande Sharmila S. , Mande Shekhar C. , Lund Peter A.
Published: January 2020

The ability of chaperonins to buffer mutations that affect protein folding pathways suggests that their abundance should be evolutionarily advantageous. Here, we investigate the effect of chaperonin overproduction on cellular fitness inEscherichia coli. We demonstrate that chaperonin abundance confers (a) an ability to tolerate higher temperatures, (b) improved cellular fitness and (c) enhanced folding of metabolic enzymes, which is expected to lead to enhanced energy harvesting potential.
Linking the association between circRNAs and Alzheimer’s disease progression by multi-tissue circular RNA characterization
Authors: Lo IJu , Hill Jamie , Vilhjálmsson Bjarni J. , Kjems Jørgen
Published: January 2020

Alzheimer’s Disease (AD) has devastating consequences for patients during its slow, progressive course. It is important to understand the pathology of AD onset. Recently, circular RNAs (circRNAs) have been found to participate in many human diseases including cancers and neurodegenerative conditions. In this study, we mined the published dataset on the AMP-AD Knowledge Portal from the Mount Sinai Brain Bank (MSBB) to describe the circRNA profiles at different AD stage in brain samples from four AD patients brain regions, anterior prefrontal cortex, superior temporal lobe, parahippocampal gyrus, and inferior frontal gyrus. We found in total 147 circRNAs to be differentially expressed (DE) during AD progression in the four regions. We also characterized the mRNA-circRNA co-expression network and annotated the potential function of circRNAs based on the co-expressed modules. Based on our results, we propose that parahippocampal gyrus is the most circRNA-regulated region during the AD progression. The strongest negatively AD stage-correlated module in parahippocampal gyrus were enriched in cognitive disability and pathological-associated pathways such as synapse organization and regulation of membrane potential. Finally, the regression model based on the expression pattern of DE circRNAs in the module could help to distinguish the disease severity of patients, further supported the importance of circRNAs in AD pathology. In conclusion, our finding indicates that circRNAs in parahippocampal gyrus are possible regulators of AD progression and potentially be a therapeutic target or of AD.
Teratogenic Drug Topiramate Upregulates TGFβ1 and SOX9 Expression in Primary Palatal Mesenchyme Cells
Authors: Rafi Syed K. , Goering Jeremy P. , Olm-Shipman Adam J. , Hipp Lauren A. , Ernst Nicholas J. , Wilson Nathan R. , Hall Everett G. , Gunewardena Sumedha , Saadi Irfan
Published: January 2020

Topiramate is a commonly prescribed anti-epileptic drug with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. We used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known OFC genes. However, among known OFC genes, only TGFβ1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFβ1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFβ1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFβ1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression may underlie the teratogenic effects of topiramate.
Chromosome-level assembly of theCaenorhabditis remaneigenome reveals conserved patterns of nematode genome organization
Authors: Teterina Anastasia A. , Willis John H. , Phillips Patrick C.
Published: January 2020

The nematodeCaenorhabditis elegansis one of the key model systems in biology, including possessing the first fully assembled animal genome. WhereasC. elegansis a self-reproducing hermaphrodite with fairly limited within-population variation, its relativeC. remaneiis an outcrossing species with much more extensive genetic variation, making it an ideal parallel model system for evolutionary genetic investigations. Here, we greatly improve on previous assemblies by generating a chromosome-level assembly of the entireC. remaneigenome (124.8 Mb of total size) using long-read sequencing and chromatin conformation capture data. Like other fully assembled genomes in the genus, we find that theC. remaneigenome displays a high degree of synteny withC. elegansdespite multiple within-chromosome rearrangements. Both genomes have high gene density in central regions of chromosomes relative to chromosome ends and the opposite pattern for the accumulation of repetitive elements.C. elegansandC. remaneialso show similar patterns of inter-chromosome interactions, with the central regions of chromosomes appearing to interact with one another more than the distal ends. The newC. remaneigenome presented here greatly augments the use of theCaenorhabditisas a platform for comparative genomics and serves as a basis for molecular population genetics within this highly diverse species.
Material category of visual objects computed from specular image structure
Authors: Schmid Alexandra C. , Barla Pascal , Doerschner Katja
Published: January 2020

Recognising materials and their properties from visual information is vital for successful interactions with our environment, from avoiding slippery floors to handling fragile objects. Yet there is no simple mapping of retinal image intensities to the physical properties that define materials. While studies have investigated how material properties like surface gloss are perceived from regularities in image structure, such as the size, sharpness, contrast, and position of bright patches caused by specular reflections, little is known how this translates to the recognition of different material classes like plastic, pearl, satin, or steel, and the underlying mechanisms involved. We investigated this by collecting human psychophysical judgments about complex glossy objects rendered in natural illumination fields. We found that variations in specular image structure – produced either by different reflectance properties or direct manipulation of image features – caused categorical shifts in material appearance, suggesting that specular reflections provide diagnostic information about a wide range of material classes, including many that should be defined by more complex scattering functions. Moreover, differences in material category were predicted by, but also appeared to mediate, cues for surface gloss, providing evidence against a traditional feedforward view of neural processing that assumes combinations of mid-level properties mediate our holistic, categorical impressions. Instead, our results suggest that the image structure that triggers our perception of surface gloss plays a direct role in visual categorisation and, importantly, that the perception and neural processing of stimulus properties should not be studied in isolation but rather in the context of recognition.
Cell shape, and not 2D migration, predicts ECM-driven 3D cell invasion in breast cancer
Authors: Baskaran Janani P. , Weldy Anna , Guarin Justinne , Munoz Gabrielle , Kotlik Michael , Subbiah Nandita , Wishart Andrew , Peng Yifan , Miller Miles A. , Cowen Lenore , Oudin Madeleine J.
Published: January 2020

Metastasis, the leading cause of death in cancer patients, requires the invasion of tumor cells through the stroma in response to migratory cues, such as those provided by the extracellular matrix (ECM). Recent advances in proteomics have led to the identification of hundreds of ECM proteins which are more abundant in tumors relative to healthy tissue. Our goal was to develop a pipeline to easily predict which of these ECM proteins is more likely to have an effect on cancer invasion and metastasis. We evaluated the effect of 4 ECM proteins upregulated in breast tumor tissue in multiple human breast cancer cell lines in 3 assays. We found there was no linear relationship between the 11 cell shape parameters we quantified when cells adhere to ECM proteins and 2D cell migration speed, persistence or 3D invasion. We then used classifiers and partial-least squares regression analysis to identify which metrics best predicted ECM-driven 2D migration and 3D invasion responses. ECM-driven 2D cell migration speed or persistence did not correlate with or predict 3D invasion in response to that same cue. However, cell adhesion, and in particular cell elongation and irregularity accurately predicted the magnitude of ECM-driven 2D migration and 3D invasion in all cell lines. Testing predictions revealed that our models are good at predicting the effect of novel ECM proteins within a given cell line, but that ECM responses are cell-line specific. Overall, our studies identify the cell morphological features that determine 3D invasion responses to individual ECM proteins. This platform will help provide insight into the functional role of ECM proteins abundant tumor tissue and help prioritize strategies for targeting tumor-ECM interactions to treat metastasis.

Funding

This work was supported by the National Institutes of Health [R00-CA207866-04 to M.J.O.]; Tufts University [Start-up funds from the School of Engineering to M.J.O.] and funds from NSF REU to A.W.

Conflict-of-interest: None.

Insight Box

Metastasis, the dissemination of tumor cells, is driven by the interaction of invading tumor cells with their local environment, in particular with the ECM, which provides structure and support to our tissues. This study presents an integrated approach to predict the effect of individual ECM proteins on 3D invasion and metastasis based on simple adhesion assays which quantify cell shape. Machine learning classification and partial-least squares regression models reveal that ECM-driven 2D cell migration metrics are not predictive of 3D invasion, and that cell shape of cells adhered to ECM can predict that protein’s effect on 3D invasion. These data provide a pipeline for predicting the effect of ECM proteins on breast cancer cell invasion and metastasis.
Multilevel integrative transcriptome analyses in humans and humanized mice define in vivo human lncRNA metabolic regulators
Authors: Ruan Xiangbo , Li Ping , Ma Yonghe , Jiang Cheng-fei , Chen Yi , Shi Yu , Gupta Nikhil , Seifuddin Fayaz , Pirooznia Mehdi , Suemizu Hiroshi , Ohnishi Yasuyuki , Yoneda Nao , Nishiwaki Megumi , Cao Haiming
Published: January 2020

A growing number of long non-coding RNAs (lncRNAs) have emerged as vital metabolic regulators in research animals suggesting that lncRNAs could also play an important role in human metabolism. However, most human lncRNAs are non-conserved, vastly limiting our ability to identify human lncRNA metabolic regulators (hLMRs). As the sequence-function relation of lncRNAs has yet to be established, the identification of lncRNA metabolic regulators in animals often relies on their regulations by experimental metabolic conditions. But it is very challenging to apply this strategy to human lncRNAs because well-controlled human data are much limited in scope and often confounded by genetic heterogeneity. In this study, we establish an efficient pipeline to identify putative hLMRs that are metabolically sensitive, disease-relevant, and population applicable. We first progressively processed human transcriptome data to select human liver lncRNAs that exhibit highly dynamic expression in the general population, show differential expression in a metabolic disease population, and response to dietary intervention in a small disease cohort. We then experimentally demonstrated the responsiveness of selected hepatic lncRNAs to defined metabolic milieus in a liver-specific humanized mouse model. Furthermore, by extracting a concise list of protein-coding genes that are persistently correlated with lncRNAs in general and metabolic disease populations, we predicted the specific function for each hLMR. Using gain- and loss-of-function approaches in humanized mice as well as ectopic expression in conventional mice, we were able to validate the regulatory role of one non-conserved hLMR in cholesterol metabolism. Mechanistically, this hLMR binds to an RNA-binding protein, PTBP1, to modulate the transcription of cholesterol synthesis genes. In summary, our study provides a pipeline to overcome the variabilities intrinsic to human data to enable the efficient identification and functional definition of hLMRs. The combination of this bioinformatic framework and humanized murine model will enable broader systematic investigation of the physiological role of disease-relevant human lncRNAs in metabolic homeostasis.
Recurrent pre-leukemic deletions in myeloid malignancies are the result of DNA double-strand breaks followed by microhomology-mediated end joining
Authors: Feldman Tzah , Bercovich Akhiad , Moskovitz Yoni , Chapal-Ilani Noa , Mitchell Amanda , Medeiros Jessie JF , Kaushansky Nathali , Biezuner Tamir , Minden Mark D , Gupta Vikas , Tanay Amos , Shlush Liran I
Published: January 2020

The mechanisms underlying myeloid malignancies deletions are not well understood, nor is it clear why specific genomic hotspots are predisposed to particular deletions. In the current study we inspected the genomic regions around recurrent deletions in myeloid malignancies, and identified microhomology-mediated end-joining (MMEJ) signatures in recurrent deletions inCALR, ASXL1andSRSF2 loci. Since MMEJ deletions are the result of DNA double-strand breaks (DSBs), we introduced CRISPR Cas9 DSBs into exon 12 of ASXL1, successfully generating recurrentASXL1deletion in human hematopoietic stem and progenitor cells (HSPCs). A systematic search of COSMIC dataset for MMEJ deletions in all cancers revealed that recurrent deletions enrich myeloid malignancies. Despite this myeloid predominance, we provide evidence that MMEJ deletions occur in multipotent HSCs. An analysis of DNA repair pathway gene expression in single human adult bone marrow HSPCs could not identify a subpopulation of multipotent HSPCs with increased MMEJ expression, however exposed differences between myeloid and lymphoid biased progenitors. Our data indicate an association between MMEJ-repaired DSBs and recurrent MMEJ deletions in human HSCs and in myeloid leukemia. A better understanding of the source of these DSBs and the regulation of the HSC MMEJ repair pathway might aid with preventing recurrent deletions in human pre-leukemia.
Histone modification dynamics as revealed by a multicolor immunofluorescence-based single-cell analysis
Authors: Hayashi-Takanaka Yoko , Kina Yuto , Nakamura Fumiaki , Becking Leontine E. , Nakao Yoichi , Nagase Takahiro , Nozaki Naohito , Kimura Hiroshi
Published: January 2020

Post-translational modifications on histones can be stable epigenetic marks and transient signals that can occur in response to internal and external stimuli. Levels of histone modifications fluctuate during the cell cycle and vary among different cell types. Here we describe a simple system to monitor the levels of multiple histone modifications in single cells by multicolor immunofluorescence using directly labeled modification-specific antibodies. We first analyzed histone H3 and H4 modifications during the cell cycle. Levels of active marks, such as acetylation and H3K4 methylation, were increased during the S phase, in association with chromatin duplication. By contrast, levels of some repressive modifications gradually increased during the G2 and the next G1 phases. We applied this method to validate the target modifications of various histone demethylases in cells using a transient overexpression system. We also screened chemical compounds in marine organism extracts that affect histone modifications and identified psammaplin A, which was previously reported to inhibit histone deacetylases. Thus, the method presented here is a powerful and convenient tool for analyzing the changes in histone modifications.
Single cell atlas of trisomy 21 cerebral cortex
Authors: Zhang Jingxuan , Wang Shiyou , Xu Zaoxu , Ding Xiangning , Li Chen , Zhang Yonghong , Chen Yin , Zhong Jixing , Liang Langchao , Chai Chaochao , Wang Xiaoling , Xiang Rong , Zhu Jiacheng , Lin Xiumei , Ding Peiwen , Zhang Qiang , Wang Mingyue , Feng Qikai , Zhang Zhijun , Guo Guangling , Xue Shen , Jin Lin , He Zhikai , Yan Li , Xiao Bing , Zhang Changjun , Xu Yan , Li Wei , Zhang Yichi , Wu Weiying , Jiang Sanjie , Xia Jun , Gao Ya , Wang Lei , Dong Shichen , Liu Si , Zhu Shida , Chen Fang , Chen Dongsheng , Xu Xun
Published: January 2020

Down syndrome (DS) is one of the most common human birth defects caused by trisomy 21 (T21), leading to a variety of cognitive impairments. The cellular composition of human brain has been explored using single cell RNA sequencing in both physiological and pathological conditions. However, the cellular heterogeneity of human brain with chromosome aneuploidy is largely unknown. Here, we profiled the transcriptome of 36046 cells in cerebral cortex of T21 human fetus, covering frontal lobe, parietal lobe, occipital lobe and temporal lobe. Intriguingly, we detected several genes positively associated with neurons maturation was dysregulated in T21 frontal cortex (HIC2, POU2F2, ZGLP1andFOXK1). To share, explore and utilized the data resources of T21 cerebral cortex, we developed a comprehensive platform named T21atlas, composing of two functional modules (T21cluster and T21talk). Overall, our study provides, as far as we know, the first single cell atlas for T21 cerebral cortex, which could promote our understanding of the molecular mechanism of DS at an unprecedented resolution and could potentially facilitate the development of novel clinical therapeutics against T21.
An antigenic diversification threshold for falciparum malaria transmission at high endemicity
Authors: He Qixin , Pascual Mercedes
Published: January 2020

In malaria and several other important infectious diseases, high prevalence occurs concomitantly with incomplete immunity. This apparent paradox poses major challenges to malaria elimination in highly endemic regions, where asymptomaticPlasmodium falciparuminfections are present across all age classes creating a large reservoir that maintains transmission. This reservoir is in turn enabled by extreme antigenic diversity of the parasite and turnover of new variants. We present here the concept of a threshold in local pathogen diversification that defines a sharp transition in transmission intensity below which new antigen-encoding genes generated by either recombination or migration cannot establish. Transmission still occurs below this threshold, but diversity of these genes can neither accumulate nor recover from interventions that further reduce it. An analytical expectation for this threshold is derived and compared to numerical results from a stochastic individual-based model of malaria transmission that incorporates the major antigen-encoding multigene family known asvar. This threshold corresponds to an “innovation” number we callRdiv; it is different from, and complementary to, the one defined by the classic basic reproductive number of infectious diseases,R0, which does not easily apply under large and dynamic strain diversity. This new threshold concept can be exploited for effective malaria control and applied more broadly to other pathogens with large multilocus antigenic diversity.

Author summary

The vast diversity of the falciparum malaria parasite as seen by the immune system of hosts in high transmission regions, underlies both high prevalence of asymptomatic infections and partial protection to re-infection despite previous exposure. This large antigenic diversity of the parasite challenges control and elimination efforts. We propose a threshold quantity for antigenic innovation, we callRdiv, measuring the potential of transmission to accumulate new antigenic variants over time. WhenRdivis pushed below one by reduced transmission intensity, new genes encoding this variation can no longer accumulate, resulting in a lower number of strains and facilitating further intervention. This innovation number can be applied to other infectious diseases with fast turnover of antigens, where large standing diversity similarly opposes successful intervention.