bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient and Caregiver Assessment of the Benefits From the Clinical Use of Amyloid PET Imaging
Authors: Mustafa Rafid , Brosch Jared R. , Rabinovici Gil D. , Dickerson Bradford C. , Carrillo Maria C. , Glazier Bradley S. , Gao Sujuan , Tierney Martha , Fargo Keith N. , Austrom Mary G. , De Santi Susan , Clark David G. , Apostolova Liana G. 
Published: November 2017

Introduction:
Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET).

Methods:
A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch.

Results:
We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (∼10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65 y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions.

Discussion:
Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning.
That’s Inappropriate! Social Norms in an Older Population-based Cohort
Authors: Ganguli Mary , Sun Zhaowen , McDade Eric , Snitz Beth , Hughes Tiffany , Jacobsen Erin , Chang Chung-Chou H. 
Published: November 2017

Background:
Social cognition is not routinely assessed in older adults. We report population-based normative data on the Social Norms Questionnaire (SNQ22) which asks individuals about the appropriateness of specific behaviors in hypothetical scenarios, errors being related either to breaking with norms or to over-adhering to perceived norms. Total SNQ scores represent the number of correct responses while subscale scores are error totals.

Methods:
We administered the SNQ22 to 744 adults aged 65+ within a population-based study, and examined the distribution of scores by demographics, other cognitive measures, and Clinical Dementia Rating (CDR).

Results:
Most participants performed well with few errors. Women and young-old individuals performed significantly better than men and older individuals on total score and over-adherence; women had fewer break-norms errors than men. No race or education effects were observed. Worse (higher) total scores and (lower) over-adherence errors were inversely associated with literacy, CDR, Mini-Mental State Examination, attention, memory, language, executive, and visuospatial domains. Break-norms errors were rare and not associated with any of the above.

Conclusions:
In population-based normative data on the SNQ22. age and sex influenced total score and over-adherence errors, which showed the expected associations with CDR and other cognitive domains. Social norms screening may be useful in the cognitive assessment of older adults.
Neuroimaging diagnostic and monitoring approaches in ophthalmology
Authors: Chwalisz Bart K. , Bouffard Marc A. , Prasad Sashank , Cestari Dean M. 
Published: November 2017

Purpose of review
We review new applications of optical coherence tomography (OCT) technology in neuro-ophthalmology. We also describe new technologies for visualizing the extracranial vessels in the diagnosis of giant cell arteritis (GCA).

Recent findings
Newer OCT modalities are expanding the evaluation of the optic disc, and are being applied to a number of neurologic conditions such as demyelinating and neurodegenerative disease. Swept-source OCT and enhanced-depth imaging OCT are refining the fine-grained analysis of the optic nerve head in the diagnosis of papilledema and optic nerve drusen. OCT-angiography is opening up new avenues to the study of the vasculature of the optic nerve head and its disorders, including ischemic optic neuropathy. Newer technologies in the diagnosis of GCA include vascular ultrasound, magnetic resonance imaging (MRI) of the extracranial vasculature and PET imaging of the large vessels.

Summary
OCT and several of its derivations are advancing diagnosis, and in some cases prognostication, in a variety of inflammatory, ischemic and compressive optic neuropathies. These technologies hold potential in the laboratory as well, yielding insights into the mechanisms of a variety of neurological conditions. In addition, further developments in MRI and ultrasonography techniques are shaping the approach to the diagnosis of GCA.
Re-conceptualizing the origins of life
Authors: Walker Sara I. , Packard N. , Cody G. D. 
Published: November 2017

Over the last several hundred years of scientific progress, we have arrived at a deep understanding of the non-living world. We have not yet achieved an analogous, deep understanding of the living world. The origins of life is our best chance at discovering scientific laws governing life, because it marks the point of departure from the predictable physical and chemical world to the novel, history-dependent living world. This theme issue aims to explore ways to build a deeper understanding of the nature of biology, by modelling the origins of life on a sufficiently abstract level, starting from prebiotic conditions on Earth and possibly on other planets and bridging quantitative frameworks approaching universal aspects of life. The aim of the editors is to stimulate new directions for solving the origins of life. The present introduction represents the point of view of the editors on some of the most promising future directions.
This article is part of the themed issue ‘Reconceptualizing the origins of life’.
Universal biology and the statistical mechanics of early life
Authors: Goldenfeld Nigel , Biancalani Tommaso , Jafarpour Farshid 
Published: November 2017

All known life on the Earth exhibits at least two non-trivial common features: the canonical genetic code and biological homochirality, both of which emerged prior to the Last Universal Common Ancestor state. This article describes recent efforts to provide a narrative of this epoch using tools from statistical mechanics. During the emergence of self-replicating life far from equilibrium in a period of chemical evolution, minimal models of autocatalysis show that homochirality would have necessarily co-evolved along with the efficiency of early-life self-replicators. Dynamical system models of the evolution of the genetic code must explain its universality and its highly refined error-minimization properties. These have both been accounted for in a scenario where life arose from a collective, networked phase where there was no notion of species and perhaps even individuality itself. We show how this phase ultimately terminated during an event sometimes known as the Darwinian transition, leading to the present epoch of tree-like vertical descent of organismal lineages. These examples illustrate concrete examples of universal biology: the quest for a fundamental understanding of the basic properties of living systems, independent of precise instantiation in chemistry or other media.
This article is part of the themed issue ‘Reconceptualizing the origins of life’.
Conceptualizing the origin of life in terms of evolution
Authors: Takeuchi N. , Hogeweg P. , Kaneko K. 
Published: November 2017

In this opinion piece, we discuss how to place evolution in the context of origin-of-life research. Our discussion starts with a popular definition: ‘life is a self-sustained chemical system capable of undergoing Darwinian evolution’. According to this definition, the origin of life is the same as the origin of evolution: evolution is the ‘end’ of the origin of life. This perspective, however, has a limitation, in that the ability of evolution in and of itself is insufficient to explain the origin of life as we know it, as indicated by Spiegelman’s and Lincoln and Joyce’s experiments. This limitation provokes a crucial question: What conditions are required for replicating systems to evolve into life? From this perspective, the origin of life includes the emergence of life through evolution: evolution is a ‘means’ of the origin of life. After reviewing Eigen’s pioneering work on this question, we mention our ongoing work suggesting that a key condition might be conflicting multi-level evolution. Taken together, there are thus two questions regarding the origin of life: how evolution gets started, and how evolution produces life. Evolution is, therefore, at the centre of the origin of life, where the two lines of enquiry must meet.This article is part of the themed issue ‘Reconceptualizing the origins of life’.
Bulk measurements of messy chemistries are needed for a theory of the origins of life
Authors: Guttenberg Nicholas , Virgo Nathaniel , Chandru Kuhan , Scharf Caleb , Mamajanov Irena 
Published: November 2017

A feature of many of the chemical systems plausibly involved in the origins of terrestrial life is that they are complex and messy—producing a wide range of compounds via a wide range of mechanisms. However, the fundamental behaviour of such systems is currently not well understood; we do not have the tools to make statistical predictions about such complex chemical networks. This is, in part, due to a lack of quantitative data from which such a theory could be built; specifically, functional measurements of messy chemical systems. Here, we propose that the pantheon of experimental approaches to the origins of life should be expanded to include the study of ‘functional measurements’—the direct study of bulk properties of chemical systems and their interactions with other compounds, the formation of structures and other behaviours, even in cases where the precise composition and mechanisms are unknown.
This article is part of the themed issue ‘Reconceptualizing the origins of life’.
Chance, necessity and the origins of life: a physical sciences perspective
Authors: Hazen Robert M. 
Published: November 2017

Earth's 4.5-billion-year history has witnessed a complex sequence of high-probability chemical and physical processes, as well as ‘frozen accidents’. Most models of life's origins similarly invoke a sequence of chemical reactions and molecular self-assemblies in which both necessity and chance play important roles. Recent research adds two important insights into this discussion. First, in the context of chemical reactions, chance versus necessity is an inherently false dichotomy—a range of probabilities exists for many natural events. Second, given the combinatorial richness of early Earth's chemical and physical environments, events in molecular evolution that are unlikely at limited laboratory scales of space and time may, nevertheless, be inevitable on an Earth-like planet at time scales of a billion years.This article is part of the themed issue ‘Reconceptualizing the origins of life’.
An intermediate level of abstraction for computational systems chemistry
Authors: Andersen Jakob L. , Flamm Christoph , Merkle Daniel , Stadler Peter F. 
Published: November 2017

Computational techniques are required for narrowing down the vast space of possibilities to plausible prebiotic scenarios, because precise information on the molecular composition, the dominant reaction chemistry and the conditions for that era are scarce. The exploration of large chemical reaction networks is a central aspect in this endeavour. While quantum chemical methods can accurately predict the structures and reactivities of small molecules, they are not efficient enough to cope with large-scale reaction systems. The formalization of chemical reactions as graph grammars provides a generative system, well grounded in category theory, at the right level of abstraction for the analysis of large and complex reaction networks. An extension of the basic formalism into the realm of integer hyperflows allows for the identification of complex reaction patterns, such as autocatalysis, in large reaction networks using optimization techniques.
This article is part of the themed issue ‘Reconceptualizing the origins of life’.
Expanding the informational chemistries of life: peptide/RNA networks
Authors: Taran Olga , Chen Chenrui , Omosun Tolulope O. , Hsieh Ming-Chien , Rha Allisandra , Goodwin Jay T. , Mehta Anil K. , Grover Martha A. , Lynn David G. 
Published: November 2017

The RNA world hypothesis simplifies the complex biopolymer networks underlining the informational and metabolic needs of living systems to a single biopolymer scaffold. This simplification requires abiotic reaction cascades for the construction of RNA, and this chemistry remains the subject of active research. Here, we explore a complementary approach involving the design of dynamic peptide networks capable of amplifying encoded chemical information and setting the stage for mutualistic associations with RNA. Peptide conformational networks are known to be capable of evolution in disease states and of co-opting metal ions, aromatic heterocycles and lipids to extend their emergent behaviours. The coexistence and association of dynamic peptide and RNA networks appear to have driven the emergence of higher-order informational systems in biology that are not available to either scaffold independently, and such mutualistic interdependence poses critical questions regarding the search for life across our Solar System and beyond.This article is part of the themed issue ‘Reconceptualizing the origins of life’.
Viral Complexity: Amino acid co-evolution in viral genomes as a possible metric
Authors: Sruthi C. K. , Prakash Meher K. 
Published: November 2017

ABSTRACTViruses are simultaneously simple and complex. Simple because they have barely around ten types of proteins compared to tens of thousands of proteins in bacteria. Complex because amino acid mutation rates are very high, challenging host immune system and drugs. In this work we use the co-evolution of amino acids and the network characteristics that arise out of it to describe the complexity hidden in the multitude of variations in a viral genome. Using large-scale genomic data, the complexity in several viruses was compared. Interestingly, the co-evolutionary relations were primarily intra-protein in avian influenza and inter-protein in HIV-1. The network degree distributions showed two universality classes: a power-law with exponent −1 in HIV-1 and avian-influenza, random co-evolutionary behavior in human flu and dengue, suggesting the co-evolution as one way to statistically classify the complexity in viruses. The observed correlation between the network densities and the strengths on virus Richter scale raises interesting questions on whether it is possible to define the complexity of viruses using their evolutionary networks.
The role of sensorimotor variability and computation in elderly’s falls
Authors: Lin Chin-Hsuan , Faisal A Aldo 
Published: November 2017

ABSTRACTThe relationship between sensorimotor variability and falls in elderly has not been well investigated. We designed and used a motor task having shared biomechanics of walking and obstacle negotiation to quantify sensorimotor variability related to locomotion across age. We also applied sensory psychophysics to pinpoint specific sensory systems associated with sensorimotor variability. We found that sensorimotor variability in foot placement increases continuously with age. We further showed that increased sensory variability, specifically increased proprioceptive variability, the vital cause of more variable foot placement in the elderly. Notably, elderly participants relied more on the vision to judge their own foot’s height compared to the young, suggesting a shift in multisensory integration strategy to compensate for degenerated proprioception. We further modelled the probability of tripping-over based on the relationship between sensorimotor variability and age and found a good correspondence between model prediction and community-based data. We revealed increased sensorimotor variability, modulated by sensation precision, a potentially vital mechanism of raised tripping-over and thus fall events in the elderly. Therefore, our tasks, which quantify sensorimotor variability, can be used for trip-over probability assessment and, with adjustments, potentially applied as a training program to mitigate trip-over risk.
Endothelial Cell-Specific MCPIP Deletion Causes Endothelial Dysfunction and Impairs Post-ischemic Angiogenesis in Vivo
Authors: Niu Jianli , Kapoor Nidhi , Liang Jian , Jin Zhuqing , Becerra Edilu , Kolattukudy Pappachan E. 
Published: November 2017

ABSTRACTVascular endothelial cells (ECs) play an important role in angiogenesis and inflammatory responses. MCPIP (also known as Zc3h12a or Regnase-1), a newly identified suppressor of cytokine signaling, is expressed in endothelial cells. To directly test the role of endothelium-derived MCPIP in cardiovascular pathophysiology, we specifically targeted deletion of the murine MCPIP gene in the endothelium by using the loxP/Cre system. A floxed MCPIP knock in mouse line was crossbred with VEcadherin5-Cre mice to generate offspring with deletion of the MCPIP gene in ECs (ECKO). Ablation of MCPIP in ECs resulted in systemic inflammation, anemia, splenomegaly, increased vessel permeability, muscle wasting, endothelial dysfunction, thrombus formation, impaired blood perfusion, and reduced lifespan in these mice. Serum levels of cytokines, chemokines, and biomarkers of EC dysfunction were significantly elevated in the ECKO mice, suggesting a hypercytokinemia. These mice also were more susceptible to lipopolysaccharide-induced death. When subjected to ischemia, these mice showed defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia and stroke models, as well as in wound healing. This effect was associated with an increased cellular infiltration, cytokine expression, and decreased angiogenic factors. Moreover, MCPIP–deficient ECs displayed decreased vascular sprouting and tube elongation in ex vivo aortic ring assay. MCPIP-knockdown in cultured ECs enhanced NF-κΒ activity and dysregulated synthesis of microRNAs linked with elevated cytokines and biomarkers of EC dysfunction. These data show, for the first time, that constitutive expression of MCPIP in ECs is essential to maintain ECs in a quiescent state by serving as an important negative feedback regulator that keeps the inflammatory signaling suppressed.
A heterochromatin domain forms gradually at a new telomere and is highly dynamic at stable telomeres
Authors: Wang Jinyu , Eisenstatt Jessica R , Audry Julien , Cornelius Kristen , Shaughnessy Matthew , Berkner Kathleen L , Runge Kurt W 
Published: November 2017

AbstractHeterochromatin domains play important roles in chromosome biology, organismal development and aging. In the fission yeastSchizosaccharomyces pombeand metazoans, heterochromatin is marked by histone H3 lysine 9 dimethylation. While factors required for heterochromatin have been identified, the dynamics of heterochromatin formation are poorly understood. Telomeres convert adjacent chromatin into heterochromatin. To form a new heterochromatic region inS. pombe, an inducible DNA double-strand break (DSB) was engineered next to 48 bp of telomere repeats in euchromatin, which caused formation of new telomere and gradual spreading of heterochromatin. However, spreading was highly dynamic even after the telomere had reached its stable length. The system also revealed the presence of repeats located at the boundaries of euchromatin and heterochromatin that are oriented to allow the efficient healing of a euchromatic DSB to cap the chromosome end with a new telomere. Telomere formation inS. pombetherefore reveals novel aspects of heterochromatin dynamics and the presence of failsafe mechanisms to repair subtelomeric breaks, with implications for similar processes in metazoan genomes.
Multi-omics profiling establishes the polypharmacology of FDA Approved CDK4/6 inhibitors and the potential for differential clinical activity
Authors: Hafner Marc , Mills Caitlin E. , Subramanian Kartik , Chen Chen , Chung Mirra , Boswell Sarah A. , Everley Robert A. , Liu Changchang , Walmsley Charlotte S. , Juric Dejan , Sorger Peter K. 
Published: November 2017

SUMMARYThe target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five different phenotypic and biochemical assays to compare approved inhibitors of cyclin-dependent kinases 4/6 – collectively regarded as breakthroughs in the treatment of hormone receptor-positive breast cancer. We find that transcriptional, proteomic and phenotypic changes induced by palbociclib, ribociclib, and abemaciclib differ significantly; abemaciclib in particular has advantageous activities partially overlapping those of alvocidib, an older polyselective CDK inhibitor. In cells and mice, abemaciclib inhibits kinases other than CDK4/6 including CDK2/Cyclin A/E – implicated in resistance to CDK4/6 inhibition – and CDK1/Cyclin B. The multi-faceted experimental and computational approaches described here therefore uncover under-appreciated differences in CDK4/6 inhibitor activities with potential importance in treating human patients.
Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42
Authors: Tseng Yu-Chou , Liva Sophia G. , Dauki Anees M. , Sovic Michael , Henderson Sally E. , Kuo Yi-Chiu , Benedict Jason A. , Kulp Samuel K. , Campbell Moray , Bekaii-Saab Tanios , Phelps Mitchell A. , Chen Ching-Shih , Coss Christopher C. 
Published: November 2017

ABSTRACTPurposeThe common colon-26 mouse (C-26) model of experimental cachexia mimics recent late stage clinical failures of anabolic anti-cachexia therapy, and does not respond to the anabolic selective androgen receptor modulator (SARM) GTx-024. Based on the demonstrated anti-cachectic efficacy of the histone deacetylase inhibitor (HDACi) AR-42 in this model, we hypothesized that combined SARM/AR-42 would provide improved anti-cachectic efficacy.DesignIn the C-26 model, we determined a reduced efficacious dose of AR-42 which was combined with anabolic SARM therapy and evaluated for anti-cachectic efficacy. The effects of treatment and tumor burden on anabolic and catabolic signaling occurring in skeletal muscle were characterized using muscle performance parameters and RNA-seq.ResultsAnabolic anti-cachexia therapy with diverse androgens had no impact on cachectic outcomes in the C-26 model. A reduced dose of the HDACi AR-42 alone provided limited anti-cachectic benefits, but when combined with the SARM GTx-024, significantly improved bodyweight (p<0.0001), hind limb muscle mass (p<0.05), and voluntary grip strength (p<0.0001) versus tumor-bearing controls. Reduced-dose AR-42 treatment suppressed the IL-6/GP130/STAT3 signaling axis without significantly impacting circulating cytokine levels. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42.ConclusionsCachectic signaling in the C-26 model is comprised of catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 treatment mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with a low dose of AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patient populations.