bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Investigation of Implicit HIV and Preexposure Prophylaxis Stigma: Evidence for Ancillary Benefits of Preexposure Prophylaxis Use
Authors: Golub Sarit A. , Lelutiu-Weinberger Corina , Surace Anthony
Published: November 2017

Background:

Preexposure prophylaxis (PrEP) stigma (ie, negative attitudes toward PrEP users) has been widely documented and is considered a significant barrier to implementation. However, few studies have examined PrEP stigma using implicit measures designed to reduce demand characteristics in responding. This study examined implicit PrEP- and HIV-related stigma among gay and bisexual men using geospatial social networking applications (ie, “hookup apps”).

Methods:

Participants were presented with 4 simulated online profiles (pretested for comparability) paired with each of the following characteristics: HIV negative, HIV positive, on PrEP, or substance user. Participants rated the profiles on attractiveness, desirability, trustworthiness, likelihood of condom use, and riskiness of sex.

Results:

There was no evidence of PrEP-related stigma, ie, participants did not rate profiles of PrEP users more negatively than profiles of HIV-negative individuals not disclosing PrEP use. However, profiles of HIV-positive individuals were rated significantly less attractive and desirable than HIV-negative or PrEP profiles. When the sample was split by history of PrEP use, negative ratings of HIV-positive profiles remained only among participants who had never taken PrEP. Participants with any history of PrEP use demonstrated no difference in ratings by HIV status.

Conclusion:

These data provide the first empirical evidence for lower HIV stigma among PrEP users. Individuals who have used PrEP may “see” HIV-positive individuals differently than those without a history of PrEP use. The lack of evidence for PrEP-related stigma is encouraging and suggests that negative stereotypes about PrEP users may not extend to negative implicit judgments about them on social networking sites.
Prenatal microRNA miR-200b Therapy Improves Nitrofen-induced Pulmonary Hypoplasia Associated With Congenital Diaphragmatic Hernia
Authors: Khoshgoo Naghmeh , Kholdebarin Ramin , Pereira-Terra Patricia , Mahood Thomas H. , Falk Landon , Day Chelsea A. , Iwasiow Barbara M. , Zhu Fuqin , Mulhall Drew , Fraser Carly , Correia-Pinto Jorge , Keijzer Richard
Published: November 2017

Objective:

We aimed to evaluate the use of miR-200b as a prenatal transplacental therapy in the nitrofen rat model of abnormal lung development and congenital diaphragmatic hernia (CDH).

Background:

Pulmonary hypoplasia (PH) and pulmonary hypertension determine mortality and morbidity in CDH babies. There is no safe medical prenatal treatment available. We previously discovered that higher miR-200b is associated with better survival in CDH babies. Here, we investigate the role of miR-200b in the nitrofen rat model of PH and CDH and evaluate its use as an in vivo prenatal therapy.

Methods:

We profiled miR-200b expression during nitrofen-induced PH using RT-qPCR and in situ hybridization in the nitrofen rat model of PH and CDH. The effects of nitrofen on downstream miR-200b targets were studied in bronchial lung epithelial cells using a SMAD luciferase assay, Western blotting and Immunohistochemistry. We evaluated miR-200b as a lung growth promoting therapy ex vivo and in vivo using lung explant culture and transplacental prenatal therapy in the nitrofen rat model.

Results:

We show that late lung hypoplasia in CDH is associated with (compensatory) upregulation of miR-200b in less hypoplastic lungs. Increasing miR-200b abundance with mimics early after nitrofen treatment decreases SMAD-driven TGF-β signaling and rescues lung hypoplasia both in vitro and in vivo. Also, prenatal miR-200b therapy decreases the observed incidence of CDH.

Conclusions:

Our data indicate that miR-200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH.
Computerized Cognitive Testing in Primary Care
Authors: Millett Geneva , Naglie Gary , Upshur Ross , Jaakkimainen Liisa , Charles Jocelyn , Tierney Mary C.
Published: November 2017

Computerized cognitive assessment tools may facilitate early identification of dementia in the primary care setting. We investigated primary care physicians’ (PCPs’) views on advantages and disadvantages of computerized testing based on their experience with the Computer Assessment of Mild Cognitive Impairment (CAMCI). Over a 2-month period, 259 patients, 65 years and older, from the family practice of 13 PCPs completed the CAMCI. Twelve PCPs participated in an individual interview. Generally, PCPs felt that the relationship between them and their patients helped facilitate cognitive testing; however, they thought available paper tests were time consuming and not sufficiently informative. Despite concerns regarding elderly patients’ computer literacy, PCPs noticed high completion rates and that their patients had generally positive experiences completing the CAMCI. PCPs appreciated the time-saving advantage of the CAMCI and the immediately generated report, but thought the report should be shortened to 1 page and that PCPs should receive training in its interpretation. Our results suggest that computerized cognitive tools such as the CAMCI can address PCPs’ concerns with cognitive testing in their offices. Recommendations to improve the practicality of computerized testing in primary care were suggested.
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.

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’.
Suspected cases of intracontinental Burkholderia pseudomallei sequence type homoplasy resolved using whole-genome sequencing
Authors: Aziz Ammar , Sarovich Derek S. , Harris Tegan M. , Kaestli Mirjam , McRobb Evan , Mayo Mark , Currie Bart J. , Price Erin P.
Published: November 2017

Burkholderia pseudomallei is a Gram-negative environmental bacterium that causes melioidosis, a disease of high mortality in humans and animals. Multilocus sequence typing (MLST) is a popular and portable genotyping method that has been used extensively to characterise the genetic diversity of B. pseudomallei populations. MLST has been central to our understanding of the underlying phylogeographical signal present in the B. pseudomallei genome, revealing distinct populations on both the intra- and the inter-continental level. However, due to its high recombination rate, it is possible for B. pseudomallei isolates to share the same multilocus sequence type (ST) despite being genetically and geographically distinct, with two cases of ‘ST homoplasy’ recently reported between Cambodian and Australian B. pseudomallei isolates. This phenomenon can dramatically confound conclusions about melioidosis transmission patterns and source attribution, a critical issue for bacteria such as B. pseudomallei that are of concern due to their potential for use as bioweapons. In this study, we used whole-genome sequencing to identify the first reported instances of intracontinental ST homoplasy, which involved ST-722 and ST-804 B. pseudomallei isolates separated by large geographical distances. In contrast, a third suspected homoplasy case was shown to be a true long-range (460 km) dispersal event between a remote Australian island and the Australian mainland. Our results show that, whilst a highly useful and portable method, MLST can occasionally lead to erroneous conclusions about isolate origin and disease attribution. In cases where a shared ST is identified between geographically distant locales, whole-genome sequencing should be used to resolve strain origin.
Viral Complexity: Amino acid co-evolution in viral genomes as a possible metric
Authors: Sruthi C. K. , Prakash Meher K.
Published: November 2017

Viruses 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

The 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

Vascular 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

Heterochromatin 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

The 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

Purpose

The 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.

Design

In 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.

Results

Anabolic 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.

Conclusions

Cachectic 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.
Comprehensive analysis of mobile genetic elements in the gut microbiome reveals phylum-level niche-adaptive gene pools
Authors: Jiang Xiaofang , Hall Andrew Brantley , Xavier Ramnik J. , Alm Eric
Published: November 2017

Mobile genetic elements (MGEs) drive extensive horizontal transfer in the gut microbiome. This transfer could benefit human health by conferring new metabolic capabilities to commensal microbes, or it could threaten human health by spreading antibiotic resistance genes to pathogens. Despite their biological importance and medical relevance, MGEs from the gut microbiome have not been systematically characterized. Here, we present a comprehensive analysis of chromosomal MGEs in the gut microbiome using a method called Split Read Insertion Detection (SRID) that enables the identification of the exact mobilizable unit of MGEs. Leveraging the SRID method, we curated a database of 5600 putative MGEs encompassing seven MGE classes called ImmeDB (Intestinal microbiome mobile element database) (https://immedb.mit.edu/). We observed that many MGEs carry genes that confer an adaptive advantage to the gut environment including gene families involved in antibiotic resistance, bile salt detoxification, mucus degradation, capsular polysaccharide biosynthesis, polysaccharide utilization, and sporulation. We find that antibiotic resistance genes are more likely to be spread by conjugation via integrative conjugative elements or integrative mobilizable elements than transduction via prophages. Additionally, we observed that horizontal transfer of MGEs is extensive within phyla but rare across phyla. Taken together, our findings support a phylum level niche-adaptive gene pools in the gut microbiome. ImmeDB will be a valuable resource for future fundamental and translational studies on the gut microbiome and MGE communities.
Deep learning accurately predicts estrogen receptor status in breast cancer metabolomics data
Authors: Alakwaa Fadhl M , Chaudhary Kumardeep , Garmire Lana X
Published: November 2017

Metabolomics holds the promise as a new technology to diagnose highly heterogeneous diseases. Conventionally, metabolomics data analysis for diagnosis is done using various statistical and machine learning based classification methods. However, it remains unknown if deep neural network, a class of increasingly popular machine learning methods, is suitable to classify metabolomics data. Here we use a cohort of 271 breast cancer tissues, 204 positive estrogen receptor (ER+) and 67 negative estrogen receptor (ER-), to test the accuracies of autoencoder, a deep learning (DL) framework, as well as six widely used machine learning models, namely Random Forest (RF), Support Vector Machines (SVM), Recursive Partitioning and Regression Trees (RPART), Linear Discriminant Analysis (LDA), Prediction Analysis for Microarrays (PAM), and Generalized Boosted Models (GBM). DL framework has the highest area under the curve (AUC) of 0.93 in classifying ER+/ER-patients, compared to the other six machine learning algorithms. Furthermore, the biological interpretation of the first hidden layer reveals eight commonly enriched significant metabolomics pathways (adjusted P-value<0.05) that cannot be discovered by other machine learning methods. Among them, protein digestion & absorption and ATP-binding cassette (ABC) transporters pathways are also confirmed in integrated analysis between metabolomics and gene expression data in these samples. In summary, deep learning method shows advantages for metabolomics based breast cancer ER status classification, with both the highest prediction accurcy (AUC=0.93) and better revelation of disease biology. We encourage the adoption of autoencoder based deep learning method in the metabolomics research community for classification.
Synchronous inhibitory pathways create both efficiency and diversity in the retina
Authors: Manu Mihai , McIntosh Lane T. , Kastner David B. , Naecker Benjamin N. , Baccus Stephen A.
Published: November 2017

Visual information is conveyed from the retina to the brain by a diverse set of retinal ganglion cells. Although they have differing nonlinear properties, nearly all ganglion cell receptive fields on average compute a difference in intensity across space and time using a region known as the classical or linear surround1,2, a property that improves information transmission about natural visual scenes3,4. The spatiotemporal visual features that create this fundamental property have not been quantitatively assigned to specific interneurons. Here we describe a generalizable causal approach using simultaneous intracellular and multielectrode recording to directly measure and manipulate the sensory feature conveyed by a neural pathway to a downstream neuron. Analyzing two inhibitory cell classes, horizontal cells and linear amacrine cells, we find that rather than transmitting different temporal features, the two inhibitory pathways act synchronously to create the salamander ganglion cell surround at different spatial scales. Using these measured visual features and theories of efficient coding, we computed a fitness landscape representing the information transmitted using different weightings of the two inhibitory pathways. This theoretical landscape revealed a ridge that maintains near-optimal information transmission while allowing for receptive field diversity. The ganglion cell population showed a striking match to this prediction, concentrating along this ridge across a wide range of positions using different weightings of amacrine or horizontal cell visual features. These results show how parallel neural pathways synthesize a sensory computation, and why this architecture achieves the potentially competing objectives of high information transmission of individual ganglion cells, and diversity among receptive fields.
Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer
Authors: Lawrence Ben , Blenkiron Cherie , Parker Kate , Tsai Peter , Fitzgerald Sandra , Shields Paula , Robb Tamsin , Yeong Mee Ling , Kramer Nicole , James Sarah , Black Mik , Fan Vicky , Poonawala Nooriyah , Yap Patrick , Coats Esther , Woodhouse Braden , Ramsaroop Reena , Yozu Masato , Robinson Bridget , Henare Kimiora , Koea Jonathan , Johnston Peter , Carroll Richard , Connor Saxon , Morrin Helen , Elston Marianne , Jackson Christopher , Reid Papaarangi , Windsor John , MacCormick Andrew , Babor Richard , Bartlett Adam , Damianovich Dragan , Knowlton Nicholas , Grimmond Sean , Findlay Michael , Print Cristin
Published: November 2017

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Analysis of gene mutation, copy number and RNA expression of 57 sporadic pNETs showed that pNET genomes are dominated by aneuploidy. Remarkably, ~25% of pNETs had genomes characterized by recurrent loss of heterozygosity (LoH) of the same 10 chromosomes, accompanied by bi-allelic MEN1 inactivation, and these cases had generally poor clinical outcome. Another ~25% of all pNETs had chromosome 11 LoH and bi-allelic MEN1 inactivation, lacking the recurrent LoH pattern – these had universally good clinical outcome. Some level of aneuploidy was common, and overall ~80% of pNETs had LoH of ≥1 chromosome. This aneuploidy led to changes in RNA expression at the level of whole chromosomes and allowed pathogenic germline variants (e.g. ATM) to be expressed unopposed, inactivating downstream tumor suppressor pathways. Some pNETs appear to utilize VHL gene methylation or mutation to activate pseudo-hypoxia. Contrary to expectation neither tumor morphology within well-differentiated pNETs nor single gene mutation had significant associations with clinical outcome, nor did expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. MEN1 was the only statistically significant recurrently mutated driver gene in pNETs. Only one pNET had clearly oncogenic and actionable SNVs (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two distinct patterns of aneuploidy described here, associated with markedly poor and good clinical outcome respectively, define a novel oncogenic mechanism and the first route to genomic precision oncology for this tumor type.
Gene expression correlates of social evolution in coral reef butterflyfishes
Authors: Nowicki Jessica P. , Pratchett Morgan S. , Walker Stefan P. W. , Coker Darren J. , O’Connell Lauren A.
Published: November 2017

Animals display remarkable variation in social behavior. However, outside of rodents, little is known about the neural mechanisms of social variation, and whether they are shared across species and sexes, limiting our understanding of how sociality evolves. Using coral reef butterflyfishes, we examined gene expression correlates of social variation (i.e., pair bonding vs. solitary living) within and between species and sexes. In several brain regions, we quantified gene expression of receptors important for social variation in mammals: oxytocin (OTR), arginine vasopressin (V1aR), dopamine (D1R, D2R), and mu-opioid (MOR). We found that social variation across individuals of the oval butterflyfish, Chaetodon lunulatus, is linked to differences in OTR,V1aR, D1R, D2R, and MOR gene expression within several forebrain regions in a sexually dimorphic manner. However, this contrasted with social variation among six species representing a single evolutionary transition from pair bonded to solitary living. Here, OTR expression within the supracommissural part of the ventral telencephalon was higher in pair bonded than solitary species, specifically in males. These results contribute to the emerging idea that nonapeptide, dopamine, and opioid signaling is a central theme to the evolution of sociality across individuals, although the precise mechanism may be flexible across sexes and species.
Non-invasive measurement of mRNA decay reveals translation initiation as the major determinant of mRNA stability
Authors: Chan Leon Y , Mugler Christopher F , Heinrich Stephanie , Vallotton Pascal , Weis Karsten
Published: November 2017

The cytoplasmic abundance of mRNAs is strictly controlled through a balance of production and degradation. Whereas the control of mRNA synthesis through transcription has been well characterized, less is known about the regulation of mRNA turnover, and a consensus model explaining the wide variations in mRNA decay rates remains elusive. Here, we combine non-invasive transcriptome-wide mRNA production and stability measurements with selective and acute perturbations to demonstrate that mRNA degradation is tightly coupled to the regulation of translation, and that a competition between translation initiation and mRNA decay -but not codon optimality or elongation- is the major determinant of mRNA stability in yeast. Our refined measurements also reveal a remarkably dynamic transcriptome with an average mRNA half-life of only 4.8 minutes - much shorter than previously thought. Furthermore, global mRNA destabilization by inhibition of translation initiation induces a dose-dependent formation of processing bodies in which mRNAs can decay over time.
A Polymorphic Residue That Attenuates the Antiviral Potential of Interferon Lambda 4 in Hominid Lineages
Authors: Bamford Connor G. G. , Aranday-Cortes Elihu , Filipe Inès Cordeiro , Sukumar Swathi , Mair Daniel , da Silva Filipe Ana , Mendoza Juan L. , Christopher Garcia K. , Fan Shaohua , Tishkoff Sarah A. , McLauchlan John
Published: November 2017

As antimicrobial signalling molecules, type III or lambda interferons (IFNλs) are critical for defence against infection by diverse pathogens. Counter-intuitively, expression of one member of the family, IFNλ4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural in-frame nucleotide insertion that abrogates IFNλ4 production improves viral clearance. To further understand how genetic variation between and within species affects IFNλ4 function, we screened a panel of extant coding variants of human IFNλ4 and identified three variants that substantially affect antiviral activity (P70S, L79F and K154E). The most notable variant was K154E, which enhancedin vitroactivity in a range of antiviral and interferon stimulated gene (ISG) assays. This more active E154 variant of IFNλ4 was found only in African Congo rainforest ‘Pygmy’ hunter-gatherers. Remarkably, E154 was highly conserved as the ancestral residue in mammalian IFNλ4s yet K154 is the dominant variant throughout evolution of the hominid genusHomo. Compared to chimpanzee IFNλ4, the human orthologue had reduced activity due to amino acid substitution of glutamic acid with lysine at position 154. Meta-analysis of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFNλ4 is consistent with differences in antiviral gene expressionin vivoduring HCV infection. Mechanistically, our data suggest that human-specific K154 likely affects IFNλ4 activity by reducing secretion and potency. We postulate that evolution of an IFNλ4 with attenuated activity in humans (K154) likely contributes to distinct host-specific responses to and outcomes of infection, such as HCV.
Genome-Wide Identification of Early-Firing Human Replication Origins by Optical Replication Mapping
Authors: Klein Kyle , Wang Weitao , Borrman Tyler , Chan Saki , Zhang Denghong , Weng Zhiping , Hastie Alex , Chen Chunlong , Gilbert David M. , Rhind Nicholas
Published: November 2017

The timing of DNA replication is largely regulated by the location and timing of replication origin firing. Therefore, much effort has been invested in identifying and analyzing human replication origins. However, the heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual origins in metazoans has made mapping the location and timing of replication initiation in human cells difficult. We have mapped early-firing origins in HeLa cells using Optical Replication Mapping, a high-throughput single-molecule approach based on Bionano Genomics genomic mapping technology. The single-molecule nature and 290-fold coverage of our dataset allowed us to identify origins that fire with as little as 1% efficiency. We find sites of human replication initiation in early S phase are not confined to well-defined efficient replication origins, but are instead distributed across broad initiation zones consisting of many inefficient origins. These early-firing initiation zones co-localize with initiation zones inferred from Okazaki-fragment-mapping analysis and are enriched in ORC1 binding sites. Although most early-firing origins fire in early-replication regions of the genome, a significant number fire in late-replicating regions, suggesting that the major difference between origins in early and late replicating regions is their probability of firing in early S-phase, as opposed to qualitative differences in their firing-time distributions. This observation is consistent with stochastic models of origin timing regulation, which explain the regulation of replication timing in yeast.
PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt
Authors: Uche Uzodinma , Szymczak-Workman Andrea L. , Grebinoski Stephanie , Piccirillo Ann , D’Cruz Louise M. , Kane Lawrence P.
Published: November 2017

Phosphatidylinositol-3 kinases (PI3Ks) modulate numerous cellular functions, including growth, proliferation and survival. Dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or Transmembrane Inhibitor of PI3K – TrIP) is a novel transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular “p85-like” domain with homology to the inter-SH2 domain of the regulatory subunit of PI3K. Although TrIP has been shown to bind to the p110 catalytic subunit of PI3K in fibroblasts, the mechanism by which TrIP functions is poorly understood. We show that both the kringle and “p85-like” domains are necessary for TrIP inhibition of PI3K. We also demonstrate that TrIP protein is down-modulated from the surface of T cells to allow T cell activation. In addition, we present evidence that the kringle domain may modulate TrIP function by binding an as-yet-unidentified ligand. Using an inducible knockout mouse model that we developed, we show that TrIP-deficient T cells exhibit more robust T cell activation, show a preference for Th1 polarization and can mediate clearance of Listeria monocytogenes infection faster than WT mice. Thus, TrIP is an important negative regulator of T cell activation and may represent a novel target for immune modulation therapies.