bluuebunny/crossref_metadata_2025 huggingface dataset:
New Rhizotomy Procedure for Primary Spasmodic Torticollis
Authors: Hua Chunhui , Pu Benfang , Liu Kaizhang , Huang Zhenyu , Li Changhua , Zhao Changyi , Li Xinyuan
Published: April 2018

Objective:

Spasmodic torticollis (ST) is an idiopathic neurologic disorder affecting the muscles of the neck. Surgery is a preferred treatment, when conservative treatments or Botulinum neurotoxin injections fail to relieve the symptoms. Our objective here is to report the outcome of a new surgical method for treating ST patients in our department.

Methods:

The new procedure consists of rhizotomy of the spinal accessory nerve (SAN) and C1–C2 nerve roots, coagulation of the distal end of SAN (Group A). The results of this procedure were compared with a group of patients who underwent only rhizotomy of the SAN and anterior C1–C2 nerve roots (Group B). Clinical data were retrospectively collected from 39 patients with laterocollis and rotatory torticollis subtypes of ST from Jun 1, 2014 to Jun 1, 2015. The effect of the surgery was evaluated by the reduction in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores preoperatively and postoperatively. The mean duration of the postoperative follow-up period was 2.57 years, ranging from 2 to 3 years.

Results:

The mean preoperative TWSTRS score was 65.89 ± 3.55 and 65.80 ± 3.45 in Groups A and B, respectively. Six months after the surgery, the TWSTRS scores decreased to 40.00 ± 12.14 and 26.04 ± 11.77, respectively. There was a statistically significant improvement preoperatively and postoperatively in both groups (P < 0.05). The decrease in TWSTRS score of Group B was more significant than that of Group A (P < 0.05). The main complications included shoulder numbness, shoulder weakness, and hoarseness.

Conclusions:

The procedure in this study provides a new and effective surgical method for patients with ST. This procedure should be recommended if conservative therapy does not offer satisfactory relief of symptoms.
Evaluation of Facial Anthropometry Using Three-Dimensional Photogrammetry and Direct Measuring Techniques
Authors: Düppe Katarina , Becker Magnus , Schönmeyr Björn
Published: April 2018

In this study, 14 standard facial distances on 10 adult volunteers were measured directly with a caliper and indirectly on two-dimensional images using the 3dMDtrio system. Two raters performed the measurements with at least 1 week between rating sessions. The intra- and inter-rater reliabilities and agreement of the measurements were calculated using intra-class correlation coefficient (ICC), mean absolute difference (MAD), and Bland-Altman plots with limits of agreement (LOA). The 2 raters had an average discrepancy (MAD) of 1.6 mm when their digital measurements were compared to their direct measurements. The reliability of the digital and direct methods varied greatly depending on which of the 14 anthropometric distances that was being assessed. Only 6 digitally and 5 directly measured anthropometric distances showed both an ICC >0.75 and a MAD <1 mm, in the intra-rater as well as the inter-rater measurements. The Bland-Altman plots and LOA displayed the same pattern. In summary, the digital and direct methods were generally compatible in terms of reliability and agreement. However, the reliability and agreement between the 14 anthropometric measurements varied considerably, indicating that poor landmark identification is the main limitation to both modern and traditional measuring techniques in the face. Consequently, some anthropometric landmarks warrant further definition or prior anthropometric training by the evaluators. The authors also recommend that the MADs and LOAs provided in this report are put into relation to the facial distance that is being evaluated and its clinical context.
GTS-21 Reduces Inflammation in Acute Lung Injury by Regulating M1 Polarization and Function of Alveolar Macrophages
Authors: Wang Jing , Li Ruiting , Peng Zhiyong , Zhou Wenhai , Hu Bo , Rao Xin , Yang Xiao , Li Jianguo
Published: April 2018

Background:

Acute lung injury (ALI) is a severe outcome of sepsis. Alveolar macrophages (AMs) play key roles in defense, resolution in ALI. The polarization of AMs is dependent on micro environmental stimuli and might influence the progression of ALI. Gainesville Tokushima scientists (GTS)-21, a selective α7 nicotinic acetylcholine receptor agonist of the cholinergic anti-inflammatory pathway (CAP), has recently been established to be promising in the treatment of ALI. However, the molecular mechanism underlying the GTS-21-mediated suppression of inflammatory responses has been explored only partially. In this study, we examined the relation between GTS-21 and AM polarization in ALI.

Methods:

The adoptive transfer of M1 (classically activated) and M2 (alternatively activated)-polarized AMs was performed to AM-depleted ALI mice, along with the administration of GTS-21 in a murine model of lipopolysaccharide (LPS)-induced ALI and in isolated AMs that had been stimulated by LPS in vitro.

Results:

The adoptive transfer of M1-polarized AMs aggravated the inflammatory response in the lung in contrast to the adoptive transfer of M2-polarized AMs. GTS-21 protected the lung from the effect of LPS, preventing injury and decreasing the number of AMs, AM-related pro-inflammatory cytokine levels, high mobility group box 1 expression levels in AMs. In addition, GTS-21 significantly diminished the number of M1-polarized AM and increased the number of M2-polarized AM, by flow cytometry, RT-PCR, enzyme-linked immunosorbent assay, and the Arg1 and iNOS activity assays.

Conclusion:

The GTS-21 substantially ameliorates LPS-induced ALI. This protection is predominantly associated with the inhibition of pulmonary AM M1 polarization and alteration in AM function.
Implications of possible interpretations of ‘greenhouse gas balance’ in the Paris Agreement
Authors: Fuglestvedt J. , Rogelj J. , Millar R. J. , Allen M. , Boucher O. , Cain M. , Forster P. M. , Kriegler E. , Shindell D.
Published: April 2018

The main goal of the Paris Agreement as stated in Article 2 is ‘holding the increase in the global average temperature to well below 2°C above pre-industrial levels and pursuing efforts to limit the temperature increase to 1.5°C’. Article 4 points to this long-term goal and the need to achieve ‘balance between anthropogenic emissions by sources and removals by sinks of greenhouse gases'. This statement on ‘greenhouse gas balance’ is subject to interpretation, and clarifications are needed to make it operational for national and international climate policies. We study possible interpretations from a scientific perspective and analyse their climatic implications. We clarify how the implications for individual gases depend on the metrics used to relate them. We show that the way in which balance is interpreted, achieved and maintained influences temperature outcomes. Achieving and maintaining net-zero CO
2
-equivalent emissions conventionally calculated using GWP
100
(100-year global warming potential) and including substantial positive contributions from short-lived climate-forcing agents such as methane would result in a sustained decline in global temperature. A modified approach to the use of GWP
100
(that equates constant emissions of short-lived climate forcers with zero sustained emission of CO
2
) results in global temperatures remaining approximately constant once net-zero CO
2
-equivalent emissions are achieved and maintained. Our paper provides policymakers with an overview of issues and choices that are important to determine which approach is most appropriate in the context of the Paris Agreement.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Stabilization of global temperature at 1.5°C and 2.0°C: implications for coastal areas
Authors: Nicholls Robert J. , Brown Sally , Goodwin Philip , Wahl Thomas , Lowe Jason , Solan Martin , Godbold Jasmin A. , Haigh Ivan D. , Lincke Daniel , Hinkel Jochen , Wolff Claudia , Merkens Jan-Ludolf
Published: April 2018

The effectiveness of stringent climate stabilization scenarios for coastal areas in terms of reduction of impacts/adaptation needs and wider policy implications has received little attention. Here we use the Warming Acidification and Sea Level Projector Earth systems model to calculate large ensembles of global sea-level rise (SLR) and ocean pH projections to 2300 for 1.5°C and 2.0°C stabilization scenarios, and a reference unmitigated RCP8.5 scenario. The potential consequences of these projections are then considered for global coastal flooding, small islands, deltas, coastal cities and coastal ecology. Under both stabilization scenarios, global mean ocean pH (and temperature) stabilize within a century. This implies significant ecosystem impacts are avoided, but detailed quantification is lacking, reflecting scientific uncertainty. By contrast, SLR is only slowed and continues to 2300 (and beyond). Hence, while coastal impacts due to SLR are reduced significantly by climate stabilization, especially after 2100, potential impacts continue to grow for centuries. SLR in 2300 under both stabilization scenarios exceeds unmitigated SLR in 2100. Therefore, adaptation remains essential in densely populated and economically important coastal areas under climate stabilization. Given the multiple adaptation steps that this will require, an adaptation pathways approach has merits for coastal areas.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels’.
The utility of the historical record for assessing the transient climate response to cumulative emissions
Authors: Millar Richard J. , Friedlingstein Pierre
Published: April 2018

The historical observational record offers a way to constrain the relationship between cumulative carbon dioxide emissions and global mean warming. We use a standard detection and attribution technique, along with observational uncertainties to estimate the all-forcing or ‘effective’ transient climate response to cumulative emissions (TCRE) from the observational record. Accounting for observational uncertainty and uncertainty in historical non-CO
2
radiative forcing gives a best-estimate from the historical record of 1.84°C/TtC (1.43–2.37°C/TtC 5–95% uncertainty) for the effective TCRE and 1.31°C/TtC (0.88–2.60°C/TtC 5–95% uncertainty) for the CO
2
-only TCRE. While the best-estimate TCRE lies in the lower half of the IPCC likely range, the high upper bound is associated with the not-ruled-out possibility of a strongly negative aerosol forcing. Earth System Models have a higher effective TCRE range when compared like-for-like with the observations over the historical period, associated in part with a slight underestimate of diagnosed cumulative emissions relative to the observational best-estimate, a larger ensemble mean-simulated CO
2
-induced warming, and rapid post-2000 non-CO
2
warming in some ensemble members.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Solar geoengineering as part of an overall strategy for meeting the 1.5°C Paris target
Authors: MacMartin Douglas G. , Ricke Katharine L. , Keith David W.
Published: April 2018

Solar geoengineering refers to deliberately reducing net radiative forcing by reflecting some sunlight back to space, in order to reduce anthropogenic climate changes; a possible such approach would be adding aerosols to the stratosphere. If future mitigation proves insufficient to limit the rise in global mean temperature to less than 1.5°C above preindustrial, it is plausible that some additional and limited deployment of solar geoengineering could reduce climate damages. That is, these approaches could eventually be considered as part of an overall strategy to manage the risks of climate change, combining emissions reduction, net-negative emissions technologies and solar geoengineering to meet climate goals. We first provide a physical-science review of current research, research trends and some of the key gaps in knowledge that would need to be addressed to support informed decisions. Next, since few climate model simulations have considered these limited-deployment scenarios, we synthesize prior results to assess the projected response if solar geoengineering were used to limit global mean temperature to 1.5°C above preindustrial in an overshoot scenario that would otherwise peak near 3°C. While there are some important differences, the resulting climate is closer in many respects to a climate where the 1.5°C target is achieved through mitigation alone than either is to the 3°C climate with no geoengineering. This holds for both regional temperature and precipitation changes; indeed, there are no regions where a majority of models project that this moderate level of geoengineering would produce a statistically significant shift in precipitation further away from preindustrial levels.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels’.
Coordinating AgMIP data and models across global and regional scales for 1.5°C and 2.0°C assessments
Authors: Rosenzweig Cynthia , Ruane Alex C. , Antle John , Elliott Joshua , Ashfaq Muhammad , Chatta Ashfaq Ahmad , Ewert Frank , Folberth Christian , Hathie Ibrahima , Havlik Petr , Hoogenboom Gerrit , Lotze-Campen Hermann , MacCarthy Dilys S. , Mason-D'Croz Daniel , Contreras Erik Mencos , Müller Christoph , Perez-Dominguez Ignacio , Phillips Meridel , Porter Cheryl , Raymundo Rubi M. , Sands Ronald D. , Schleussner Carl-Friedrich , Valdivia Roberto O. , Valin Hugo , Wiebe Keith
Published: April 2018

The Agricultural Model Intercomparison and Improvement Project (AgMIP) has developed novel methods for Coordinated Global and Regional Assessments (CGRA) of agriculture and food security in a changing world. The present study aims to perform a proof of concept of the CGRA to demonstrate advantages and challenges of the proposed framework. This effort responds to the request by the UN Framework Convention on Climate Change (UNFCCC) for the implications of limiting global temperature increases to 1.5°C and 2.0°C above pre-industrial conditions. The protocols for the 1.5°C/2.0°C assessment establish explicit and testable linkages across disciplines and scales, connecting outputs and inputs from the Shared Socio-economic Pathways (SSPs), Representative Agricultural Pathways (RAPs), Half a degree Additional warming, Prognosis and Projected Impacts (HAPPI) and Coupled Model Intercomparison Project Phase 5 (CMIP5) ensemble scenarios, global gridded crop models, global agricultural economics models, site-based crop models and within-country regional economics models. The CGRA consistently links disciplines, models and scales in order to track the complex chain of climate impacts and identify key vulnerabilities, feedbacks and uncertainties in managing future risk. CGRA proof-of-concept results show that, at the global scale, there are mixed areas of positive and negative simulated wheat and maize yield changes, with declines in some breadbasket regions, at both 1.5°C and 2.0°C. Declines are especially evident in simulations that do not take into account direct CO
2
effects on crops. These projected global yield changes mostly resulted in increases in prices and areas of wheat and maize in two global economics models. Regional simulations for 1.5°C and 2.0°C using site-based crop models had mixed results depending on the region and the crop. In conjunction with price changes from the global economics models, productivity declines in the Punjab, Pakistan, resulted in an increase in vulnerable households and the poverty rate.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Impacts on terrestrial biodiversity of moving from a 2°C to a 1.5°C target
Authors: Smith Pete , Price Jeff , Molotoks Amy , Warren Rachel , Malhi Yadvinder
Published: April 2018

We applied a recently developed tool to examine the reduction in climate risk to biodiversity in moving from a 2°C to a 1.5°C target. We then reviewed the recent literature examining the impact of (a) land-based mitigation options and (b) land-based greenhouse gas removal options on biodiversity. We show that holding warming to 1.5°C versus 2°C can significantly reduce the number of species facing a potential loss of 50% of their climatic range. Further, there would be an increase of 5.5–14% of the globe that could potentially act as climatic refugia for plants and animals, an area equivalent to the current global protected area network. Efforts to meet the 1.5°C target through mitigation could largely be consistent with biodiversity protection/enhancement. For impacts of land-based greenhouse gas removal technologies on biodiversity, some (e.g. soil carbon sequestration) could be neutral or positive, others (e.g. bioenergy with carbon capture and storage) are likely to lead to conflicts, while still others (e.g. afforestation/reforestation) are context-specific, when applied at scales necessary for meaningful greenhouse gas removal. Additional effort to meet the 1.5°C target presents some risks, particularly if inappropriately managed, but it also presents opportunities.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
The legal character and operational relevance of the Paris Agreement's temperature goal
Authors: Rajamani Lavanya , Werksman Jacob
Published: April 2018

This article assesses the legal character and operational relevance of the Paris Agreement's 1.5°C temperature goal. This article begins with a textual analysis of the 1.5°C goal. It considers whether the goal creates individual or collective obligations for Parties, and whether it is sufficiently specific to enable the tracking of individual or collective performance. Next, it assesses the operational relevance of the 1.5°C temperature goal, by considering the role it will play in the Paris Agreement's institutions and procedures. To the extent that the goal plays a role, and implies global limits on greenhouse gas emissions, this article observes that it could have implications for the sharing of the effort between Parties. Thus, this article considers the relevance of equity and the principle of common but differentiated responsibilities and respective capabilities, in the light of different national circumstances, to understanding how the 1.5°C goal could be reached. In this context, this article explores whether the 1.5°C goal could play a role in the Paris Agreement's ‘ambition cycle’. Finally, this article asks whether there are any legal or political implications, individually or collectively under the Paris Agreement, should the Parties fail to achieve the 1.5°C goal.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels’.
Uncertain impacts on economic growth when stabilizing global temperatures at 1.5°C or 2°C warming
Authors: Pretis Felix , Schwarz Moritz , Tang Kevin , Haustein Karsten , Allen Myles R.
Published: April 2018

Empirical evidence suggests that variations in climate affect economic growth across countries over time. However, little is known about the relative impacts of climate change on economic outcomes when global mean surface temperature (GMST) is stabilized at 1.5°C or 2°C warming relative to pre-industrial levels. Here we use a new set of climate simulations under 1.5°C and 2°C warming from the ‘Half a degree Additional warming, Prognosis and Projected Impacts' (HAPPI) project to assess changes in economic growth using empirical estimates of climate impacts in a global panel dataset. Panel estimation results that are robust to outliers and breaks suggest that within-year variability of monthly temperatures and precipitation has little effect on economic growth beyond global nonlinear temperature effects. While expected temperature changes under a GMST increase of 1.5°C lead to proportionally higher warming in the Northern Hemisphere, the projected impact on economic growth is larger in the Tropics and Southern Hemisphere. Accounting for econometric estimation and climate uncertainty, the projected impacts on economic growth of 1.5°C warming are close to indistinguishable from current climate conditions, while 2°C warming suggests statistically lower economic growth for a large set of countries (median projected annual growth up to 2% lower). Level projections of gross domestic product (GDP)per capitaexhibit high uncertainties, with median projected global average GDPper capitaapproximately 5% lower at the end of the century under 2°C warming relative to 1.5°C. The correlation between climate-induced reductions inper capitaGDP growth and national income levels is significant at thep < 0.001 level, with lower-income countries experiencing greater losses, which may increase economic inequality between countries and is relevant to discussions of loss and damage under the United Nations Framework Convention on Climate Change.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Building equity in: strategies for integrating equity into modelling for a 1.5°C world
Authors: Sonja Klinsky , Harald Winkler
Published: April 2018

Emission pathways consistent with limiting temperature increase to 1.5°C raise pressing questions from an equity perspective. These pathways would limit impacts and benefit vulnerable communities but also present trade-offs that could increase inequality. Meanwhile, rapid mitigation could exacerbate political debates in which equity has played a central role. In this paper, we first develop a set of elements we suggest are essential for evaluating the equity implications of policy actions consistent with 1.5°C. These elements include (i) assess climate impacts, adaptation, loss and damage; (ii) be sensitive to context; (iii) compare costs of mitigation and adaptation policy action; (iv) incorporate human development and poverty; (v) integrate inequality dynamics; and (vi) be clear about normative assumptions and responsive to users. We then assess the ability of current modelling practices to address each element, focusing on global integrated assessment models augmented by national modelling and scenarios. We find current practices face serious limitations across all six dimensions although the severity of these varies. Finally, based on our assessment we identify strategies that may be best suited for enabling us to generate insights into each of the six elements in the context of assessing pathways for a 1.5°C world.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Can ‘loss and damage’ carry the load?
Authors: Verchick Robert R. M.
Published: April 2018

Even assuming a heroic rush towards carbon reduction and adaptation, some regions of the world will be hammered hard by climate impacts. Thus, a global consensus now sees the need for a supplemental plan to deal with the kind of harms that cannot be avoided—what Parties call ‘loss and damage’. For a loss-and-damage plan to work, it must be capable of carrying the load, the load being whatever minimal standards that morality and political consensus require. But if residual risk climbs too high, it will fall short of even the most basic expectations. The Paris Agreement calls for holding the rise in global average temperature to ‘well below 2°C above pre-industrial levels’, while working to limit the increase to 1.5°C. How much difference is in that half-degree? From the point of view of residual risk, quite a lot. According to a 2016 study published by the European Geosciences Union, a jump from 1.5°C to 2°C could produce outsize impacts, particularly in tropical latitudes. That difference could mark the line between a plan that is politically and morally defensible and one that is not. At the very least, the difference is enough to inform the design and expectations of any future plan.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels’.
Mitigation gambles: uncertainty, urgency and the last gamble possible
Authors: Shue Henry
Published: April 2018

A rejection by current generations of more ambitious mitigation of carbon emissions inflicts on future generations inherently objectionable risks about which they have no choice. Any gains through savings from less ambitious mitigation, which are relatively minor, would accrue to current generations, and all losses, which are relatively major, would fall on future generations. This mitigation gamble is especially unjustifiable because it imposes a risk of unlimited losses until carbon emissions cease. Ultimate physical collapses remain possible. Much more ominous is prior social collapse from political struggles over conflicting responses to threatened physical collapse. The two most plausible objections to the thesis that less ambitious mitigation is unjustifiable rely, respectively, on the claim that negative emissions will allow a later recovery from a temporary overshoot in emissions and on the claim that ambitious mitigation is incompatible with poverty alleviation that depends on inexpensive fossil fuels. Neither objection stands up. Reliance on negative emissions later instead of ambitious mitigation now permits the passing of tipping points for irreversible change meanwhile, and non-carbon energy is rapidly becoming price competitive in developing countries like India that are committed to poverty alleviation.

This article is part of the themed issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels’.
The impact of Earth system feedbacks on carbon budgets and climate response
Authors: Lowe Jason A. , Bernie Daniel
Published: April 2018

A number of studies have examined the size of the allowable global cumulative carbon budget compatible with limiting twenty-first century global average temperature rise to below 2°C and below 1.5°C relative to pre-industrial levels. These estimates of cumulative emissions have a number of uncertainties including those associated with the climate sensitivity and the global carbon cycle. Although the IPCC fifth assessment report contained information on a range of Earth system feedbacks, such as carbon released by thawing of permafrost or methane production by wetlands as a result of climate change, the impact of many of these Earth system processes on the allowable carbon budgets remains to be quantified. Here, we make initial estimates to show that the combined impact from typically unrepresented Earth system processes may be important for the achievability of limiting warming to 1.5°C or 2°C above pre-industrial levels. The size of the effects range up to around a 350 GtCO
2
budget reduction for a 1.5°C warming limit and around a 500 GtCO
2
reduction for achieving a warming limit of 2°C. Median estimates for the extra Earth system forcing lead to around 100 GtCO
2
and 150 GtCO
2
, respectively, for the two warming limits. Our estimates are equivalent to several years of anthropogenic carbon dioxide emissions at present rates. In addition to the likely reduction of the allowable global carbon budgets, the extra feedbacks also bring forward the date at which a given warming threshold is likely to be exceeded for a particular emission pathway.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels’.
The myriad challenges of the Paris Agreement
Authors: Mitchell Dann , Allen Myles R. , Hall Jim W. , Muller Benito , Rajamani Lavanya , Le Quéré Corinne
Published: April 2018

The much awaited and intensely negotiated Paris Agreement was adopted on 12 December 2015 by the Parties to the United Nations Framework Convention on Climate Change. The agreement set out a more ambitious long-term temperature goal than many had anticipated, implying more stringent emissions reductions that have been under-explored by the research community. By its very nature a multidisciplinary challenge, filling the knowledge gap requires not only climate scientists, but the whole Earth system science community, as well as economists, engineers, lawyers, philosophers, politicians, emergency planners and others to step up. To kick start cross-disciplinary discussions, the University of Oxford's Environmental Change Institute focused its 25th anniversary conference upon meeting the challenges of the Paris Agreement for science and society. This theme issue consists of review papers, opinion pieces and original research from some of the presentations within that meeting, covering a wide range of issues underpinning the Paris Agreement.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Efficient inverse graphics in biological face processing
Authors: Yildirim Ilker , Belledonne Mario , Freiwald Winrich , Tenenbaum Joshua
Published: April 2018

Vision must not only recognize and localize objects, but perform richer inferences about the underlying causes in the world that give rise to sensory data. How the brain performs these inferences remains unknown: Theoretical proposals based on inverting generative models (or “analysis-by-synthesis”) have a long history but their mechanistic implementations have typically been too slow to support online perception, and their mapping to neural circuits is unclear. Here we present a neurally plausible model for efficiently inverting generative models of images and test it as an account of one high-level visual capacity, the perception of faces. The model is based on a deep neural network that learns to invert a three-dimensional (3D) face graphics program in a single fast feedforward pass. It explains both human behavioral data and multiple levels of neural processing in non-human primates, as well as a classic illusion, the “hollow face” effect. The model fits qualitatively better than state-of-the-art computer vision models, and suggests an interpretable reverse-engineering account of how images are transformed into percepts in the ventral stream.
Deletion of genes encoding PU.1 and Spi-B leads to B cell acute lymphoblastic leukemia associated with driver mutations in Janus Kinases
Authors: Batista Carolina R. , Lim Michelle , Laramée Anne-Sophie , Abu-Sardanah Faisal , Xu Li S. , Hossain Rajon , DeKoter Rodney P.
Published: April 2018

Precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with recurrent mutations that occur in cancer-initiating cells. There is a need to understand how spontaneous driver mutations influence clonal evolution in leukemia. The ETS-transcription factors PU.1 and Spi-B (encoded bySpi1andSpib) execute a critical role in B cell development and serve as complementary tumour suppressors by opposing the proliferative events mediated by IL-7R signaling. Here, we used a mouse model to conditionally deleteSpi1andSpibgenes in developing B cells. These mice developed B-ALL with a median time to euthanasia of 18 weeks. We performed RNA and whole-exome sequencing (WES) on leukemias isolated from Mb1-CreΔPB mice and identified single-nucleotide variants (SNVs) inJak1,Jak3andIkzf3genes, resulting in amino acid changes and in the gain of early stop-codons. JAK3 mutations resulted in amino acid substitutions located in the pseudo-kinase (R653H, V670A) and in the kinase (T844M) domains. Introduction of these mutations into wild-type pro-B cells conferred survival and proliferation advantages. We conclude that mutations in Janus kinases represent secondary drivers of leukemogenesis in the absence of Spi-B and PU.1 transcription factors. This mouse model represents an useful tool to study clonal evolution and tumour heterogeneity in B-ALL.
Structures of DPAGT1 explain glycosylation disease mechanisms and advance TB antibiotic design
Authors: Dong Yin Yao , Wang Hua , Pike Ashley C.W. , Cochrane Stephen A. , Hamedzadeh Sadra , Wyszyński Filip J. , Bushell Simon R. , Royer Sylvain F. , Widdick David A. , Sajid Andaleeb , Boshoff Helena I. , Lucas Ricardo , Liu Wei-Min , Lee Seung Seo , Machida Takuya , Mehmood Shahid , Belaya Katsiaryna , Liu Wei-Wei , Chu Amy , Shrestha Leela , Mukhopadhyay Shubhashish M.M. , Burgess-Brown Nicola A. , Bibb Mervyn J. , Barry Clifton E. , Robinson Carol V. , Beeson David , Davis Benjamin G. , Carpenter Elisabeth P.
Published: April 2018

Protein glycosylation is a widespread post-translational modification. The first committed step to the lipid-linked glycan used for this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and congenital disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use as antibiotics. However, little is known about the mechanism or the effects of disease-associated mutations in this essential enzyme. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (and thus cause disease) and allow design of non-toxic ‘lipid-altered’ tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed design of potent antibiotics forMycobacterium tuberculosis, enabling treatmentin vitro,in celluloandin vivothereby providing a promising new class of antimicrobial drug.

Highlights

Structures of DPAGT1 with UDP-GlcNAc and tunicamycin reveal mechanisms of catalysis

DPAGT1 mutants in patients with glycosylation disorders modulate DPAGT1 activity

Structures, kinetics and biosynthesis reveal role of lipid in tunicamycin

Lipid-altered, tunicamycin analogues give non-toxic antibiotics against TB
Integrative analysis of pharmacogenomics in major cancer cell line databases using CellMinerCDB
Authors: Rajapakse Vinodh N. , Luna Augustin , Yamade Mihoko , Loman Lisa , Varma Sudhir , Sunshine Margot , Iorio Francesco , Sousa Fabricio G. , Elloumi Fathi , Aladjem Mirit I. , Thomas Anish , Sander Chris , Kohn Kurt , Benes Cyril H. , Garnett Mathew , Reinhold William C. , Pommier Yves
Published: April 2018

As precision medicine demands molecular determinants of drug response, CellMinerCDB provides (https://discover.nci.nih.gov/cellminercdb/) a web-based portal for multiple forms of pharmacological, molecular, and genomic analyses, unifying the richest cancer cell line datasets (NCI-60, NCI-SCLC, Sanger/MGH GDSC, and Broad CCLE/CTRP). CellMinerCDB enables genomic and pharmacological data queries for identifying pharmacogenomic determinants, drug signatures, and gene regulatory networks for researchers without requiring specialized bioinformatics support. It leverages overlaps of cell lines and tested drugs to allow assessment of data reproducibility. It builds on the complementarity and strength of each dataset. A panel of 41 drugs evaluated in parallel in the NCI-60 and GDSC is reported, supporting drug reproducibility across databases, repositioning of bisacodyl and acetalax for triple negative breast cancer, and identifying novel drug response determinants and genomic signatures for topoisomerase inhibitors and schweinfurthins in development. CellMinerCDB also allowed the identification ofLIX1Las a novel mesenchymal gene regulating cellular migration and invasiveness.
P. falciparum PfATP4 Multi-Drug Resistance Resistance to KAE609 (Cipargamin) is Present in Africa
Authors: McCulloch James
Published: April 2018

The PfATP4 (PF3D7 1211900) multi-drug resistance mutation G223R is found in Africa by genetically analyzing 2640 worldwide Plasmodium falciparum blood stage isolates (the MalariaGen Pf3k resource). This mutation confers an approximate 8 fold [4] increase in the PfATP4 IC50 of Spiroindolones (KAE609 & KAE678) [14],[16],[4],[10] and Aminopyrazoles (GNF-Pf4492) [4]. It is postulated that the G223R mutation may be a consequence of the drug resistant Southeast Asian Dd2 genotype becoming more dominant in Africa [3]. The presence of this mutation has important policy implications for the eventual general deployment of the Spiroindolone KAE609 (Cipargamin) which is currently undergoing stage 2 clinical trials.
Development of a joint evolutionary model for the genome and the epigenome
Authors: Lu Jia , Cao Xiaoyi , Zhong Sheng
Published: April 2018

Background

Interspecies epigenome comparisons yielded functional information that cannot be revealed by genome comparison alone, begging for theoretical advances that enable principled analysis approaches. Whereas probabilistic genome evolution models provided theoretical foundation to comparative genomics studies, it remains challenging to extend DNA evolution models to epigenomes.

Results

We present an effort to develop ab initio evolution models for epigenomes, by explicitly expressing the joint probability of multispecies DNA sequences and histone modifications on homologous genomic regions. This joint probability is modeled as a mixture of four components representing four evolutionary hypotheses, namely dependence and independence of interspecies epigenomic variations to sequence mutations and to sequence insertions and deletions (indels). For model fitting, we implemented a maximum likelihood method by coupling downhill simplex algorithm with dynamic programming. Based on likelihood comparisons, the model can be used to infer whether interspecies epigenomic variations depend on mutation or indels in local genomic sequences. We applied this model to analyze DNase hypersensitive regions and spermatid H3K4me3 ChIP-seq data from human and rhesus macaque. Approximately 5.5% of homologous regions in the genomes exhibited H3K4me3 modification in either species, among which approximately 67% homologous regions exhibited sequence-dependent interspecies H3K4me3 variations. Mutations accounted for less sequence-dependent H3K4me3 variations than indels. Among transposon-mediated indels, ERV1 insertions and L1 insertions were most strongly associated with H3K4me3 gains and losses, respectively.

Conclusion

This work initiates a class of probabilistic evolution models that jointly model the genomes and the epigenomes, thus helps to bring evolutionary principles to comparative epigenomic studies.
Rainbow-seq: combining cell lineage tracking with single-cell RNA sequencing in preimplantation embryos
Authors: Biase Fernando , Wu Qiuyang , Calandrelli Riccardo , Rivas-Astroza Marcelo , Zhou Shuigeng , Zhong Sheng
Published: April 2018

Single-cell RNA-seq experiments cannot record cell division history and therefore cannot directly connect intercellular differences at a later developmental stage to their progenitor cells. We developed Rainbow-seq to combine cell division lineage tracing with single-cell RNA-seq. With distinct fluorescent protein genes as lineage markers, Rainbow-seq enables each single-cell RNA-seq experiment to simultaneously read single-cell transcriptomes and decode the lineage marker genes. We traced the lineages deriving from each blastomere in two-cell mouse embryos and observed inequivalent contributions to the embryonic and abembryonic poles in 72% of the blastocysts evaluated. Rainbow-seq on four- and eight-cell embryos with lineage tracing triggered at two-cell stage exhibited remarkable transcriptome-wide differences between the two cell lineages at both stages, including genes involved in negative regulation of transcription and signaling. These data provide critical insights on cell fate choices in cleavage embryos. Rainbow-seq bridged a critical gap between cellular division history and single-cell RNA-seq assays.
Fast and simple comparison of semi-structured data, with emphasis on electronic health records
Authors: Robinson Max , Hadlock Jennifer , Yu Jiyang , Khatamian Alireza , Aravkin Aleksandr Y. , Deutsch Eric W. , Price Nathan D. , Huang Sui , Glusman Gustavo
Published: April 2018

We present a locality-sensitive hashing strategy for summarizing semi-structured data (e.g., in JSON or XML formats) into ‘data fingerprints’: highly compressed representations which cannot recreate details in the data, yet simplify and greatly accelerate the comparison and clustering of semi-structured data by preserving similarity relationships. Computation on data fingerprints is fast: in one example involving complex simulated medical records, the average time to encode one record was 0.53 seconds, and the average pairwise comparison time was 3.75 microseconds. Both processes are trivially parallelizable.

Applications include detection of duplicates, clustering and classification of semi-structured data, which support larger goals including summarizing large and complex data sets, quality assessment, and data mining. We illustrate use cases with three analyses of electronic health records (EHRs): (1) pairwise comparison of patient records, (2) analysis of cohort structure, and (3) evaluation of methods for generating simulated patient data.
Scene complexity modulates degree of feedback activity during object recognition in natural scenes
Authors: Groen Iris I. A. , Jahfari Sara , Seijdel Noor , Ghebreab Sennary , Lamme Victor A. F. , Scholte H. Steven
Published: April 2018

Object recognition is thought to be mediated by rapid feed-forward activation of object-selective cortex, with limited contribution of feedback. However, disruption of visual evoked activity beyond feed-forward processing stages has been demonstrated to affect object recognition performance. Here, we unite these findings by reporting that the detection of target objects in natural scenes is selectively characterized by enhanced feedback when these objects are embedded in high complexity scenes. Human participants performed an animal target detection task on scenes with low, medium or high complexity as determined by a biologically plausible computational model of low-level contrast statistics. Three converging lines of evidence indicate that feedback was enhanced during categorization of scenes with high, but not low or medium complexity. First, functional magnetic resonance imaging (fMRI) activity in early visual cortex (V1) was selectively enhanced for target objects in scenes with high complexity. Second, event-related potentials (ERPs) evoked by high complexity scenes were selectively enhanced from 220 ms after stimulus-onset. Third, behavioral performance deteriorated for highly complex scenes when participants were pressed for time, but not when they could process the scenes fully and thereby benefit from the enhanced feedback. Formal modeling of the reaction time distributions revealed that object information accumulated more slowly for high complexity scenes (resulting in more errors especially for fast decisions), and directly related to the build-up of the feedback activity that was observed exclusively for high complexity scenes. Together, these results suggest that while feed-forward activity may suffice for simple scenes, the brain employs recurrent processing more adaptively in naturalistic settings, using minimal feedback for sparse, coherent scenes and increasing feedback for complex, fragmented scenes.

Author summary

How much neural processing is required to detect objects of interest in natural scenes? The astonishing speed of object recognition suggests that fast feed-forward buildup of perceptual activity is sufficient. However, this view is contradicted by findings that show that disruption of slower neural feedback leads to decreased detection performance. Our study unites these discrepancies by identifying scene complexity as a critical driver of neural feedback. We show how feedback is enhanced for complex, cluttered scenes compared to simple, well-organized scenes. Moreover, for complex scenes, more feedback is associated with better performances. These findings relate the flexibility of neural processes to perceptual decision-making by demonstrating that the brain dynamically directs neural resources based on the complexity of real-world visual inputs.
Velocity and Diameter Measurements of Penetrating Arteries by Model Based Analysis of Complex Difference Images in Phase Contrast MRI
Authors: Zong Xiaopeng , Lin Weili
Published: April 2018

Pathological changes of penetrating arteries (PAs) within deep white matter (WM) may be an important contributing factor of cerebral small vessel disease (SVD). Quantitative characterization of the PAs is important for further illuminating their roles in SVD but remains challenging due to their sub-voxel sizes. We propose a quantitative MRI approach for measuring the diameters and flow velocities of PAs based on model based analysis of complex difference images in phase contrast MRI. The complex difference image of each PA is fitted by a model image calculated by taking into account the partial volume effect and signal enhancement due to in flow effects to obtain velocity , diameter (D), and volume flow rate (VFR) of the PAs. Simulation, phantom, and in vivo studies were carried out to evaluate the accuracy and measurement errors of the proposed method. Our results suggest that PAs with velocities ≥ 0.8 cm/s can be accurately measured with , D, and VFR errors of 0.28 cm/s, 20 μm, and 0.024 mm3/s, respectively, although the mean lumen area occupies only 18% of the acquired pixel area. The PAs have a distribution peak at ~1.2 cm/s and diameters distribution mostly in the range of 88 – 200 μm Quantitative measurements of PAs with the MBAC method may serve as an invaluable tool for illuminating the role of PAs in the aetiopathogenesis of cerebral SVD.
Hippocampal Pattern Separation Supports Reinforcement Learning
Authors: Ballard Ian , Wagner Anthony D. , McClure Samuel M.
Published: April 2018

1

Animals rely on learned associations to make decisions. Associations can be based on relationships between object features (e.g., the three-leaflets of poison ivy leaves) and outcomes (e.g., rash). More often, outcomes are linked to multidimensional states (e.g., poison ivy is green in summer but red in spring). Feature-based reinforcement learning fails when the values of individual features depend on the other features present. One solution is to assign value to multifeatural conjunctive representations. We tested if the hippocampus formed separable conjunctive representations that enabled learning of response contingencies for stimuli of the form: AB+, B-, AC-, C+. Pattern analyses on functional MRI data showed the hippocampus formed conjunctive representations that were dissociable from feature components and that these representations influenced striatal PEs. Our results establish a novel role for hippocampal pattern separation and conjunctive representation in reinforcement learning.