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The deposition of soluble gases to the sea surface is physical process that impacts the biogeochemical cycling of sulfur, carbon, nitrogen, phosphorus and latent and sensible heat. Soluble atmospheric gases such as SO2, nitric acid and ammonia play key roles in global climate and air quality through their influence on aerosol and cloud formation, and tropospheric photochemistry. Direct air/sea flux measurements of soluble trace gases are rare and most of what we know stems from studies of latent and sensible heat. Lack of fundamental understanding of the physical controls of air/sea deposition of soluble gases limits the accuracy of models simulating some global biogeochemical cycles. This study involved direct flux measurements of SO2, water vapor, sensible heat and momentum from the atmosphere to the sea surface. These measurements were done at piers located in San Diego, CA and Duck, NC. The goal of the study is to gain insight into the physical controls on soluble trace gas fluxes by comparing these measurements to each other and to various air/sea flux numerical parameterizations. The results of this analysis demonstrate that SO2 flux measurements are a viable approach to studying the physics of soluble trace gas flux over the ocean. Furthermore, the results show the transfer velocity of SO2 is ~ 20 % lower than that of water vapor. This reduction is attributed to resistance to gas transfer due to diffusion in the interfacial layer immediately above the sea surface. This study represents the first ever in situ measurement of diffusive resistance in the interfacial layer. The magnitude of diffusive resistance calculated from these measurements is ~ 18 % larger than the current gas transfer parameterizations (Fairall et al., 2000).

PurposeIn this study, we investigated the performance of deep learning (DL) models to differentiate between normal and glaucomatous visual fields (VFs) and classify glaucoma from early to the advanced stage to observe if the DL model can stage glaucoma as Mills criteria using only the pattern deviation (PD) plots. The DL model results were compared with a machine learning (ML) classifier trained on conventional VF parameters.MethodsA total of 265 PD plots and 265 numerical datasets of Humphrey 24-2 VF images were collected from 119 normal and 146 glaucomatous eyes to train the DL models to classify the images into four groups: normal, early glaucoma, moderate glaucoma, and advanced glaucoma. The two popular pre-trained DL models: ResNet18 and VGG16, were used to train the PD images using five-fold cross-validation (CV) and observed the performance using balanced, pre-augmented data (n= 476 images), imbalanced original data (n=265) and feature extraction. The trained images were further investigated using the Grad-CAM visualization technique. Moreover, four ML models were trained from the global indices: mean deviation (MD), pattern standard deviation (PSD) and visual field index (VFI), using five-fold CV to compare the classification performance with the DL model’s result.ResultsThe DL model, ResNet18 trained from balanced, pre-augmented PD images, achieved high accuracy in classifying the groups with an overall F1-score: 96.8%, precision: 97.0%, recall: 96.9%, and specificity: 99.0%. The highest F1 score was 87.8% for ResNet18 with the original dataset and 88.7% for VGG16 with feature extraction. The DL models successfully localized the affected VF loss in PD plots. Among the ML models, the random forest (RF) classifier performed best with an F1 score of 96%.ConclusionThe DL model trained from PD plots was promising in differentiating normal and glaucomatous groups and performed similarly to conventional global indices. Hence, the evidence-based DL model trained from PD images demonstrated that the DL model could stage glaucoma using only PD plots like Mills criteria. This automated DL model will assist clinicians in precision glaucoma detection and progression management during extensive glaucoma screening.

Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here we explored how distinct embryonic neural progenitor pools in the lateral ganglionic eminence (LGE) contribute to the synaptic circuit connectivity and neuronal diversity in the postnatal mouse striatum. In utero labeling of apical intermediate progenitors (aIP), as well as other progenitors (OP), revealed that both generate spiny projection neurons (SPNs), consisting of D1-expressing direct pathway (dSPNs) as well as D2-expressing indirect pathway (iSPNs) found intermingled in the medial aspects of striatum, with similar electrophysiological and anatomical properties. Subsequent optogenetic circuit-mapping of local synaptic connections between these SPNs showed that neurogenic stage rather than progenitor origin controls the strength of lateral GABAergic connections. However, embryonic progenitor origin conveyed strong biases in their long-range cortical inputs, in that aIP-derived SPNs were preferentially driven by inputs from the medial prefrontal cortex whereas OP-derived SPNs were strongly driven by inputs from the visual cortex. Combined, these results demonstrate critical roles for embryonic origin in shaping the inhibitory and excitatory synaptic circuits in the striatum.

Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0456-2) contains supplementary material, which is available to authorized users.

Summary Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here, we explore how distinct embryonic neural progenitor pools in the lateral ganglionic eminence contribute to neuronal diversity and synaptic circuit connectivity in the mouse striatum. In utero labeling of Tα1-expressing apical intermediate progenitors (aIP), as well as other progenitors (OP), reveals that both progenitors generate direct and indirect pathway spiny projection neurons (SPNs) with similar electrophysiological and anatomical properties and are intermingled in medial striatum. Subsequent optogenetic circuit-mapping experiments demonstrate that progenitor origin significantly impacts long-range excitatory input strength, with medial prefrontal cortex preferentially driving aIP-derived SPNs and visual cortex preferentially driving OP-derived SPNs. In contrast, the strength of local inhibitory inputs among SPNs is controlled by birthdate rather than progenitor origin. Combined, these results demonstrate distinct roles for embryonic progenitor origin in shaping neuronal and circuit properties of the postnatal striatum., Graphical abstract, Highlights • The Tα1 promoter distinguishes two embryonic progenitor pools in the LGE • Both pools generate intermixed spiny projection neurons in dorsomedial striatum • Excitatory cortical inputs are biased toward SPNs of different embryonic origin • Neurogenic stage rather impacts local inhibitory connections among SPNs, van Heusden et al. demonstrate significant roles for distinct embryonic progenitor pools in the formation of postnatal striatal synaptic circuits. Diverse progenitor pools generate striatal spiny projection neurons with similar intrinsic properties and convey biases in their excitatory cortical synaptic inputs, whereas birthdate affects strength of local inhibitory synaptic inputs.

The Port of Portland, Oregon recently (2015) completed a comprehensive, port-wide seismic risk assessment as part of a long-term plan to improve the Port’s seismic resiliency. The Port targeted 20 of their most important marine and aviation assets for this risk analysis and retained a team to develop and apply a seismic performance evaluation of each asset. A multi-hazard level approach was implemented that addressed the range of return periods (i.e. ground motions) commonly applied for both marine and building structures. The seismic performance of each asset was evaluated using inertial loading based on estimated site-specific ground motions and kinematic loading based on estimated seismically-induced soil displacements. This paper focuses on the geotechnical and structural approaches utilized for the marine facilities, and the integrated approach to evaluating dynamic soil-structure interaction for the waterfront structures. Key discussion points include the synthesis and application of archival data, the need for site-specific ground motions due to limitations in code-based soil factors, appropriate level of analyses for seismic risk assessment, and considerations associated with structural and geotechnical mitigation strategies suggested for the subsequent benefit/cost analyses. These analyses provided requisite input for the subsequent port and regional seismic risk analyses addressed in the companion paper by Graf and others (2016).

Stress Counseling: A Rational Emotive Approach Albert Ellis, Jack Gordon, Michael Neenan, and Stephen Palmer. New York: Springer Publishing Company, 1998, 200 pp. Softcover, $32.95 (U.S.), $36.80 (outside the U.S.). Website: www.springerpub.com Albert Ellis's vastly influential Rational Emotive Behavior Therapy (REBT) has been around for some 40 years and is one of the best-known psychological theories: Hundreds of articles and books have described REBT, and virtually all counselors and psychologists trained in the United States have been exposed to the theory in courses, books, and videos. This state of affairs can constitute quite a hurdle for the aspiring REBT author: What ground is left to cover? While Stress Counseling casts REBT within a stress counseling framework, many of the ideas and techniques elaborated in this book can indeed be found in many other works such as A New Guide to Rational Living (Ellis & Harper, 1975) and The RET Resource Book for Practitioners (Bernard & Wolfe, 1993). Given the popularity of REBT, however, a book that details the theory should be judged not on the newness of the material but on how it succeeds in engaging and educating. On this score, Stress Counseling delivers. After a preface by Ellis, Stress Counseling begins with a chapter that describes the stress process from a REBT perspective. Human beings are said to create most of their own stress by what they tell themselves about events. Perception, beliefs, and ineffective behaviors are said to be the key elements in stress. In effect, then, stress is recast as "distress," the emotional consequence or "C" (in Ellis's "ABC" rubric) of holding irrational beliefs. This gives the authors an opportunity to spend most of the remainder of the book elaborating on counseling within the REBT framework. In this theory-as chapter 1 illustrates and as most of us know-it is not the environmental activating event (A) that causes the distressing emotional consequence (C), but rather our beliefs (B) about the event. Irrational beliefs lead to undue emotional distress and self-defeating or ineffective behaviors; rational beliefs lead to appropriate emotion and effective coping. Elevation of our preferences about ourselves, others, and the world into implicit "shoulds," "oughts," and "musts" is said to cause most human distress. For example, when the preference "I prefer that people like me and treat me fairly" becomes elevated into the irrational belief "People must like me and treat me well at all times or they're evil and deserving of punishment," unhealthy emotions and ineffective behaviors occur. Learning to recognize and dispute these irrational beliefs and to replace them with rational beliefs leads to emotional balance and effective action. Chapter 1 proceeds to detail specific emotions connected with the three major types of irrational beliefs, and ends with a rather lengthy case vignette that is used to illustrate various REBT principles and interventions. Although chapter 1 offers little or nothing "new," it offers a well-organized, lucid, and readable depiction of distress and REBT. Later chapters of Stress Counseling are equally clear and engaging in their depiction, respectively, of assessment; the beginning, middle, and final stages of stress counseling; additional REBT counseling techniques; brief psychotherapy with crisis intervention; "How to Deal with Difficult Clients;" and "Occupational Stress and Group Work." The book ends with a listing of organizations that provide additional training in REBT. Appendixes contain several very useful forms and techniques whose applications are detailed in the text. Stress Counseling is likely to be particularly useful to the practicing counselor or psychotherapist. For instance, the text depicts specific techniques or procedures such as "inference chaining" (p. 20), "the 13 steps of the counseling sequence" (p. 41), and the "money example" for teaching clients about REBT (p. …

The purpose of these studies was to determine the levels of intrinsic activity in vitro at muscarinic receptor pharmacological subtypes (M1, M2, and M3) that would optimize cognitive activity while minimizing acute adverse cholinergic effects in vivo. These levels of intrinsic efficacy at M1, M2, and M3 receptor subtypes, the target profile, could then be used to assess novel compounds for antidementia potential. To accomplish this, a series of muscarinic agonists (spirofuranone analogues) was prepared, and compounds with variable intrinsic activity at M1, M2, and M3 receptor subtypes were selected for characterization in a series of in vivo tests (reversal of scopolamine-induced memory impairment, and agonist-induced salivation, lacrimation, diarrhea, hypothermia, and bradycardia). Memory enhancement was found to correspond best to M1 activity with an apparent threshold of intrinsic activity of approximately 50% in human M1-transfected CHO cells. Surprisingly, a preferential M3 agonist (ARL 16037) produced a partial reversal of scopolamine-induced memory impairment, but only at high doses that resulted in severe diarrhea. However, it was unclear whether this memory effect was due to the weak M1 or strong M3 agonist activity of this compound. Three muscarinic agonists (ARL 14995, ARL 15467, and ARL 15424) reversed the scopolamine-induced memory deficits, as well as the cholinesterase inhibitor tacrine, suggesting that muscarinic agonists may be at least as clinically effective as cholinesterase inhibitors. Acute cholinergic side effects (diarrhea, salivation, lacrimation) corresponded best to M3 activity (contraction of guinea pig trachea) and were greatly diminished with in vitro intrinsic M3 activity of 50% or less. Agonist-induced heart rate reduction corresponded best to M2 receptor efficacy (inhibition of rat heart adenylyl cyclase). Identification of compounds without detectable in vitro intrinsic activity but with measurable heart rate effects suggested that signal amplification at M2 receptors in vitro limited detection of weak partial agonists. Development of the target profile has proven useful in rapid evaluation of compounds for optimization of muscarinic pharmacological properties. Drug Dev. Res. 40:117–132, 1997. © 1997 Wiley-Liss, Inc.

Robert A. Cherny, Paul A. Adlard, David I. Finkelstein, Elisabeth Gautier, Penny Huggins, Jack Parsons, Craig W. Ritchie, Elysia Robb, Mikhalina Cortes, Irene Volitakis, Xiang Liu, Jeffrey P. Smith, Keyla Perez, Katrina Laughton, Qiao-Xin Li, Susan A. Charman, Joseph A. Nicolazzo, Simon Wilkins, Karolina Deleva, Gaik Kok, Roberto Cappai, Rudi E. Tanzi, Colin L. Masters, Kevin J. Barnham, Ashley I. Bush, The Mental Health Research Institute of Victoria & The University of Melbourne, Parkville, VIC, Australia; MHRI & The University of Melbourne, Parkville, Australia; Prana Biotechnology Ltd, Parkville, Australia; Imperial College London, London, United Kingdom; MHRI, Parkville, Australia; The University of Melbourne, Parkville, Australia; Centre for Drug Candidate Optimisation, Parkville, Australia; Bio 21 Institute, The University of Melbourne, Parkville, Australia; Genetics & Aging Research Unit, MGH, Boston, MA, USA. Contact e-mail: rcherny@mhri.edu.au