bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroprotection and the Ischemic Cascade
Authors: Felberg Robert A. , Burgin W. Scott , Grotta James C.
Published: August 2016

Brain ischemia is a process of delayed neuronal cell death, not an instantaneous event. The concept of neuroprotection is based on this principle. Diminished cerebral blood flow initiates a series of events (the “ischemic cascade”) that lead to cell destruction. This ischemic cascade is akin to a spreading epidemic starting from a hypothesized core of ischemia and radiating outward. If intervention occurs early, the process may be halted.

Interventions have been directed toward salvaging the ischemic penumbra. Hypothermia decreases the size of the ischemic insult in both anecdotal clinical and laboratory reports. In addition, a wide variety of agents have been shown to reduce infant volume in animal models. Pharmacologic interventions that involve thrombolysis, calcium channel blockade, and cell membrane receptor antagonism have been studied and have been found to be beneficial in animal cortical stroke models. Human trials of neuroprotective therapies have been disappointing. Other than thrombolytics, no agents, have shown an unequivocal benefit. The future of neuroprotection will require a logical extension of what has been learned in the laboratory and previous human trials. A sensible approach to the use of multiple-agent cocktails used in combination with thrombolytics is likely to offer the highest chance for benefit.
Perspectives on Current Directions in the Neurobiology of Addiction Disorders Relevant to Genetic Risk Factors
Authors: Hurd Yasmin L.
Published: August 2016

There is a significant heritability of drug addiction disorders, but potential genes that may underlie such vulnerability have not been clearly identified. Common neurobiological candidates for drug abuse include genes related to dopamine, opioid neuropeptide, and glutamate transmission that play important roles in drug reward and inhibitory control. This article provides an overview of genetic polymorphisms linked to these neurobiological systems, particularly in relation to psychostimulant- and opioid-addiction vulnerability.
Nature Against Nurture: Calcification in the Right Thalamus in a Young Man with Anorexia Nervosa and Obsessive-Compulsive Personality Disorder
Authors: Conrad Rupert , Wegener Ingo , Geiser Franziska , Imbierowicz Katrin , Liedtke Reinhard
Published: August 2016

This report describes the case of a young man with a large calcification in the right thalamus that was first diagnosed at 9 years of age. Case history reveals specific eating rituals and other obsessive-compulsive personality traits during the patient's childhood and adolescence, fulfilling diagnostic criteria of obsessive-compulsive personality disorder. After a critical life event the patient develops anorexia nervosa. We suggest that our case and further literature provide evidence for an involvement of specific thalamic structures, such as the dorsomedial nucleus, in the development of anorexia nervosa. Furthermore, the treatment of the patient by a combined psychotherapeutic and pharmacotherapeutic approach is described. We focus on the beneficial effect of the atypical antipsychotic olanzapine, which can induce weight gain by an increase of leptin levels.
Substance P Antagonists: Meet the New Drugs, Same as the Old Drugs? Insights From Transgenic Animal Models
Authors: Santarelli Luca , Saxe Michael D.
Published: August 2016

Antidepressants that primarily target the reuptake of monoamines have been highly successful treatments. However, therapies with these drugs still have several drawbacks, namely severe side effects, delays in the onset of action, and a significant percentage of non-responders. Recently, non-peptidic antagonists of the neurokinin 1 receptor, or substance P antagonists, have emerged as a novel class of drugs with antidepressant efficacy that is comparable to current drugs, but a potentially reduced side effect profile. This review summarizes the pre-clinical evidence derived from pharmacological and transgenic animal studies that suggests an important role for the substance P/neurokinin 1 system in anxiety and depression. Also, potential mechanisms by which substance P antagonists may produce their therapeutic effects are discussed.
Emerging Therapeutics for Alzheimer's Disease: An Avenue of Hope
Authors: Samuels Steven C. , Grossman Hillel
Published: August 2016

Emerging therapies for Alzheimer's disease offer hope to patients and their caregivers. Future treatments will probably include combination approaches with agents that modify amyloid processing, deposition, and clearance. One example, the AD vaccine, reduced amyloid burden and changed behavior in animal models of AD, but the human trial was halted when several subjects developed brain inflammation. Anti-inflammatory agents have epidemiologic support, but clinical trials have been disappointing, possibly related to inadequate study with anti-inflammatory agents that modify amyloid processing. Agents that target known cardiovascular risk factors, such as hypercholesterolemia, hypertension, and insulin resistance, have epidemiologic, preclinical, and clinical evidence to warrant further investigation. Heavymetal chelators, antioxidants, neurotrophic factors, glutaminergic modulators, and agents that modify hyper-phosphorylation of Tau are other approaches in research and development.
Beyond Intravenous Thrombolysis
Authors: Lee Kiwon , Muppidi Srikanth , Siddiq Farhan , Pineda Carissa , Brock David G. , Bell Rodney D.
Published: August 2016

The National Institute of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator has been considered a landmark study in the acute treatment of ischemic stroke. Unfortunately, only a small percentage of all ischemic stroke patients presents to the hospital in time to receive the drug. Moreover, the recannalization rate of a major artery occlusion, such as the proximal middle cerebral artery or top of the internal carotid artery occlusion, after intravenous (IV) thrombolytic therapy has been disappointingly low. Since the Food and Drug Administration's approval of IV plasminogen activator, there have been numerous randomized clinical trials investigating the safety and efficacy of different thrombolytics administered in various time frames. In addition to the IV administration, efforts have been made in order to study the radiographic as well as clinical effects of intra-arterial (IA) thrombolysis. The combination of IV and IA thrombolysis has been studied. For patients who do not qualify for receiving chemical thrombolysis, new devices have been developed for mechanical thrombectomy.
Anxiety as a Primary Symptom in Cycloid Psychosis
Authors: Strik Werner K.
Published: August 2016

Psychotic anxiety has not been systematically included in standard psychopathologic and diagnostic literature, presumably because anxiety is implicitly perceived to be an emphatically comprehensible consequence of the cognitive symptoms of psychosis. This review gives an overview of neurophysiologic studies that indicate different pathogenic mechanisms for different types of psychosis. Convergent and complementary structural and functional imaging findings, biochemical and neuropsychological data allow conjecture as to neurophysiologic-psychopathologic links in cycloid psychosis. Intriguing results suggest that in cycloid psychosis, a generalized hyperasousal related to the tonus of the noradrenergic system may be the basic disturbance causing the delusionary and perceptual psychotic distortions. The findings are specific for cycloid psychoses, which are diagnosed as polymorphous psychosis in the International Classification of Diseases and Related Health Problems, 10th Edition. Furthermore, these findings are consistent with the author's hypothesis that the emotional derailment is the primary disturbance in cycloid psychosis (anxiety-elation). In contrast, cognitive disturbances are secondary and remit after the exceptional emotional state is rebalanced.
Sexual and Other Axis I Diagnoses of 60 Males Arrested for Crimes Against Children Involving the Internet
Authors: Krueger Richard B. , Kaplan Meg S. , First Michael B.
Published: August 2016

Objective:This study was conducted to describe Axis I sexual diagnoses of 60 males arrested for possession of child pornography obtained via the Internet and/or attempting to meet children via the Internet.

Methods:Data was obtained from a chart review of evaluations conducted on 60 males referred for a psychosexual evaluation following an arrest for possession of child pornography and/or attempting to meet children. All crimes involved use of the Internet. Information obtained from the chart review was entered into SAS. All diagnoses were made according to theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Simple descriptive statistics were computed and cross tabulations were tested for significance using χ2 or Fisher's Exact test.

Results:Of the total sample, 40% had at least one paraphilia. Thirty-one percent had a diagnosis of pedophilia and 18% of a paraphilia not otherwise specified (NOS). Thirty-three percent had a sexual disorder NOS, characterized by hypersexuality. Seventy percent of the total sample had an Axis I disorder that antedated and was judged to be contributory to the behavior leading to their arrest.

Conclusions:This sample of men arrested for committing crimes against children and adolescents via the Internet has a high incidence of lifetime sexual and other psychopathology.
Cognitive Factors in Schizophrenia: Causes, Impact, and Treatment
Authors: Meltzer Herbert Y.
Published: August 2016

Greater attention has been given to the cognitive dimension in schizophrenia in recent years. This has resulted from increased recognition that cognitive impairment and negative symptoms of the disease have a greater impact on quality of life (QOL) compared to positive symptoms. Successful treatment of positive symptoms in patients with schizophrenia has not been shown to robustly translate into improvements in employment status or social relationships, while cognitive improvements are strongly associated with these important aspects of QOL and independence. These findings are based on extensive testing with standard cognitive tests for measuring executive function, verbal learning and memory, word recall, verbal working memory, spatial working memory, attention, and vigilance. Verbal learning and executive function, in particular, have been found to be valid predictors of employment success independent of the degree of severity of positive symptoms.
Clinical Trials of Amyloid-Based Therapies for Alzheimer's Disease
Authors: Tariot Pierre N.
Published: August 2016

We appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (activeβ-amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.
Integrating Symptomatic- and Disease-Modifying Treatments
Authors: Cummings Jeffrey L.
Published: August 2016

Although treatments for Alzheimer’s disease (AD) currently focus on symptomatic therapies, we are entering into an era of disease-modifying therapies. Central to disease modification is early diagnosis; the disease should be slowed as early as possible, maximizing the preservation of cognitive integrity. Ideally, AD should be diagnosed before the onset of dementia, perhaps with the use of biomarkers.

Some therapies suggest that cholinesterase inhibitors and memantine have disease-modifying properties, though not all studies agree. Doody and colleagues have produced data suggesting that these agents may modify the course of AD, but it is not clear that they affect the underlying mechanisms that lead to cell death. Rather than being disease-modifying agents, cholinesterase inhibitors and memantine have potential as disease-course-modifying agents. Language precision will be extremely important in describing these therapies. One European consensus conference concluded that affecting disease course is not adequate for disease modification, but this has not been largely endorsed.

Symptomatic therapies are those affecting the course of the disease. Their benefits are multidimensional, improving cognition, global assessment, activities of daily living, behavior, and caregiver burden. Symptomatic therapies should defer decline. Clinical trials show that symptomatic therapies produce an initial improvement above baseline. However, some patients experience observable changes and some experience none. These therapies are believed to produce ~1 point improvement on the Mini-Mental State Examination (MMSE) average, and a decline that is otherwise parallel to a placebo group after a period of delayed progression (Slide 1).
The Psychobiology of Resilience
Authors: Stein Dan J.
Published: August 2016

Although adverse environments are well known to be a risk factor for psychopathology, many individuals respond adaptively to such environments. There is growing interest in the underlying mechanisms involved in such resilience. Several cognitive-affective processes may be involved, and these may be mediated by particular neuronal circuits and neurochemical systems. This article summarizes some of the relevant work on the role of fear conditioning, reward processing, and social behavior in resilience. There is a growing body of data on how particular gene-environment interactions affect these processes, and thus underpin resilience. Ultimately, a better understanding of the mechanisms underpinning resilience may lead to novel interventions.
Update on the Etiology and Treatment of Schizophrenia and Bipolar Disorder
Authors: Buckley Peter F.
Published: August 2016

Schizophrenia and bipolar disorder are two debilitating mental health disorders, both of which manifest early in adulthood and are associated with severe impairment as well as increased suicide risk. In addition, factors affecting disease severity, such as substance abuse, are often prevalent in these patient populations. In the United States, the prevalence of bipolar disorder is believed to be ~3.5%, while the rate for schizophrenia is ~1%. Although each disorder presents with its own symptom profile, the approaches to treatment are similar and include early diagnosis and use of psychosocial therapy. Research initiatives, such as genetic studies, are used in both disorders as well. For schizophrenia, treatment typically includes the combination of an antipsychotic and psychosocial intervention. For bipolar disorder, clinicians commonly prescribe mood-stabilizing drugs (eg, lithium, valproic acid) as first-line treatment. Many of the second-generation antipsychotics have been approved by the US Food and Drug Administration for bipolar disorder treatment in the manic phase. Patients who are affected by either disorder also face the challenges of treatment nonadherence, which can be affected by substance abuse and can hinder symptom remission as well as spur unnecessary medication switches due to nonresponse. Family members play a key role in the treatment of either disorder.

This expert review supplement focuses on treatment options and research strategies being utilized for the management and advanced understanding of schizophrenia and bipolar disorder. Research examining the pharmacology of commonly used medications for the treatment of both disorders is also presented.
A New Mechanism for Nitrogen Cycling in the Southern Ocean
Authors: Stanley Sarah
Published: July 2016

A nitrite-oxidizing enzyme may work in reverse for some microbes in the Antarctic autumn.
Tackling the Paris Temperature Targets
Authors: Crane Leah
Published: July 2016

The global temperature targets established in Paris in 2015 are ambitious; new research examines what it would take to achieve those targets.
Amoeba People Sing Quirky Tunes About Geoscience
Authors: Showstack Randy
Published: July 2016

A whimsical backstory identifies the musicians as aliens from the planet Crouton sent to Earth to transmit scientific information back home in song.
An improvement of performance in n-channel organic field effect transistors with N-phenyl[60]fulleropyrrolidines by molecular doping
Authors: Long Dang Xuan , Karakawa Makoto , Noh Yong-Young
Published: July 2016

The high performance of soluble [60]fulleropyrrolidine upon its use as the active layer of n-channel organic field-effect transistors (OFETs) is reported.
Precise control and measurement of solid–liquid interfacial temperature and viscosity using dual-beam femtosecond optical tweezers in the condensed phase
Authors: Mondal Dipankar , Mathur Paresh , Goswami Debabrata
Published: July 2016

We present a novel method of microrheology based on femtosecond optical tweezers, which in turn enables us to directly measure and controlin situtemperature at microscale volumes at the solid–liquid interface.
Charge transfer reactions between gas-phase hydrated electrons, molecular oxygen and carbon dioxide at temperatures of 80–300 K
Authors: Akhgarnusch Amou , Tang Wai Kit , Zhang Han , Siu Chi-Kit , Beyer Martin K.
Published: July 2016

With a combination of mass spectrometry and quantum chemistry, we derive hydration enthalpies for CO2˙− and O2˙− and show that the charge transfer from CO2˙− to O2 proceeds via a CO4˙− intermediate.
Hydrated forms of fluoroacetic acid: a rotational study
Authors: Feng Gang , Gou Qian , Evangelisti Luca , Spada Lorenzo , Blanco Susana , Caminati Walther
Published: July 2016

Two conformers have been observed in the rotational spectrum of the 1 : 1 adduct of fluoroacetic acid and water.
An ontological and epistemological analysis of the presentation of the first law of thermodynamics in school and university textbooks
Authors: Poblete Joaquín Castillo , Rojas Rocío Ogaz , Merino Cristian , Quiroz Waldo
Published: July 2016

Considering the relevance of thermodynamics to the scientific discipline of chemistry and the curriculum of the Western school system, the philosophical system of Mario Bunge, particularly his ontology and epistemology, is used herein to analyze the presentation of the first law of thermodynamics in 15 school and university textbooks. The ontological analysis shows that the concepts heat “q” and work “w” are categorized as processes, while the concepts of internal energy “U”, pressure “P”, volume “V” and temperature “T” are categorized as properties. The results reveal that 8 of the 15 textbooks incorrectly present work “w” as a property, while 7 textbooks incorrectly present heat “q” as a property. Furthermore, 3 textbooks present the concept of energy as a property and assign it a merely operational definition as the capacity to do work. The analysis also examined patterns of causality and the mechanism used to explain the connection between the variables of cause and effect in three thermodynamic systems. The results indicated that only 2 textbooks contain such a mechanism.
Two-step synthesis of binary Ni–Fe sulfides supported on nickel foam as highly efficient electrocatalysts for the oxygen evolution reaction
Authors: Dong Bin , Zhao Xin , Han Guan-Qun , Li Xiao , Shang Xiao , Liu Yan-Ru , Hu Wen-Hui , Chai Yong-Ming , Zhao Hui , Liu Chen-Guang
Published: July 2016

A facile two-step method has been used to synthesize binary Ni–Fe sulfides supported on nickel foam (NF) as electrocatalysts for the oxygen evolution reaction (OER).
One-step fabrication of a mixed-halide perovskite film for a high-efficiency inverted solar cell and module
Authors: Chiang Chien-Hung , Lin Jun-Wei , Wu Chun-Guey
Published: July 2016

Combining halogen composition and film casting engineering, a high quality homogeneous film with a large area can be prepared using a one-step method. Inverted solar cells and modules, based on mixed-halide perovskite films, achieved the highest efficiency of 16.52% and 14.3%, respectively.
Hybrid of gold nanostar and indocyanine green for targeted imaging-guided diagnosis and phototherapy using low-density laser irradiation
Authors: Du Baoji , Gu Xiaoxiao , Zhao Wenjing , Liu Zuojia , Li Dan , Wang Erkang , Wang Jin
Published: July 2016

A general strategy was used to design APP–ICG with the following functions: target ability, synergistic therapy, near-infrared and thermal imaging.
Nano-KTN@Ag/PVDF composite films with high permittivity and low dielectric loss by introduction of designed KTN/Ag core/shell nanoparticles
Authors: Chen Gaoru , Wang Xuan , Lin Jiaqi , Yang Wenlong , Li Haidong , Wen Yinian , Li Landi , Jiang Zhichao , Lei Qingquan
Published: July 2016

Nano-KTN with an intrinsic dipole moment was used as a nucleus, which makes Ag shells generate induced polarization to enhance the polarizability in the composites.
Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors
Authors: Ito Genta , Katsemonova Kristina , Tonelli Francesca , Lis Pawel , Baptista Marco A.S. , Shpiro Natalia , Duddy Graham , Wilson Steve , Ho Philip Wing-Lok , Ho Shu-Leong , Reith Alastair D. , Alessi Dario R.
Published: July 2016

Autosomal dominant mutations that activate the leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson's disease. Recent work has revealed that LRRK2 directly phosphorylates a conserved threonine/serine residue in the effector-binding switch-II motif of a number of Rab GTPase proteins, including Rab10. Here we describe a facile and robust method to assess phosphorylation of endogenous Rab10 in mouse embryonic fibroblasts (MEFs), lung and spleen-derived B-cells, based on the ability of the Phos-tag reagent to retard the electrophoretic mobility of LRRK2-phosphorylated Rab10. We exploit this assay to show that phosphorylation of Rab10 is ablated in kinase-inactive LRRK2[D2017A] knockin MEFs and mouse lung, demonstrating that LRRK2 is the major Rab10 kinase in these cells/tissue. We also establish that the Phos-tag assay can be deployed to monitor the impact that activating LRRK2 pathogenic (G2019S and R1441G) knockin mutations have on stimulating Rab10 phosphorylation. We show that upon addition of LRRK2 inhibitors, Rab10 is dephosphorylated within 1–2 min, markedly more rapidly than the Ser935 and Ser1292 biomarker sites that require 40–80 min. Furthermore, we find that phosphorylation of Rab10 is suppressed in LRRK2[S910A+S935A] knockin MEFs indicating that phosphorylation of Ser910 and Ser935 and potentially 14-3-3 binding play a role in facilitating the phosphorylation of Rab10 by LRRK2 in vivo. The Rab Phos-tag assay has the potential to significantly aid with evaluating the effect that inhibitors, mutations and other factors have on the LRRK2 signalling pathway.
Loss of cargo binding in the human myosin VI deafness mutant (R1166X) leads to increased actin filament binding
Authors: Arden Susan D. , Tumbarello David A. , Butt Tariq , Kendrick-Jones John , Buss Folma
Published: July 2016

Mutations in myosin VI have been associated with autosomal-recessive (DFNB37) and autosomal-dominant (DFNA22) deafness in humans. Here, we characterise an myosin VI nonsense mutation (R1166X) that was identified in a family with hereditary hearing loss in Pakistan. This mutation leads to the deletion of the C-terminal 120 amino acids of the myosin VI cargo-binding domain, which includes the WWY-binding motif for the adaptor proteins LMTK2, Tom1 as well as Dab2. Interestingly, compromising myosin VI vesicle-binding ability by expressing myosin VI with the R1166X mutation or with single point mutations in the adaptor-binding sites leads to increased F-actin binding of this myosin in vitro and in vivo. As our results highlight the importance of cargo attachment for regulating actin binding to the motor domain, we perform a detailed characterisation of adaptor protein binding and identify single amino acids within myosin VI required for binding to cargo adaptors. We not only show that the adaptor proteins can directly interact with the cargo-binding tail of myosin VI, but our in vitro studies also suggest that multiple adaptor proteins can bind simultaneously to non-overlapping sites in the myosin VI tail. In conclusion, our characterisation of the human myosin VI deafness mutant (R1166X) suggests that defects in cargo binding may leave myosin VI in a primed/activated state with an increased actin-binding ability.
Inositol hexakisphosphate kinase 1 (IP6K1) activity is required for cytoplasmic dynein-driven transport
Authors: Chanduri Manasa , Rai Ashim , Malla Aushaq Bashir , Wu Mingxuan , Fiedler Dorothea , Mallik Roop , Bhandari Rashna
Published: July 2016

Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP7), are conserved eukaryotic signaling molecules that possess pyrophosphate and monophosphate moieties. Generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine pyrophosphorylation. Here, we report inositol pyrophosphates as novel regulators of cytoplasmic dynein-driven vesicle transport. Mammalian cells lacking IP6K1 display defects in dynein-dependent trafficking pathways, including endosomal sorting, vesicle movement, and Golgi maintenance. Expression of catalytically active but not inactive IP6K1 reverses these defects, suggesting a role for inositol pyrophosphates in these processes. Endosomes derived from slime mold lacking inositol pyrophosphates also display reduced dynein-directed microtubule transport. We demonstrate that Ser51 in the dynein intermediate chain (IC) is a target for pyrophosphorylation by IP7, and this modification promotes the interaction of the IC N-terminus with the p150Glued subunit of dynactin. IC–p150Glued interaction is decreased, and IC recruitment to membranes is reduced in cells lacking IP6K1. Our study provides the first evidence for the involvement of IP6Ks in dynein function and proposes that inositol pyrophosphate-mediated pyrophosphorylation may act as a regulatory signal to enhance dynein-driven transport.
Inhibitory effect of NBL1 on PDGF-BB-induced human PASMC proliferation through blockade of PDGFβ-p38MAPK pathway
Authors: Cui Chuanjue , Zhang Hongliang , Guo Lin-Na , Zhang Xiaoling , Meng Liukun , Pan Xiangbin , Wei Yingjie
Published: July 2016

Pulmonary artery remodelling is a key feature in the pathological progress of pulmonary arterial hypertension (PAH). Moreover, excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) plays a critical role in the pathogenesis of pulmonary artery remodelling. Neuroblastoma suppressor of tumorigenicity 1 (NBL1) has been previously shown to induce growth inhibition in tumour cells. However, the effect of NBL1 in the regulation of human PASMC proliferation remains unclear. In cultured human PASMCs, we observed a dose-dependent inhibitory effect of NBL1 on platelet derived growth factor (PDGF)-BB-induced cell growth, DNA synthesis and proliferating cell nuclear antigen (PCNA) expression, as measured by MTS assay, 5-ethynil-2-deoxyuridine (EdU) analysis and western blots respectively. We also detected the expression and activities of cell-cycle positive regulators (cyclin D1, cyclin E, CDK2, CDK4 and CDK6) and negative regulators (p21 and p27) in human PASMCs by western blots and co-immuoprecipitation (IP). Our results show that NBL1-induced growth suppression is associated with the decreased activity of cyclin D1–CDK4 and the decreased phosphorylation of p27 in PDGF-BB-treated human PASMCs. By western blots using the phosphor-specific antibodies, we further demonstrated that NBL1 induced growth suppression is mediated by blockade of the up-stream PDGF-receptor β (PDGFRβ)-p38 mitogen-activated protein kinase (MAPK). In conclusion, our results suggest that NBL1 could inhibit PDGF-BB-induced human PASMC proliferation, and the underlying mechanism is associated with the decreased cyclin D1–CDK4 activity and up-regulated p27 by decreasing the phosphorylation of p27 via blockade of PDGFRβ-p38MAPK signal cascade. Our findings may provide a potential therapeutic target for PAH.
Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury
Authors: Rantakari Pia , Patten Daniel A. , Valtonen Joona , Karikoski Marika , Gerke Heidi , Dawes Harriet , Laurila Juha , Ohlmeier Steffen , Elima Kati , Hübscher Stefan G. , Weston Chris J. , Jalkanen Sirpa , Adams David H. , Salmi Marko , Shetty Shishir
Published: July 2016

Significance

Organ fibrosis is a major cause of global morbidity and mortality. It is driven by chronic inflammation and associated oxidative stress with depletion of cellular antioxidant defenses. We demonstrate a pathway in which the evolutionarily conserved receptor stabilin-1 on tissue-infiltrating macrophages provides a second-line defense to prevent tissue damage from oxidative stress. Stabilin-1
+
monocytes take up malondialdehyde-LDL (MDA-LDL), a major product of oxidative lipid peroxidation, to form ceroid-laden macrophages. Through the uptake of MDA-LDL, stabilin-1 suppresses production of the profibrogenic chemokine CCL3 and prevents excessive collagen deposition in experimental models of liver fibrosis. We propose that macrophage stabilin-1 is a critical defense against oxidative tissue damage and thereby maintains tissue homeostasis.
Effect of Ti content on structure and mechanical properties of Cr–Ti–N films
Authors: Feng X. , Zhou H. , Wan Z. , Zhang K.
Published: July 2016

Cr–Ti–N films are deposited on the surface of Ti6Al4V alloy by unbalanced multi-targets reactive magnetron sputtering. In this study, the effect of the Ti content on microstructure, hardness, modulus and tribological behaviours of Cr–Ti–N films are systematically investigated. The XRD shows that with the increasing of Ti content, the phase structure evolves from Cr + Cr2N + TiN → amorphous → FCC solid solution. The hardness and modulus of Cr–Ti–N films are increased by improving Ti content in the films and Cr32.5Ti24.6N42.9 film reaches maximum values of 25.8 and 362.7 GPa, respectively. The wear rate of the Cr–Ti–N films is gradually decreased with increasing Ti content and the Cr32.5Ti24.6N42.9 film decreases five times and 25 times than Cr50.7Ti10.1N39.2 and substrate, respectively.
The role of Arabidopsis Actin-Related Protein 3 in amyloplast sedimentation and polar auxin transport in root gravitropism
Authors: Zou Jun-Jie , Zheng Zhong-Yu , Xue Shan , Li Han-Hai , Wang Yu-Ren , Le Jie
Published: July 2016

Gravitropism is vital for shaping directional plant growth in response to the forces of gravity. Signals perceived in the gravity-sensing cells can be converted into biochemical signals and transmitted. Sedimentation of amyloplasts in the columella cells triggers asymmetric auxin redistribution in root tips, leading to downward root growth. The actin cytoskeleton is thought to play an important role in root gravitropism, although the molecular mechanism has not been resolved. DISTORTED1 ( DIS1 ) encodes the ARP3 subunit of the Arabidopsis Actin-Related Protein 2/3 (ARP2/3) complex, and the ARP3/DIS1 mutant dis1-1 showed delayed root curvature after gravity stimulation. Microrheological analysis revealed that the high apparent viscosity within dis1-1 central columella cells is closely associated with abnormal movement trajectories of amyloplasts. Analysis using a sensitive auxin input reporter DII-VENUS showed that asymmetric auxin redistribution was reduced in the root tips of dis1-1 , and the actin-disrupting drug Latrunculin B increased the asymmetric auxin redistribution. An uptake assay using the membrane-selective dye FM4-64 indicated that endocytosis was decelerated in dis1-1 root epidermal cells. Treatment and wash-out with Brefeldin A, which inhibits protein transport from the endoplasmic reticulum to the Golgi apparatus, showed that cycling of the auxin-transporter PIN-FORMED (PIN) proteins to the plasma membrane was also suppressed in dis1-1 roots. The results reveal that ARP3/DIS1 acts in root gravitropism by affecting amyloplast sedimentation and PIN-mediated polar auxin transport through regulation of PIN protein trafficking.
Point-of-Care Viral Load Testing for Sub-Saharan Africa: Informing a Target Product Profile
Authors: Phillips Andrew N. , Cambiano Valentina , Nakagawa Fumiyo , Ford Deborah , Apollo Tsitsi , Murungu Joseph , Rousseau Christine , Garnett Geoff , Ehrenkranz Peter , Bansi-Matharu Loveleen , Vojnov Lara , Katz Zachary , Peeling Rosanna , Revill Paul
Published: July 2016

Point-of-care viral load tests are being developed to monitor patients on antiretroviral therapy (ART) in sub-Saharan Africa. Test design involves trade-offs between test attributes, including accuracy, complexity, robustness, and cost. We used a model of the human immunodeficiency virus epidemic and ART program in Zimbabwe and found that the attributes of a viral load testing approach that are most influential for cost effectiveness are avoidance of a high proportion of failed tests or results not received, use of an approach that best facilitates retention on ART, and the ability to facilitate greater use of differentiated care, including through expanding coverage of testing availability.
Prevalence and Outcomes of Hepatitis B Coinfection and Associated Liver Disease Among Antiretroviral Therapy-Naive Individuals in a Rural Tanzanian Human Immunodeficiency Virus Cohort
Authors: Ramírez-Mena Adrià , Glass Tracy R. , Winter Annja , Kimera Namvua , Ntamatungiro Alex , Hatz Christoph , Tanner Marcel , Battegay Manuel , Furrer Hansjakob , Wandeler Gilles , Letang Emilio ,   The KIULARCO Study Group, Asantiel Aschola , Battegay Manuel , Chale Adolphina , Faini Diana , Felger Ingrid , Francis Gideon , Furrer Hansjakob , Gamell Anna , Glass Tracy , Hatz Christoph , Hwaya Speciosa , Kalinjuma Aneth Vedastus , Kasuga Bryson , Kimera Namvua , Kisunga Yassin , Klimkait Thomas , Letang Emilio , Luhombero Antonia , Luwanda Lameck B , Mapesi Herry , Mbwile Leticia , Mkulila Mengi , Mkumbo Julius , Mkusa Margareth , Mnzava Dorcus K , Mossad Germana , Mpundunga Dolores , Mtandanguo Athumani , Mwamelo Kim , Myeya Selerine , Nahota Sanula , Ndaki Regina , Ngulukila Agatha , Ntamatungiro Alex John , Samson Leila , Sikalengo George , Tanner Marcel , Vanobberghen Fiona , Weisser Maja
Published: July 2016

Background.  We evaluated the prevalence of chronic hepatitis B virus (HBV) infection and liver fibrosis/cirrhosis in human immunodeficiency virus (HIV)-infected individuals enrolled in a rural Tanzanian prospective cohort and assessed hepatic fibrosis progression 12–24 months after antiretroviral treatment (ART) initiation.

Methods.  All ART-naive HIV-infected adults ≥15-year-old enrolled in the Kilombero and Ulanga Antiretroviral Cohort who started ART between 2005 and 2015 were included. Pre-ART factors associated with significant liver fibrosis (aspartate aminotransferase-to-platelet ratio index [APRI] >1.5) and cirrhosis (APRI > 2.0) were identified using logistic regression.

Results.  Of 3097 individuals screened, 227 (7.3%; 95% CI, 6.4–8.2) were hepatitis B surface antigen (HBsAg) positive. Before ART initiation, 9.1% individuals had significant liver fibrosis and 5.3% had cirrhosis. Human immunodeficiency virus/HBV-coinfected individuals were more likely to have an APRI score indicating significant fibrosis (14.2% vs 8.7%, P = .03) and cirrhosis (9.2% vs 4.9%, P = .03) than HBV-uninfected patients. CD4 cell count <200 cell/μL and alcohol consumption were independently associated with pre-ART APRI score, indicating significant fibrosis and cirrhosis in multivariable analyses. Among individuals with elevated APRI measurements pre- and 12–24 months post-ART initiation, 53 of 57 (93.0%) of HIV-monoinfected and 4 of 5 (80.0%) of HIV/HBV-coinfected had a regression to APRI < 1.5.

Conclusions.  Hepatic fibrosis and cirrhosis were common in our cohort, especially among HIV/HBV-coinfected individuals. The APRI improved in most patients. Pre-ART HBsAg screening and early onset of tenofovir-based ART for HIV/HBV-coinfection should be prioritized in sub-Saharan Africa.
Insurance Status and the Risk of Severe Respiratory Syncytial Virus Disease in United States Preterm Infants Born at 32–35 Weeks Gestational Age
Authors: Franklin Jeremy A. , Anderson Evan J. , Wu Xionghua , Ambrose Christopher S. , Simões Eric A. F.
Published: July 2016

Background.  Database studies have identified that public health insurance status is associated with an increased risk of severe respiratory syncytial virus (RSV) disease in US infants. However, these studies did not adjust for the presence of other risk factors and did not evaluate the risk in preterm infants.

Methods.  In this study, we evaluate the independent association between public insurance and severe RSV disease outcomes adjusting for other risk factors. The prospective, observational RSV Respiratory Events among Preterm Infants Outcomes and Risk Tracking (REPORT) study was conducted over 2 consecutive RSV seasons at 188 US clinical sites that enrolled preterm infants born at 32–35 wGA who had not received RSV immunoprophylaxis with palivizumab. Adjusted incidence rates per 100 infant-seasons of the RSV-associated endpoints of outpatient lower respiratory tract infection (LRI), emergency department (ED) visits, RSV hospitalizations (RSVHs), and intensive care unit admissions during peak RSV season (November–March) were compared for infants with private and public insurance.

Results.  Of 1642 evaluable infants enrolled in the REPORT study, 50.1% had private insurance and 49.9% had public health insurance. Adjusted rates of RSV outpatient LRIs were similar; however, rates of ED visits (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.20–3.45) were higher for subjects with public insurance, with a similar but nonsignificant trend observed for hospitalization (HR, 1.61; 95% CI, .93–2.78).

Conclusions.  Socioeconomic status, as evaluated by public versus private healthcare insurance, is a significant independent risk factor for ED use in US preterm infants and may contribute to increased RSVHs in this population.
Probiotics in Human Immunodeficiency Virus Infection: A Systematic Review and Evidence Synthesis of Benefits and Risks
Authors: Carter George M. , Esmaeili Aryan , Shah Hardikkumar , Indyk Debbie , Johnson Matthew , Andreae Michael , Sacks Henry S.
Published: July 2016

People living with human immunodeficiency virus frequently use dietary supplements, including probiotics, but concern exists about ingesting live organisms. We performed a systematic review of the benefits of probiotics and a meta-analysis of sepsis risk. We undertook a protocol-driven, comprehensive review to identify all relevant studies, assess their quality, and summarize the evidence. Of 2068 references, 27 were analyzed. The data suggest possible benefits for CD4 count, recurrence or management of bacterial vaginosis, and diarrhea management. We examined randomized, controlled studies explicitly assessing sepsis in any patient population, and we found zero cases of supplement-associated bacteremia or fungemia in 39 randomized controlled trials comprising 9402 subjects. The estimated number needed to harm is 7369 in Bayesian approach (95% credible interval: 1689, ∞), which should reassure clinicians. No or mild adverse effects were reported. Longer duration studies investigating different individual and mixed strains for plausible indications are needed to establish best practices.
A multi-line ammonia survey of the Galactic center region with the Tsukuba 32 m telescope. I. Observations and data
Authors: Arai Hitoshi , Nagai Makoto , Fujita Shinji , Nakai Naomasa , Seta Masumichi , Yamauchi Aya , Kaneko Hiroyuki , Hagiwara Kenzaburo , Mamyoda Koh-ichi , Miyamoto Yusuke , Horie Masa-aki , Ishii Shun , Koide Yusuke , Ogino Mitsutoshi , Maruyama Masaki , Hirai Katsuaki , Oshiro Wataru , Nagai Satoshi , Akiyama Daiki , Konakawa Keita , Nonogawa Hiroaki , Salak Dragan , Terabe Yuki , Nihonmatsu Yoshiki , Funahashi Fumiyoshi
Published: July 2016

We present survey data of six NH3 (J, K) = (1, 1), (2, 2), (3, 3), (4, 4), (5, 5), and (6, 6) lines, simultaneously observed with the Tsukuba 32 m telescope, in the main part of the central molecular zone of the Galaxy. The total number of on-source positions was 2655. The three lower transitions were detected with S/N > 3 at 2323 positions (93% of all the on-source positions). Among 2323, the S/N 's of (J, K) = (4, 4), (5, 5), and (6, 6) exceeded 3.0 at 1426(54%), 1150(43%), and 1359(51%) positions, respectively. Simultaneous observations of the lines enabled us to accurately derive intensity ratios with less systematic errors. Boltzmann plots indicate that there are two temperature components: cold (∼20 K) and warm (∼100 K). Typical intensity ratios of Tmb(2, 2)/Tmb(1, 1), Tmb(4, 4)/Tmb(2, 2), Tmb(5, 5)/Tmb(4, 4), and Tmb(6, 6)/Tmb(3, 3) were 0.71, 0.45, 0.65, and 0.17, respectively. These line ratios correspond to the diversity of the rotational temperature, which results from mixing of the two temperature components.
Negative selection in humans and fruit flies involves synergistic epistasis
Authors: Sohail Mashaal , Vakhrusheva Olga A. , Sul Jae Hoon , Pulit Sara , Francioli Laurent ,   GoNL Consortium, Alzheimer’s Disease Neuroimaging Initiative, van den Berg Leonard H. , Veldink Jan H. , de Bakker Paul , Bazykin Georgii A. , Kondrashov Alexey S. , Sunyaev Shamil R.
Published: July 2016

Negative selection against deleterious alleles produced by mutation is the most common form of natural selection, which strongly influences within-population variation and interspecific divergence. However, some fundamental properties of negative selection remain obscure. In particular, it is still not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis must produce negative linkage disequilibrium between deleterious alleles, and therefore, underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function (LoF) alleles in eight independent datasets from modern human andDrosophila melanogasterpopulations. Thus, ongoing selection against deleterious alleles is characterized by synergistic epistasis, which can explain how human and fly populations persist despite very high genomic deleterious mutation rates.
Receptive field formation by interacting excitatory and inhibitory synaptic plasticity
Authors: Clopath Claudia , Vogels Tim P. , Froemke Robert C. , Sprekeler Henning
Published: July 2016

The stimulus selectivity of synaptic currents in cortical neurons often shows a co-tuning of excitation and inhibition, but the mechanisms that underlie the emergence and plasticity of this co-tuning are not fully understood. Using a computational model, we show that an interaction of excitatory and inhibitory synaptic plasticity reproduces both the developmental and – when combined with a disinhibitory gate – the adult plasticity of excitatory and inhibitory receptive fields in auditory cortex. The co-tuning arises from inhibitory plasticity that balances excitation and inhibition, while excitatory stimulus selectivity can result from two different mechanisms. Inhibitory inputs with a broad stimulus tuning introduce a sliding threshold as in Bienenstock-Cooper-Munro rules, introducing an excitatory stimulus selectivity at the cost of a broader inhibitory receptive field. Alternatively, input asymmetries can be amplified by synaptic competition. The latter leaves any receptive field plasticity transient, a prediction we verify in recordings in auditory cortex.
Posterior parietal cortex guides visual decisions in rats
Authors: Licata Angela M. , Kaufman Matthew T. , Raposo David , Ryan Michael B. , Sheppard John P. , Churchland Anne K.
Published: July 2016

Neurons in putative decision-making structures can reflect both sensory and decision signals, making their causal role in decisions unclear. Here, we tested whether rat posterior parietal cortex (PPC) is causal for processing visual sensory signals or instead for accumulating evidence for decision alternatives. We optogenetically disrupted PPC activity during decision-making and compared effects on decisions guided by auditory vs. visual evidence. Deficits were largely restricted to visual decisions. To further test for visual dominance in PPC, we evaluated electrophysiological responses following individual sensory events and observed much larger responses following visual stimuli than auditory stimuli. Finally, we measured spike count variability during stimulus presentation and decision formation. This sharply decreased, suggesting the network is stabilized by inputs, unlike what would be expected if sensory signals were locally accumulated. Our findings argue that PPC plays a causal role in discriminating visual signals that are accumulated elsewhere.