Francisco José Sanz1,2, Cristina Solana-Manrique1,2, Verónica Muñoz-Soriano1,2 and Nuria Paricio1,2,*

1Departamento de Genética, Facultad CC Biológicas, Universidad de Valencia, 46100 Burjassot, Spain
2Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain

DOI: 10.29245/2572.942X/2017/9.1149 View / Download Pdf

Takako Takemiya

Medical Research Institute, Tokyo Women’s Medical University, Shinjuku, Tokyo 162-8666, Japan

Astrocytes interact closely with neurons via glutamate; this astrocyte-neuron circuit may play a pivotal role in synaptic transmission. In addition, astrocytes contact vascular endothelial cells (ECs) with their end-feet; therefore, ECs may have some role in regulating neuronal activity via astrocytes in the brain. In our studies, we found that kainic acid (KA) microinjection induced the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in venous ECs and the expression of the prostaglandin E2 (PGE2) receptor EP3 on astrocytes. Moreover, endothelial mPGES-1 exacerbated KA-induced neuronal injury in the mouse brain. In in vitro experiments, mPGES-1 produced PGE2, which increased astrocytic Ca2+ levels and Ca2+-dependent glutamate release, thus aggravating neuronal injury. We found ECs had a role under pathological conditions and brain ECs are not merely a physiological barrier between the blood and brain; instead, they may also act as a signal transducer or amplifier. Moreover, the endothelium-astrocyte-neuron signaling pathway may be crucial for driving neuronal injury elicited by repetitive seizures and may be a new therapeutic target for epilepsy.

DOI: 10.29245/2572.942X/2017/8.1148 View / Download Pdf

José M. Brito-Armas and Rafael Castro-Fuentes*

Department of Basic Medical Sciences, University of La Laguna, Tenerife, Spain


DOI: 10.29245/2572.942X/2017/8.1144 View / Download Pdf

Benoit Michot1

1Department of Endodontics, New York University - College of Dentistry, 345 E. 24th Street 1008S, New York, NY 10010, United States.

DOI: 10.29245/2572.942X/2017/8.1147 View / Download Pdf

Marilene Demasi and Bruna Franciele Faria

Laboratory of Biochemistry and Biophysics, Instituto Butantan, São Paulo-SP, Brazil

Since the discovery of the proteasome (1986), many years passed before researchers explored the benefits of its activation. However, its inhibition, which was first observed in the beginning of the 1990s, gained wide acceptance because of its anti-tumor effect, as proteasome inhibition induces apoptosis. Currently, a proteasome inhibitor is utilized as a clinical tool. However, proteasome activation has been shown to either extend the life span of many cellular and animal models or prevent the accumulation of protein aggregates. Later effect might have an important contribution to neurodegenerative diseases with the hallmark of protein aggregation and the impairment of the proteasome. This short review presents prominent data on proteasome activation, focusing on the 20S catalytic proteasome particle. In addition, the benefits and consequences of proteasome activation in tumor development and progression are discussed.

DOI: 10.29245/2572.942X/2017/8.1146 View / Download Pdf

Zui Narita1 and Yuma Yokoi1

1Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry Japan 

DOI: 10.29245/2572.942X/2017/7.1142 View / Download Pdf

Willeke M. Menks1, Christina Stadler1 and Nora M. Raschle1

1Department of Child and Adolescent Psychiatry, University of Basel, Psychiatric University Hospital Basel, Switzerland.

Antisocial behavior in youths constitutes a major public health problem worldwide. Conduct disorder is a severe variant of antisocial behavior with higher prevalence rates for boys (12%) as opposed to girls (7%). A better understanding of the underlying neurobiological mechanisms of conduct disorder is warranted to improve identification, diagnosis, or treatment. Functional and structural neuroimaging studies have indicated several key brain regions within the limbic system and prefrontal cortex that are altered in youths with conduct disorder. Examining the structural connectivity, i.e. white matter fiber tracts connecting these brain areas, may further inform about the underlying neural mechanisms. Diffusion tensor imaging (DTI) is a non-invasive technique that can evaluate the white matter integrity of fiber tracts throughout the brain. To date, DTI studies have found several white matter tracts that are altered in youths with conduct disorder. However, a majority of these studies have focused on male or mixed-gender groups, and only a few studies have specifically investigated white matter alterations in girls with conduct disorder. Ultimately, studies that directly compare boys and girls with conduct disorder are necessary to identify possible sexual dimorphic neural alterations and developmental trajectories of conduct disorder in youths.

DOI: 10.29245/2572.942X/2017/7.1139 View / Download Pdf

Caroline Lücke1*, Alexandra P. Lam1, Helge H. O. Muller1, Alexandra Philipsen1,2

1Medical Campus University of Oldenburg, School of Medicine and Health Sciences, Psychiatry and Psychotherapy – University Hospital, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany
2Department of Psychiatry and Psychotherapy, Medical Faculty, University Medical Center – University of Freiburg, Freiburg, Germany

Cognitive behavioral therapy (CBT) is the standard form of psychotherapy currently used in adult attention deficit hyperactivity disorder (ADHD). However, biographical factors, such as chronic negative feedback in childhood, which may likely play a role in ADHD as a developmental disorder, are usually not substantially addressed by CBT. In recent years, schema therapy has received increasing attention as an effective therapy approach for chronic psychiatric disorders. A core feature of schema therapy is the identification and targeting of early maladaptive schemas, which are dysfunctional patterns and beliefs resulting from childhood experiences. Recently, two studies have demonstrated an increased prevalence of maladaptive schemas in adult ADHD. Thus, schema therapy might constitute a potentially promising approach in the treatment of ADHD, especially with regard to secondary problems such as poor coping strategies or impaired self-perception. However, randomized controlled clinical studies are needed to support that theory. Here, we provide an overview on the topic of biography-oriented therapy approaches in relation to adult ADHD, summarize current literature and discuss implications for future research.

DOI: 10.29245/2572.942X/2017/7.1138 View / Download Pdf

Maggie M. K. Wong1, Lauren M. Watson1 and Esther B. E. Becker1

1Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom

The cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.

DOI: 10.29245/2572.942X/2017/7.1134 View / Download Pdf

Lauren M. Wolf,1 Shannon L. Servoss,2 and Melissa A. Moss1,3,*

1Biomedical Engineering Program, University of South Carolina, Columbia, SC, USA
2Ralph E. Martin Department of Chemical Engineering, University of Arkansas, Fayetteville, AR, USA
3Department of Chemical Engineering, University of South Carolina, Columbia, SC, USA

In recent decades, the increasing prevalence of age-associated neurodegenerative diseases has underscored the need for targeted therapeutic strategies and novel diagnostics. Peptide-based neurotherapeutics offer high specificity and tolerability but are limited by proteolytic degradation in vivo. Peptoids, or N-substituted glycines, are versatile peptidomimetics that evade proteolytic degradation yet maintain many qualities that render peptides attractive neurotherapeutic candidates. These molecules may be engineered to their application through modifications that enhance structural stability and reactivity and can withstand various physiological stressors to retain their intended function within anomalous microenvironments.

Peptoids generally demonstrate greater cellular permeability than their corresponding peptides, are less immunogenic, and can be administered intranasally, all properties that enhance their potential as neurotherapeutics. Peptoids have primarily been explored as aggregation inhibitors to prevent the deleterious protein plaque deposition associated with several neurodegenerative disorders. However, novel research has uncovered the potential of peptoids toward additional neurotherapeutic applications. Peptoids can modulate cell signaling pathways involved in axonal function and current modulation and can block cell signaling events associated with apoptosis. In addition, these peptidomimetics are able to function as anti- inflammatory agents via multiple mechanisms. Moreover, the versatility and low cost of peptoids render them ideal instruments in biomarker detection, discovery, and imaging. This mini-review explores these diverse applications of peptoids within the context of neurodegenerative disease.

DOI: 10.29245/2572.942X/2017/7.1135 View / Download Pdf

Shinji Ohara

Department of Neurology, Matsumoto Medical Center, Chushin-Matsumoto Hospital, 811 Kotobuki, Matsumoto, 399-0021 Japan

Acute disseminated encephalomyelitis (ADEM) and Multiple sclerosis (MS) are both immunologically mediated inflammatory demyelinating disease of the CNS. ADEM and MS have long been considered as a separate disease entities, but clinical differentiation of ADEM from the first attack of MS is often difficult because of overlapping clinical features. Pathologically, perivenous demyelination and discrete confluent demyelination (plaque) have been generally regarded as the hallmark of ADEM and MS, respectively. It is also known that in contrast to MS, which shows quite diverse heterogeneous pathologic patterns, ADEM shows generally homogenous pathological features of inflammatory demyelination. However, hybrid cases showing pathological features of both ADEM and MS do exist, suggesting that ADEM may share some common underlying pathologic mechanisms with certain stages or subgroups of MS.

DOI: 10.29245/2572.942X/2017/6.1131 View / Download Pdf

Jun Sun

Department of Medicine, University of Illinois at Chicago 840 S Wood Street, Room 704 CSB, MC716, USA

DOI: 10.29245/2572.942X/2017/6.1136 View / Download Pdf

Shun Aritake, Hiroaki Oguro*, Kenichi Iwasa, Shingo Mitaki, Hiroyuki Takayoshi, Satoshi Abe, Keiichi Onoda, Shuhei Yamaguchi

Department of Neurology, Shimane University Hospital, 89-1 Enya-cho, Izumo city, Shimane 693-8501, Japan

We studied prognosis in 156 acute stoke patients treated by ozagrel and edaravone with the Japanese Standard Stroke Registry database in our hospital. They were examined as to their stroke types, neurological severity according to the NIH Stroke Scale (NIHSS) and clinical outcomes at admission by the modified Rankin Scale (mRS).  Acute noncardioembolic stroke patients with lacunar and atherothrombosis showed functional recovery by both of ozagrel monotherapy and the combination therapy of ozagrel and edaravone. Although ozagrel monotherapy in atherothrombotic infarction showed most improved by 2.4 points, we did not find significant difference among four groups according to ozagrel monotherapy or the combination therapy in atherothrombotic or lacunar infarct after adjusted for age. 

DOI: 10.29245/2572.942X/2017/6.1137 View / Download Pdf

Norishi Ueda

Department of Pediatrics, Public Central Hospital of Matto Ishikawa, 3-8 Kuramitsu, Hakusan, 924-8588 Ishikawa, Japan

We previously reviewed clinical characteristics of all reported pediatric cases of Mycoplasma pneumonia (M.pneumoniae)-associated mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). It dominantly occurs in Asian and Caucasian children, suggesting age/race as predisposing factors of MERS. Fever is the most common non-neurological symptom, while more than half of the cases have no respiratory symptoms. Thus, M.pneuminiae-associated MERS may be underestimated and should be a differential diagnosis of febrile children with neurological abnormalities. The mechanism of the disease is unknown. However, susceptibility of immature corpus callosum in young children to immune response-mediated neuroinflammattory stimuli induced by M.pneuminiae, including interleukin-6, reactive oxygen species and toll-like receptors, rather than direct invasion of the organism in central nervous system may contribute to the pathogenesis of MERS. A role of autoantibodies awaits further investigations. Despite excellent prognosis in type I MERS, it remains elusive whether type II MERS is highly associated with neurological sequel.

DOI: 10.29245/2572.942X/2017/6.1133 View / Download Pdf

Chiara Stella Di Stadio1, Filomena Altieri1, Giuseppina Minopoli1, Giuseppina Miselli1, Emilia Rippa1*, Paolo Arcari1,2*

1Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
2CEINGE, Advanced Biotechnology scarl, Via Gaetano Salvatore 486, I-80145, Naples, Italy

Gastrokine 1 (GKN1) is a 18 kDa stomach protein highly expressed in normal gastric tissue but absent in gastric cancer. GKN1 plays its major role in maintaining gastric mucosal integrity. Because of the presence in its central region of a BRICHOS domain, GKN1 is characterized by multifunctional properties since it interacts and regulates the activity of several proteins. The BRICHOS domain consists of about 100 amino acids and has been found in protein families often associated with major human diseases like familial British and Danish dementia (BRI2) or respiratory distress syndrome (surfactant protein C) (SP-C), both associated with amyloid formation. It has been shown that BRICHOS is a chaperon domain that has the property of binding precursor protein regions with high β-sheet tendencies, thereby preventing them from amyloid formation. Like the BRICHOS domains from BRI2 and SP-C precursor (proSP-C), also GKN1 is able to prevent fibrils formation of amyloid-beta peptide (Aβ) and to interact with the C-terminal region of APP thus hindering the γ-secretase proteolytic sites. Indeed, amyloid is of great medical importance since it originates in several major fatal diseases such as Alzheimer, Parkinson and diabetes mellitus. The results collected until now on the BRICHOS properties of GKN1 and those from other BRICHOS suggest that the different amyloids recognized by BRICHOS should contain similar structural elements therefore, the BRICHOS domain represents a potential powerfull tool for therapeutic approaches against amyloid associated diseases.

Abbreviations: AD, Alzheimer disease; Aβ, amyloid-beta peptide; APP, amyloid precursor protein; CTFs, APP C-Terminal Fragments; GC, gastric cancer; DAPT, N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; DMSO, dimethyl sulfoxyde; GC, gastric cancer; GKN1, gastrokine 1; flGKN1, full-lenght GKN1; MS, mass spectrometry; rGKN1, recombinant GKN1; SPR, surface plasma resonance; TM, transmembrane; TMpred, transmembrane prediction.

DOI: 10.29245/2572.942X/2017/6.1132 View / Download Pdf

Le Gjerum & Mette Midttun*

Department of Internal Medicine, Geriatric section, Copenhagen University Hospital, Herlev, Denmark

DOI: 10.29245/2572.942X/2017/6.1129 View / Download Pdf

Chiara Cupidi, Valentina Laganà, Nicoletta Smirne, Amalia Cecilia Bruni*

Centro Regionale di Neurogenetica, Azienda Sanitaria Provinciale Catanzaro, Viale A. Perugini, 88046 Lamezia Terme (CZ), Italy,

Starting from a proband for whom a family history of neurodegenerative disorder has been reported, clinical and genealogical methods are often used together to reconstruct the pedigree of many large families affected by hereditary diseases.
This approach was fundamental in the rebuilding of the N family, the kindred originated from southern Italy affected by early onset autosomal dominant Alzheimer’s disease (AD), that has given an important contribution to the discovery of Presenilin 1, the main gene responsible for AD.
The identification of several patients in this pedigree, encompassing 11 generations with several hundred of affected subjects, was achieved through the meticulous study of medical records in the archives of the Provincial Psychiatric Hospital of Girifalco in Italy and in the municipal and parish archives of many towns belonging to the same geographical area. The research on N family triggered several other studies on hereditary neurodegenerative disorders in Southern Italy. Investigation focusing on antique archives and the analysis of phenotypes allowed to reconstruct and clinically detail large pedigrees of hereditary diseases, such as frontotemporal dementia and spinocerebellar ataxia 17, even before the discovery of their causative genes.

DOI: 10.29245/2572.942X/2017/5.1127 View / Download Pdf

Yoon-Sang Oh, Dong-Woo Ryu, Jee-Eun Lee, Joong-Seok Kim*

Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Cognitive dysfunction and dementia are important causes of disability and mortality in the elderly population. Over a decade, many studies have found evidence that greater arterial stiffness is associated with impaired cognitive function. Stiff arteries have a direct effect on the brain microvasculature. In this review, we present evidence that arterial stiffness is linked to cognitive dysfunction in neurodegenerative disorders represented by Alzheimer’s disease and Parkinson’s disease. We also discuss possible mechanisms of arterial stiffness and cognitive dysfunction other than the universal pathologic features of beta-amyloid for Alzheimer’s disease and alpha-synuclein for Parkinson’s disease.

DOI: 10.29245/2572.942X/2017/5.1130 View / Download Pdf

Soon Young Park, Veerakumar Balasubramaniyan, and John F. de Groot*

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

DOI: 10.29245/2572.942X/2017/5.1125 View / Download Pdf

Tarek Nafee, Dima Nimri, Gerald Chi, Serge Korjian, Yazan Daaboul, Douglas Arbetter, Megan Yee, Purva Jain, Seyedmahdi Pahlavani, Haleigh Williams, Nathan Michalak, Megan Merlo, Usama Talib, C. Michael Gibson*

Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Stroke is one of the leading causes of mortality and morbidity worldwide. It results in considerable costs to the healthcare system in the United States. Pharmacologic stroke prophylaxis has been well-studied in patients with atrial fibrillation and in patients with a history of stroke. In-hospital strokes constitute 2.2% to 17% of all strokes and often go undiagnosed in acute medically ill patients. A retrospective analysis of the APEX trial identifies an acutely ill hospitalized patient population that may benefit from extended duration prophylaxis. The hospitalized medically ill are a novel population to target for stroke prophylaxis. This article will discuss the primary results of the APEX sub-study and other trials that have demonstrated stroke reduction with extended duration anticoagulation in this population. This article additionally comments on the clinical relevance of these findings and the importance of the development of short-term risk stratification models to aid clinicians in deciding whether or not to provide pharmacologic stroke prophylaxis to their acutely ill patients at hospital admission.

DOI: 10.29245/2572.942X/2017/5.1124 View / Download Pdf

Julien Leblond1, Anne-Claude Juillerat Van der Linden1,2, and Martial Van der Linden1,3*

1Psychopathology and Cognitive Neuropsychology Unit, Faculty of Psychology and Educational Sciences, University of Geneva, Boulevard du Pont d’Arve 40, CH-1205 Geneva, Switzerland

2Consultation Vieillir et Bien Vivre, Clinique et Permanence d’Onex, Cité Générations, Route de Chancy 98, CH-1213 Onex, Switerland

3Swiss Center for Affective Sciences, Campus Biotech, University of Geneva, Case Postale 60, CH-1211 Geneva, Switzerland

The dominant biomedical position considers Alzheimer’s disease (AD) to be intrinsically different from normal ageing and other neurodegenerative diseases and proposes that, by pursuing extensive research on what are considered the specific neuropathological characteristics of AD (i.e., neurotic plaques and neurofibrillary tangles), we will eventually be able to identify the cause of this disease and develop medical treatments that will allow us to successfully cure it. However, results of numerous recent studies go against this essentialist and category-based view and instead suggest that the cognitive, emotional, behavioural, and functional difficulties that some people experience as they grow older are modulated by a myriad of factors and mechanisms that interact throughout the lifespan. Importantly, this alternative way of conceptualising Alzheimer’s disease implies a shift of focus in terms of research objectives and calls for significant changes in terms of neuropsychological assessment and intervention in clinical practice.

DOI: 10.29245/2572.942X/2017/4.1121 View / Download Pdf

Valéria Meszlényi1, Roland Patai2, Bernát Nógrádi1, József I. Engelhardt3, László Siklós2

1Foundation for the Future of Biomedical Sciences in Szeged, Pálfy u. 52/d, H-6725 Szeged, Hungary

2Institute of Biophysics, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62, H-6726 Szeged, Hungary

3Department of Neurology, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary

Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disorder characterized by the progressive loss of motor neurons in the central nervous system and neuromuscular junctions in the periphery. The pathomechanism behind the disease, except from some familiar cases associated with genetic mutations, remains unclear, however, numerous mechanisms contributing to the disease have already been disclosed. The key components are the oxidative stress, excitotoxicity, mitochondrial dysfunctions and inflammatory processes. In addition, increased intracellular calcium, which is another identified pathological event, could merge these individual toxic mechanisms into a single, escalating and self-perpetuating cycle of neuronal degeneration. Our previous results suggest that calcium homeostasis might be preserved by modulating the transmembrane calcium flux with therapeutic compounds or via altering the calcium binding protein content to maintain an enhanced calcium buffer capacity. The scope of this commentary is to accentuate the reciprocal calcium dependence of the pathological events associated with amyotrophic lateral sclerosis and to discuss possible therapeutic strategies based on the restoration of calcium homeostasis.

DOI: 10.29245/2572.942X/2017/4.1123 View / Download Pdf

Magalie Chéron1 and Henriette Löffler-Stastka1*

1Department for Psychoanalysis and Psychotherapy, Advanced Postgraduate Program for Psychotherapy Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria

DOI: 10.29245/2572.942X/2017/4.1126 View / Download Pdf

Clare C. Yu1, Babu J. N. Reddy2, Juliana C. Wortman1, Steven P. Gross1,2

1Department of Physics and Astronomy, University of California, Irvine, Irvine, California, USA
2Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, USA

Long-distance intracellular axonal transport is predominantly microtubulebased, and its impairment is linked to neurodegeneration. Here we review recent theoretical and experimental evidence that suggest that near the axon boundaries (walls), the effective viscosity can become large enough to impede cargo transport in small (but not large) caliber axons. Theoretical work suggests that this opposition to motion increases rapidly as the cargo approaches the wall. However, having parallel microtubules close enough together to enable a cargo to simultaneously engage motors on more than one microtubule dramatically enhances motor activity, and thus decreases the effects due to such opposition. Experimental evidence supports this hypothesis: in small caliber axons, microtubule density is higher, increasing the probability of having parallel microtubules close enough that they can be used simultaneously by motors on a cargo. For transport toward the minus-end of microtubules, e.g., toward the cell body in an axon, a recently discovered forceadaptation system can also contribute to overcoming such opposition to motion.

DOI: 10.29245/2572.942X/2017/3.1118 View / Download Pdf

A Duruflé1, C Le Meur1, P Gallien1, C Lozach1, MP Reillon1, N Clerc1, M Jambou1, B Nicolas1

1Pôle Saint Hélier, 54 rue Saint Hélier, 35 043 Rennes cedex, France

Many mobile teams were created over the past decade in various medical specialties including physical medicine and rehabilitation.

The Pole Saint Helier has created a mobile team of reintegration - rehabilitation (EM2R) in December 2012 with support from the Regional Health Agency of Brittany. It operates on the health territory No. 5 of Brittany near people experiencing neurological disability. Its main mission is to implement the necessary devices to facilitate the home return of people hospitalized after a neurological event or maintaining to home people with neurological disorders.

The number of supported annual is about 200. People with brain lesions account for 2/3 of the population, mean age 60 years, with a high degree of dependence. The complexity of the patients become clearer with a minimum of two professionals involved by patient. Occupational therapy represents the majority of requests for intervention. New activities have emerged: supported to people with brain tumor, collaborations with palliative mobile teams and home hospital, formation and education of caregivers.

This activity outside is an alternative to the PMR care offer in link especially with the recommendations of the French Society of Physical Medicine and Rehabilitation and High Autority of Health on the organization of care pathway of stroke.

DOI: 10.29245/2572.942X/2017/3.1097 View / Download Pdf