Proposing a quick, objective, comprehensive analysis of impaired spoken discourse in post-stroke aphasia

Anthony Pak-Hin Kong,Adam Reres 한국언어재활사협회 2021 Clinical Archives of Communication Disorders Vol.6 No.3

Purpose: Aphasia is an acquired language disorder, most commonly caused by a stroke, that adversely affects one’s ability to understand, speak, read, and write. Diagnosis of aphasia is typically done through administration of standardized aphasia batteries, many of which lack a detailed and adequate evaluation of spoken discourse. The aim of this paper was to propose a quick, objective, and comprehensive analytic system that addressed the micro- and macro-linguistic aspects of oral narratives in persons with aphasia (PWA). Methods: Using a subgroup of unimpaired native speakers of English from the public corpus of AphasiaBank, task-specific normative data of three narrative tasks were constructed. Scoring criteria on the production of events, use of corresponding lexical items in these events, and the order of sequence of presenting the events were also developed. Twelve PWA were recruited and their spoken discourse was quantified using this newly proposed analytic system. Results: Significant correlations were found between PWA’s performance on formal aphasia batteries and selected indices on the number of events produced as well as informative words used. Fluent and non-fluent PWA performed significantly differently in terms of their use of informative words and event sequence. The analytic system also demonstrated excellent intra- and inter-rater reliabilities. Conclusions: The clinical feasibility and diagnostic values of this proposed approach to quantify PWA’s spoken output are confirmed. The present investigation also offered more evidence in supporting the needed psychometric properties of spoken discourse analysis that can supplement traditional formal aphasia batteries.

Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5′ flap DNA: basis of interstrand cross-link repair by FAN1

Gwon, Gwang Hyeon,Kim, Youngran,Liu, Yaqi,Watson, Adam T.,Jo, Aera,Etheridge, Thomas J.,Yuan, Fenghua,Zhang, Yanbin,Kim, YoungChang,Carr, Anthony M.,Cho, Yunje Cold Spring Harbor Laboratory Press 2014 Genes & development Vol.28 No.20

<P>Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in FA genes responsible for processing DNA interstrand cross-links (ICLs). FA-associated nuclease (FAN1) is recruited to lesions by a monoubiquitinated FANCI–FANCD2 (ID) complex and participates in ICL repair. Here, Gwon et al. determined the crystal structure of <I>Pseudomonas aeruginosa</I> FAN1 (<I>Pa</I>FAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5′ flap DNA. The <I>Pa</I>FAN1 structure provides insights into how FAN1 integrates with the FA complex to participate in ICL repair.</P><P>Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in any of 15 FA genes responsible for processing DNA interstrand cross-links (ICLs). The ultimate outcome of the FA pathway is resolution of cross-links, which requires structure-selective nucleases. FA-associated nuclease 1 (FAN1) is believed to be recruited to lesions by a monoubiquitinated FANCI–FANCD2 (ID) complex and participates in ICL repair. Here, we determined the crystal structure of <I>Pseudomonas aeruginosa</I> FAN1 (<I>Pa</I>FAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5′ flap DNA. All four domains of the right-hand-shaped <I>Pa</I>FAN1 are involved in DNA recognition, with each domain playing a specific role in bending DNA at the nick. The six-helix bundle that binds the junction connects to the catalytic viral replication and repair (VRR) nuclease (VRR nuc) domain, enabling FAN1 to incise the scissile phosphate a few bases distant from the junction. The six-helix bundle also inhibits the cleavage of intact Holliday junctions. <I>Pa</I>FAN1 shares several conserved features with other flap structure-selective nucleases despite structural differences. A clamping motion of the domains around the wedge helix, which acts as a pivot, facilitates nucleolytic cleavage. The <I>Pa</I>FAN1 structure provides insights into how archaeal Holliday junction resolvases evolved to incise 5′ flap substrates and how FAN1 integrates with the FA complex to participate in ICL repair.</P>

Effects of innate immune receptor stimulation on extracellular α-synuclein uptake and degradation by brain resident cells

Kim Changyoun,Kwon Somin,Iba Michiyo,Spencer Brian,Rockenstein Edward,Mante Michael,Adame Anthony,Shin Soo Jean,Fields Jerel A.,Rissman Robert A.,Lee Seung-Jae,Masliah Eliezer 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-

Synucleinopathies are age-related neurological disorders characterized by the progressive deposition of α-synuclein (α-syn) aggregates and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Although cell-to-cell α-syn transmission is thought to play a key role in the spread of α-syn pathology, the detailed mechanism is still unknown. Neuroinflammation is another key pathological feature of synucleinopathies. Previous studies have identified several immune receptors that mediate neuroinflammation in synucleinopathies, such as Toll-like receptor 2 (TLR2). However, the species of α-syn aggregates varies from study to study, and how different α-syn aggregate species interact with innate immune receptors has yet to be addressed. Therefore, we investigated whether innate immune receptors can facilitate the uptake of different species of α-syn aggregates. Here, we examined whether stimulation of TLRs could modulate the cellular uptake and degradation of α-syn fibrils despite a lack of direct interaction. We observed that stimulation of TLR2 in vitro accelerated α-syn fibril uptake in neurons and glia while delaying the degradation of α-syn in neurons and astrocytes. Internalized α-syn was rapidly degraded in microglia regardless of whether TLR2 was stimulated. However, cellular α-syn uptake and degradation kinetics were not altered by TLR4 stimulation. In addition, upregulation of TLR2 expression in a synucleinopathy mouse model increased the density of Lewy-body-like inclusions and induced morphological changes in microglia. Together, these results suggest that cell type-specific modulation of TLR2 may be a multifaceted and promising therapeutic strategy for synucleinopathies; inhibition of neuronal and astroglial TLR2 decreases pathogenic α-syn transmission, but activation of microglial TLR2 enhances microglial extracellular α-syn clearance.

Pathogenic variant in NLRP7 (19q13.42) associated with recurrent gestational trophoblastic disease: Data from early embryo development observed during in vitro fertilization

Sills, E. Scott,Obregon-Tito, Alexandra J.,Gao, Harry,McWilliams, Thomas K.,Gordon, Anthony T.,Adams, Catharine A.,Slim, Rima The Korean Society for Reproductive Medicine 2017 Clinical and Experimental Reproductive Medicine Vol.44 No.1

Objective: To describe in vitro development of human embryos derived from an individual with a homozygous pathogenic variant in NLRP7 (19q13.42) and recurrent hydatidiform mole (HM), an autosomal recessive condition thought to occur secondary to an oocyte defect. Methods: A patient with five consecutive HM pregnancies was genomically evaluated via next generation sequencing followed by controlled ovarian hyperstimulation, in vitro fertilization (IVF) with intracytoplasmic sperm injection, embryo culture, and preimplantation genetic screening. Findings in NLRP7 were recorded and embryo culture and biopsy data were tabulated as a function of parental origin for any identified ploidy error. Results: The patient was found to have a pathogenic variant in NLRP7 (c.2810+2T>G) in a homozygous state. Fifteen oocytes were retrieved and 10 embryos were available after fertilization via intracytoplasmic sperm injection. Developmental arrest was noted for all 10 embryos after 144 hours in culture, thus no transfer was possible. These non-viable embryos were evaluated by karyomapping and all were diploid biparental; two were euploid and eight had various aneuploidies all of maternal origin. Conclusion: This is the first report of early human embryo development from a patient with any NLRP7 mutation. The pathogenic variant identified here resulted in global developmental arrest at or before blastocyst stage. Standard IVF should therefore be discouraged for such patients, who instead need to consider oocyte (or embryo) donation with IVF as preferred clinical methods to treat infertility.

Higher Binding Affinity and In Vitro Potency of Reslizumab for Interleukin-5 Compared With Mepolizumab

Mark Liddament,Jean Husten,Tanya Estephan,David Laine,David Mabon,Laurie Pukac,Jacquelyn Lyons,Adam W. Clarke,Anthony Doyle 대한천식알레르기학회 2019 Allergy, Asthma & Immunology Research Vol.11 No.2

Reslizumab and mepolizumab are recently approved monoclonal antibodies for the treatment of severe (uncontrolled) eosinophilic asthma. Both are effective in neutralizing the function of interleukin-5 (IL-5). This study is the first to compare the binding affinity and in vitro potency of both antibodies in head-to-head assays. Two assays assessed binding affinity (using the equilibrium dissociation constant [KD]) of each drug for human IL-5. In the Biacore surface plasmon resonance assay, the association constant (kon) values for human IL-5 for reslizumab and mepolizumab were 3.93 × 106 and 1.83 × 105, respectively. The dissociation constant (koff) values were 4.29 × 10−4 and 2.14 × 10−4, respectively. Calculated KD values for human IL-5 for reslizumab and mepolizumab were 109 and 1,170 pM, respectively, representing an approximately 11-fold stronger binding affinity with reslizumab. In the Kinetic Exclusion Assay, the kon values for human IL-5 for reslizumab and mepolizumab were 3.17 × 106 and 1.32 × 105, respectively. The koff values were 1.36 × 10−5 and 1.48 × 10−5, respectively. Measured KD values for human IL-5 for reslizumab and mepolizumab were 4.3 and 112 pM, respectively, representing an approximately 26-fold stronger binding affinity for reslizumab. A human-IL-5-dependent cell proliferation assay was developed to assess in vitro potency, based on a human cell line selected for enhanced surface expression of IL-5 receptor-alpha and consistent proliferation response to IL-5. The concentration at which 50% inhibition occurred (IC50) was determined for both antibodies. Reslizumab and mepolizumab inhibited IL-5-dependent cell proliferation, with IC50 values of approximately 91.1 and 286.5 pM, respectively, representing on average 3.1-fold higher potency with reslizumab. In conclusion, comparative assays show that reslizumab has higher affinity binding for and in vitro potency against human IL-5 compared with mepolizumab. However, these results do not take into consideration the different methods of administration of reslizumab and mepolizumab.