Unravelling the effect of paramagnetic Ni2+ on the 13C NMR shift tensor for carbonate in Mg2-xNixAl layered double hydroxides by quantum-chemical computations.

Structural disorder and low crystallinity render it challenging to characterise the atomic-level structure of layered double hydroxides (LDH). We report a novel multi-step, first-principles computational workflow for the analysis of paramagnetic solid-state NMR of complex inorganic systems such as LDH, which are commonly used as catalysts and energy storage materials. A series of 13CO32--labelled Mg2-xNixAl-LDH, x ranging from 0 (Mg2Al-LDH) to 2 (Ni2Al-LDH), features three distinct eigenvalues δ11, δ22 and δ33 of the experimental 13C chemical shift tensor. The δii correlate directly with the concentration of the paramagnetic Ni2+ and span a range of |δ11 - δ33| ≈ 90 ppm at x = 0, increasing to 950 ppm at x = 2. In contrast, the isotropic shift, δiso(13C), only varies by -14 ppm in the series. Detailed insight is obtained by computing (1) the orbital shielding by periodic density-functional theory involving interlayer water, (2) the long-range pseudocontact contribution of the randomly distributed Ni2+ ions in the cation layers (characterised by an ab initio susceptibility tensor) by a lattice sum, and (3) the close-range hyperfine terms using a full first-principles shielding machinery. A pseudohydrogen-terminated two-layer cluster model is used to compute (3), particularly the contact terms. Due to negative spin density contribution at the 13C site arising from the close-by Ni2+ sites, this step is necessary to reach a semiquantitative agreement with experiment. These findings influence future NMR investigations of the formally closed-shell interlayer species within LDH, such as the anions or water. Furthermore, the workflow is applicable to a variety of complex materials.

Child, Parent, and Play - An Insight into These Dimensions Among Children with and without Receptive Expressive Language Disorder Using Video-Based Analysis.

PURPOSE: Language development in children aged 3-6 years is shaped by their pre-linguistic abilities, communication patterns and play behaviors along with parental communicative roles. Little is known about how these aspects are distributed among children with receptive expressive language disorder (CWRELD) in comparison to typically developing children (CWTDL). The present research explores these differences between the two groups using a video-based analysis with a belief that an understanding of these aspects may facilitate age-appropriate speech and language acquisition in children with language delay. METHODS: A video-based analysis of parent-child interactions was carried out for 10 children each with receptive expressive language disorder and typical language development, respectively. The two groups were compared for the child's turn-taking skills, eye contact span, autonomous instances, communication patterns, play behaviors and parental communication roles. RESULTS: Children with receptive expressive language disorder exhibited significantly fewer proportion of turns and autonomous instances along with a greater proportion of eye contact to objects than the parent. Majority of the children with language delay were at the "Requester" or "Early communicators" stage and demonstrated either "Exploratory" or "Functional play" behaviors. Most of the typically developing children were at the "Partner stage" of communication and exhibited "Functional", "Constructive" or "Symbolic Play". Parents of children with language delay mostly exhibited "Helper" type communicative roles while parents from typically developing groups showed "Partner" type communicative profile. CONCLUSION: A quantitative planning and monitoring of pre-linguistic skills, determination of communicative patterns and play behaviors is important for clinicians working with children having a language delay. Assessing and modifying parental communicative roles are also crucial. Understanding the distribution of these research variables among CWRELD in comparison to CWTDL may help clinicians in planning precise treatment goals, monitoring specific linguistic progress, ensuring better parental participation and delivering better outcomes during language therapy.

A Comparative Study of the Communication Profile of Typically Developing Children and Children with Receptive-Expressive Language Disorders: A Parental Perceptive.

BACKGROUND: Parental concerns pertaining to communication abilities are essential as it does aid in the identification of the children at risk of physical and mental health problems. OBJECTIVES: The current study followed a cross sectional study design. The study focussed on developing a questionnaire targeting the parental concerns in Typically developing (TD) children and children with Receptive-Expressive Language Disorders (CWRELD) between 3.7 and 6.6 years of age; to administer the developed questionnaire on parents of TD children and CWRELD; and to analyse and compare the concerns faced by parents of TD children and CWRELD across 3.7 and 6.6 years of age. METHODS: Fifty-one parents of TD children and 51 parents of CWRELD participated in the study. The study was carried out in three phases- Phase I included the development and validation of questionnaire; Phase II included data collection using the developed questionnaire; and Phase III included performing statistical analysis. Descriptive statistics was done to determine the mean and standard deviation (SD) for both the TD and CWRELD groups. RESULTS: The results revealed that the concerns exhibited by parents of CWRELD were significantly higher than that of parents of TD children. Chi square results indicated statistically significant findings across all the domains between TD children and CWRELD (p<0.05). CONCLUSION: The developed questionnaire can be used in clinical settings to help track parental concerns which may aid in the early identification of children at risk of various communication disorders. Additionally, this questionnaire may be considered for monitoring parental concerns throughout the course of the intervention program.

Role of the VPS35 D620N mutation in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder involving the loss of dopaminergic neurons in the brain. Following the discovery of the PD-causing D620N mutation in the VPS35 (Vacuolar sorting protein 35) gene, dysfunction in the subcellular retromer complex has been strongly implicated in pathogenesis of PD. Although the function and dysfunction of the retromer has been a focus of study for some time, the role of this complex in the development of PD is not fully understood. Investigating cellular alterations that occur when the retromer is rendered dysfunctional, such as when the D620N disease-causing mutation is introduced into various model systems, shows that endosomal processing defects are major contributors to the disease phenotype. Altered trafficking of retromer cargo molecules, reduced cellular survival and altered processing of alpha-synuclein have all been observed in the presence of the D620N mutation. In addition, interactions between the retromer and the protein products of other familial Parkinsonism-related genes, has made the retromer a prime target of research in PD. This review gives an overview of the changes in retromer function, identified thus far, that may contribute to the neurodegeneration observed in PD.

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.

Evaluation of Abbreviated Impactor Measurements (AIM) and Efficient Data Analysis (EDA) for Dry Powder Inhalers (DPIs) Against the Full-Resolution Next Generation Impactor (NGI).

The full-resolution next generation impactor (NGI) and three abbreviated impactor systems were used to obtain the apparent aerodynamic particle size distribution (APSD) and other quality measures for marketed dry powder inhalers (DPIs) using the compendial method and efficient data analysis (EDA). APSD for the active pharmaceutical ingredient (API) in Spiriva® Handihaler®, Foradil® Aerolizer®, and Relenza® Diskhaler® was obtained using a full-resolution NGI at 39, 60, and 90 L/min, respectively. Two reduced NGI (rNGI) configurations, the filter-only configuration (rNGI-f) and the modified-cup configuration (rNGI-mc), and the fast-screening impactor (FSI) with appropriate inserts to provide a 5-µm cut size were evaluated. The fine particle dose (FPD) obtained using the FSI for Spiriva was statistically similar to that obtained using the full NGI. However, the FPD for both Foradil and Relenza obtained using the FSI was significantly different from that obtained using the full NGI. Despite this, no significant differences were observed for the fine particle fraction (FPF) obtained using the FSI relative to that obtained from the full NGI for any of the DPIs. The use of abbreviated impactor systems appears promising with good agreement observed with the full-resolution NGI, except for small differences observed for the rNGI-mc configuration. These small differences may be product- and/or flow rate-specific, and further evaluation will be required to resolve these differences.

The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer.

The retromer is a trimeric cargo-recognition protein complex composed of Vps26, Vps29 and Vps35 associated with protein trafficking within endosomes. Recently, a pathogenic point mutation within the Vps35 subunit (D620N) was linked to the manifestation of Parkinson's disease (PD). Here, we investigated details underlying the molecular mechanism by which the D620N mutation in Vps35 modulates retromer function, including examination of retromer's subcellular localization and its capacity to sort cargo. We show that expression of the PD-linked Vps35 D620N mutant redistributes retromer-positive endosomes to a perinuclear subcellular localization and that these endosomes are enlarged in both model cell lines and fibroblasts isolated from a PD patient. Vps35 D620N is correctly folded and binds Vps29 and Vps26A with the same affinity as wild-type Vps35. While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of α-synuclein, a causative agent of PD. In summary, we find that the expression of Vps35 D620N leads to endosomal alterations and trafficking defects that may partly explain its action in PD.