Outcomes for Adults With Intellectual and Developmental Disabilities Receiving Long-Term Services and Supports: A Systematic Review of the Literature.

The impact of long-term services and supports on the quality of life of adults with intellectual and developmental disabilities (IDD) is not well understood given the highly complex nature of researching this topic. To support future research addressing this topic, we conducted a systematic literature review of studies addressing outcomes of adults with IDD receiving long-term services and supports. Results of this review describe current outcomes for adults with IDD who receive long-term services and supports and can be used to inform program evaluation, policy development, and future research.

Mechanisms of RNF168 nucleosome recognition and ubiquitylation.

RNF168 plays a central role in the DNA damage response (DDR) by ubiquitylating histone H2A at K13 and K15. These modifications direct BRCA1-BARD1 and 53BP1 foci formation in chromatin, essential for cell-cycle-dependent DNA double-strand break (DSB) repair pathway selection. The mechanism by which RNF168 catalyzes the targeted accumulation of H2A ubiquitin conjugates to form repair foci around DSBs remains unclear. Here, using cryoelectron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy, and functional assays, we provide a molecular description of the reaction cycle and dynamics of RNF168 as it modifies the nucleosome and recognizes its ubiquitylation products. We demonstrate an interaction of a canonical ubiquitin-binding domain within full-length RNF168, which not only engages ubiquitin but also the nucleosome surface, clarifying how such site-specific ubiquitin recognition propels a signal amplification loop. Beyond offering mechanistic insights into a key DDR protein, our study aids in understanding site specificity in both generating and interpreting chromatin ubiquitylation.

Modelling and Molecular Dynamics Predict the Structure and Interactions of the Glycine Receptor Intracellular Domain.

Glycine receptors (GlyRs) are glycine-gated inhibitory pentameric ligand-gated ion channels composed of α or α + ß subunits. A number of structures of these proteins have been reported, but to date, these have only revealed details of the extracellular and transmembrane domains, with the intracellular domain (ICD) remaining uncharacterised due to its high flexibility. The ICD is a region that can modulate function in addition to being critical for receptor localisation and clustering via proteins such as gephyrin. Here, we use modelling and molecular dynamics (MD) to reveal details of the ICDs of both homomeric and heteromeric GlyR. At their N and C ends, both the α and ß subunit ICDs have short helices, which are major sites of stabilising interactions; there is a large flexible loop between them capable of forming transient secondary structures. The α subunit can affect the ß subunit ICD structure, which is more flexible in a 4α2:1ß than in a 4α1:1ß GlyR. We also explore the effects of gephyrin binding by creating GlyR models bound to the gephyrin E domain; MD simulations suggest these are more stable than the unbound forms, and again there are α subunit-dependent differences, despite the fact the gephyrin binds to the ß subunit. The bound models also suggest that gephyrin causes compaction of the ICD. Overall, the data expand our knowledge of this important receptor protein and in particular clarify features of the underexplored ICD.

An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering.

The recruitment of 53BP1 to chromatin, mediated by its recognition of histone H4 dimethylated at lysine 20 (H4K20me2), is important for DNA double-strand break repair. Using a series of small molecule antagonists, we demonstrate a conformational equilibrium between an open and a pre-existing lowly populated closed state of 53BP1 in which the H4K20me2 binding surface is buried at the interface between two interacting 53BP1 molecules. In cells, these antagonists inhibit the chromatin recruitment of wild type 53BP1, but do not affect 53BP1 variants unable to access the closed conformation despite preservation of the H4K20me2 binding site. Thus, this inhibition operates by shifting the conformational equilibrium toward the closed state. Our work therefore identifies an auto-associated form of 53BP1-autoinhibited for chromatin binding-that can be stabilized by small molecule ligands encapsulated between two 53BP1 protomers. Such ligands are valuable research tools to study the function of 53BP1 and have the potential to facilitate the development of new drugs for cancer therapy.

Computer Vision Analysis of Rheumatoid Arthritis Synovium Reveals Lymphocytic Inflammation Is Associated With Immunoglobulin Skewing in Blood.

OBJECTIVE: We sought to develop computer vision methods to quantify aggregates of cells in synovial tissue and compare these with clinical and gene expression parameters. METHODS: We assembled a computer vision pipeline to quantify five features encompassing synovial cell density and aggregates and compared these with pathologist scores, disease classification, autoantibody status, and RNA expression in a cohort of 156 patients with rheumatoid arthritis (RA) and 149 patients with osteoarthritis (OA). RESULTS: All five features were associated with pathologist scores of synovial lymphocytic inflammation (P < 0.0001). Three features that related to the cells per unit of tissue were significantly increased in patients with both seronegative and seropositive RA compared with those with OA; on the other hand, aggregate features (number and diameter) were significantly increased in seropositive, but not seronegative, RA compared with OA. Aggregate diameter was associated with the gene expression of immunoglobulin heavy-chain genes in the synovial tissue. Compared with blood, synovial immunoglobulin isotypes were skewed from IGHM and IGHD to IGHG3 and IGHG1. Further, patients with RA with high levels of lymphocytic infiltrates in the synovium demonstrated parallel skewing in their blood with a relative decrease in IGHGM (P < 0.002) and IGHD (P < 0.03) and an increase in class-switched immunoglobulin genes IGHG3 (P < 0.03) and IGHG1 (P < 0.002). CONCLUSION: High-resolution automated identification and quantification of synovial immune cell aggregates uncovered skewing in the synovium from naïve IGHD and IGHM to memory IGHG3 and IGHG1 and revealed that this process is reflected in the blood of patients with high inflammatory synovium.

An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering.

The recruitment of 53BP1 to chromatin, mediated by its recognition of histone H4 dimethylated at lysine 20 (H4K20me2), is important for DNA double-strand break repair. Using a series of small molecule antagonists, we demonstrate a conformational equilibrium between an open and a pre-existing lowly populated closed state of 53BP1 in which the H4K20me2 binding surface is buried at the interface between two interacting 53BP1 molecules. In cells, these antagonists inhibit the chromatin recruitment of wild type 53BP1, but do not affect 53BP1 variants unable to access the closed conformation despite preservation of the H4K20me2 binding site. Thus, this inhibition operates by shifting the conformational equilibrium toward the closed state. Our work therefore identifies an auto-associated form of 53BP1 - autoinhibited for chromatin binding - that can be stabilized by small molecule ligands encapsulated between two 53BP1 protomers. Such ligands are valuable research tools to study the function of 53BP1 and have the potential to facilitate the development of new drugs for cancer therapy.

The Impact of Administration Formats on SIS-A Scores.

Many U.S. states use the Supports Intensity Scale-Adult Version (SIS-A; Thompson et al., 2015) to inform the distribution of public funds for long-term services and supports. Throughout the COVID-19 pandemic, many states began administering the SIS-A virtually instead of in person. Because administration format has the potential to influence SIS-A scores and, consequently, impact the funding people receive for long-term services and supports, this study examined the stability of support need scores, as measured by the SIS-A, over two time periods: (a) when assessments were conducted in person and (b) when assessments were conducted virtually using remote technology. Specifically, the influence of assessment administration formats on SIS-A scores and on the perceptions of SIS-A assessors were investigated. Results revealed that the virtual administration format impacted SIS-A scores, but the impact was of little to no practical importance.

Rheumatoid Arthritis Synovial Inflammation Quantification Using Computer Vision.

OBJECTIVE: We quantified inflammatory burden in rheumatoid arthritis (RA) synovial tissue by using computer vision to automate the process of counting individual nuclei in hematoxylin and eosin images. METHODS: We adapted and applied computer vision algorithms to quantify nuclei density (count of nuclei per unit area of tissue) on synovial tissue from arthroplasty samples. A pathologist validated algorithm results by labeling nuclei in synovial images that were mislabeled or missed by the algorithm. Nuclei density was compared with other measures of RA inflammation such as semiquantitative histology scores, gene-expression data, and clinical measures of disease activity. RESULTS: The algorithm detected a median of 112,657 (range 8,160-821,717) nuclei per synovial sample. Based on pathologist-validated results, the sensitivity and specificity of the algorithm was 97% and 100%, respectively. The mean nuclei density calculated by the algorithm was significantly higher (P < 0.05) in synovium with increased histology scores for lymphocytic inflammation, plasma cells, and lining hyperplasia. Analysis of RNA sequencing identified 915 significantly differentially expressed genes in correlation with nuclei density (false discovery rate is less than 0.05). Mean nuclei density was significantly higher (P < 0.05) in patients with elevated levels of C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and cyclized citrullinated protein antibody. CONCLUSION: Nuclei density is a robust measurement of inflammatory burden in RA and correlates with multiple orthogonal measurements of inflammation.

Impact of Different Pairings of Respondents on Scores on the Supports Intensity Scale-Adult Version (SIS-A).

This secondary analysis examined the impact of respondent-level factors on scores on the Supports Intensity Scale-Adult Version (SIS-A) to determine if there were patterns of differences in SIS-A scores based on the number of respondents and the pairings of respondents that were included in SIS-A interviews. Results indicated that having fewer respondents led to a greater variability in SIS-A scores whereas having more respondents led to higher mean, overall support need scores. When respondents included an adult with intellectual disability (ID) the mean score was significantly lower. However, there were complex influences of pairing an adult with ID with either a professional or family member on SIS-A scores. Implications for administering and using the SIS-A are discussed.

COVID-19 and the Field of Intellectual and Developmental Disabilities: Where Have We Been? Where Are We? Where Do We Go?

The coronavirus (COVID-19) pandemic has affected, and will continue to affect, every aspect of the intellectual and developmental disabilities (IDD) community. We provide recommendations to (a) support people with IDD and the broader of field of IDD during the course of the pandemic, and (b) place the IDD community in a strong position when the health threats associated with the pandemic abate and post-pandemic social and policy structures are formed.

The Supports Intensity Scale Children's Version-Icelandic Translation: Examining Measurement Properties.

An innovation in developing the Supports Intensity Scale-Children's Version (SIS-C) was the adoption of latent variable modeling approaches to norm development. In regard to translated versions of the SIS-C, the latent modeling approaches provided opportunities to leverage the large standardization sample generated in the United States (n = 4,015) to generate translation-specific norms from data collected on smaller samples in other countries and enable future cross-cultural analyses. In this study, data were collected on children in Iceland who received special education services (as defined and delivered in Iceland), a more diverse group of children with disabilities than the U.S. sample. This provided a unique context to explore cross-cultural differences. Findings indicated the structure of the SIS-C (i.e., seven support need domains organized under an overall support needs construct), was supported in the Icelandic context. However, findings also suggested that supports planning teams in Iceland must consider specific age-related factors that differ from other cultural contexts.

Design and Evaluation of PEGylated Liposomal Formulation of a Novel Multikinase Inhibitor for Enhanced Chemosensitivity and Inhibition of Metastatic Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among cancers. Chemotherapy is the standard first-line treatment, but only modest survival benefits are observed. With the advent of targeted therapies, epidermal growth factor receptor (EGFR) has been acknowledged as a prospective target in PDAC since it is overexpressed in up to 60% of cases. Similarly, the tyrosine-protein kinase Met (cMET) is also overexpressed in PDAC (27-60%) and is a prognostic marker for poor survival. Interestingly, EGFR and cMET share some common signaling pathways including PI3K/Akt and MAPK pathways. Small molecule inhibitors or bispecific antibodies that can target both EGFR and cMET are therefore emerging as novel options for cancer therapy. We previously developed a dual EGFR and cMET inhibitor (N19) that was able to inhibit tumor growth in nonsmall cell lung cancer models resistant to EGFR tyrosine kinase inhibitors (TKI). Here, we report the development of a novel liposomal formulation of N19 (LN19) and showed significant growth inhibition and increased sensitivity toward gemcitabine in the pancreatic adenocarcinoma orthotopic xenograft model. Taken together, our results suggest that LN19 can be valued as an effective combination therapy with conventional chemotherapy such as gemcitabine for PDAC patients.

Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein.

Dynamic protein interaction networks such as DNA double-strand break (DSB) signaling are modulated by post-translational modifications. The DNA repair factor 53BP1 is a rare example of a protein whose post-translational modification-binding function can be switched on and off. 53BP1 is recruited to DSBs by recognizing histone lysine methylation within chromatin, an activity directly inhibited by the 53BP1-binding protein TIRR. X-ray crystal structures of TIRR and a designer protein bound to 53BP1 now reveal a unique regulatory mechanism in which an intricate binding area centered on an essential TIRR arginine residue blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of-function mutation that abolishes TIRR-mediated regulation in cells renders 53BP1 hyperactive in response to DSBs, highlighting the key inhibitory function of TIRR. This 53BP1 inhibition is relieved by TIRR-interacting RNA molecules, providing proof-of-principle of RNA-triggered 53BP1 recruitment to DSBs.

Detecting Changes in Support Needs Over Time.

Assessment of support needs has received significant attention in the disability field, however, little is known about the stability of support needs scores over time. Data from 82 adults with intellectual and developmental disabilities (IDD) who were reassessed with the Supports Intensity Scale-Adult (SIS-A) version as well as the SIS-A Annual Review Protocol (SIS-A ARP) were analyzed. The findings suggest stability of SIS-A scores over a one- to three-year period in adults with IDD. Several sections of the SIS-A ARP showed discriminative power, particularly sections that asked if there had been changes in a subset of specific life activities assessed on the SIS-A and in medical and behavioral needs. Implications for further research and practice are discussed.

Examining Measurement Invariance and Differences in Age Cohorts on the Supports Intensity Scale-Children's Version-Catalan Translation.

Data from 949 children and adolescents with intellectual disability ages 5 to 16 for whom the Supports Intensity Scale-Children's Version-Catalan Translation was completed was used, in combination with data from the U.S. standardization sample, to examine measurement invariance and latent differences in the Catalonian sample. Results suggest that the same set of items can be used to measure support needs across U.S. and Catalonia samples and that there are age-related differences in support needs in the Catalonia sample, particularly between children ages 5 to 10 and 11 to 16 years of age. This differs from findings with the U.S. sample, where differences were found in a greater number of age cohorts. Implications for future research and practice are discussed.

Defining the Architecture of the Core Machinery for the Assembly of Fe-S Clusters in Human Mitochondria.

Although Fe-S clusters may assemble spontaneously from elemental iron and sulfur in protein-free systems, the potential toxicity of free Fe2+, Fe3+, and S2- ions in aerobic environments underscores the requirement for specialized proteins to oversee the safe assembly of Fe-S clusters in living cells. Prokaryotes first developed multiprotein systems for Fe-S cluster assembly, from which mitochondria later derived their own system and became the main Fe-S cluster suppliers for eukaryotic cells. Early studies in yeast and human mitochondria indicated that Fe-S cluster assembly in eukaryotes is centered around highly conserved Fe-S proteins (human ISCU) that serve as scaffolds upon which new Fe-S clusters are assembled from (i) elemental sulfur, provided by a pyridoxal phosphate-dependent cysteine desulfurase (human NFS1) and its stabilizing-binding partner (human ISD11), and (ii) elemental iron, provided by an iron-binding protein of the frataxin family (human FXN). Further studies revealed that all of these proteins could form stable complexes that could reach molecular masses of megadaltons. However, the protein-protein interaction surfaces, catalytic mechanisms, and overall architecture of these macromolecular machines remained undefined for quite some time. The delay was due to difficulties inherent in reconstituting these very large multiprotein complexes in vitro or isolating them from cells in sufficient quantities to enable biochemical and structural studies. Here, we describe approaches we developed to reconstitute the human Fe-S cluster assembly machinery in Escherichia coli and to define its remarkable architecture.

The Support Needs of Children with Intellectual Disability and Autism: Implications for Supports Planning and Subgroup Classification.

The Supports Intensity Scale-Children's version (SIS-C) was developed to provide a standardized measure of support needs of children with intellectual disability. Over half of the norming sample had a secondary diagnosis of autism. Using this subset of the sample, we engaged in exploratory analysis to examine the degree to which latent clusters were present in the data, and after identifying these clusters, the degree to which they mapped on the SIS-C standard scores. A four latent class solution provided the best fit to the data. When mapped on SIS-C standard scores, specific patterns of differences were found in life activity domain scores and overall support needs scores. Implications for future research and practice are discussed.

Examining age-related differences in support needs on the Supports Intensity Scale-Children's Version-Spanish translation / Diferencias relacionadas con la edad en las necesidades de apoyo: análisis de la versión española de la Escala de Intensidad de Apoyos para Niños y Adolescentes

Background: Interest in the support needs of people with intellectual disability has directed attention to developing assessments to measure of the pattern and intensity of supports which people need to participate in valued life activities. Assessments of the support needs of children must account for the influence of age. Method: Four hundred fifty (450) Spanish children with intellectual disability (ages 5-16) were assessed with the SIS-C Spanish. To test for measurement invariance and latent differences, the SIS-C Spanish standardization sample was linked to the SIS-C English normative sample. Models developed during the norming process were used to investigate measurement equivalence across age groups, differences in latent means, and differences in latent variances and standard deviations. Results: Findings suggested that all items on the SIS-C Spanish could reliably be used to measure support needs of children ages 5-16. When exploring age-related differences at the latent level, however, data showed latent mean differences in support need domain scores across age cohorts. Conclusions: The same set of items can be used to measure support needs in children ages 5-16, but age-related influences must be considered in developing norms for theSIS-C Spanish as well as in planning supports for children (AU)

Antecedentes: El interés en las necesidades de apoyo de las personas con discapacidad intelectual debe centrarse en la evaluación del patrón e intensidad de los apoyos requeridos para realizar las actividades diarias. Cuando se evalúan estas necesidades en niños, se debe considerar además la influencia de la edad. Método: Se evaluaron 450 personas con discapacidad intelectual (5-16 años) mediante la versión española de la SIS-C. La invarianza de medida y las diferencias latentes fueron analizadas relacionando la muestra española con la muestra normativa de la versión en inglés. Los modelos desarrollados para la creación de baremos se utilizaron para estudiar las equivalencias de medida en los distintos grupos de edad y las diferencias latentes de sus medias, varianzas y desviaciones típicas. Resultados: Los ítems de la versión española de la SIS-C son fiables para medir las necesidades de apoyo en personas de entre 5 y 16 años. A nivel latente, los datos mostraron diferencias en las medias de las puntuaciones de diferentes grupos de edad. Conclusiones: Pueden utilizarse los mismos ítems para medir las necesidades de apoyo de niños y adolescentes, pero debe considerarse la influencia de la edad tanto en la creación de baremos como en la planificación de apoyos (AU)

Construct Validation of the Supports Intensity Scale - Children and Adult Versions: An Application of a Pseudo Multitrait-Multimethod Approach.

This study examined the convergent validity of the Supports Intensity Scale - Adult Version (SIS-A; Thompson et al., 2015a ) and Supports Intensity Scale - Children's Version (SIS-C; Thompson et al., 2016a ). Data from SISOnline (n = 129,864) for the SIS-A and from the SIS-C standardization sample (n = 4,015) were used for analyses. Using a pseudo multitrait-multimethod model, we estimated observed support needs scores as shared trait (support needs concept) and method (type, frequency, and daily support time) variances. Overall, trait variances more strongly influenced support needs scores than method variances, supporting the convergent validity of both versions of SIS. Findings also suggested that each of three methods of measuring support needs uniquely contributed to observed support needs ratings although different patterns existed between the SIS-A and SIS-C.