Recovery from Severe Mental Illness – Pilot Research Paving the Way

poster abstractThe ACT Center of Indiana is a research and training center devoted to helping organizations provide services to adults with severe mental illness that are based on the best research evidence and promote recovery. We briefly highlight 5 recent pilot studies that ultimately may help improve care. These involve measuring factors that promote recovery (pilot #1), strategies to involving family members in recovery (pilot #2), ensuring active participation of consumers (pilot#3), reducing burnout in staff (pilot #4), and cost-effective ways to measure program implementation (pilot #5)

Mirizzi Syndrome Type I: A Case Presentation.

Mirizzi syndrome (MS) is a rare complication of chronic cholelithiasis. The syndrome describes gallstone obstruction of Hartmann\u27s pouch or the cystic duct that extrinsically compresses the common hepatic duct, causing obstructive jaundice. In advanced cases, the gallstones may erode into the biliary tree creating a fistula, requiring prompt diagnosis and careful surgical management. We present a case of an 82-year-old female who presented with upper abdominal pain and jaundice, later diagnosed with suspected MS type I, and managed surgically. We aim to highlight MS type I because of the potential progression and damage to the bile duct, creating complications that may affect overall patient outcome

Caregiver self-efficacy providing nutritional support for pediatric patients undergoing hematopoietic stem cell transplant is associated with psychosocial factors

IntroductionCaregiver self-efficacy in providing nutritional support to pediatric hematopoietic stem cell transplantation (HSCT) patients has been little studied despite the increased risk of these children potentially being over- or under-nourished after HSCT, and nutritional status could possibly affect treatment outcomes. The current study aimed to describe caregiver dietary self-efficacy and its associated psychosocial factors and barriers to following dietary recommendations.MethodsCaregivers completed questionnaires pre-HSCT and 30 days, 100 days, and one year post-HSCT. A subset provided a 24-h recall of food intake.ResultsResults showed generally high caregiver confidence and low difficulty supporting their child nutritionally. However, lower confidence was associated with higher caregiver depression, anxiety, and stress 30 days post-HSCT. Further, higher difficulty at various time points was correlated with lower income, higher depression and anxiety, stress, and miscarried helping (i.e., negative caregiver-child interactions surrounding eating), as well as child overweight status and failure to meet protein intake guidelines. Nutritional criteria for protein, fiber, added sugar, and saturated fat were met by 65%, 0%, 75%, and 75%, respectively. Caregiver attitudes and child behavior were the most frequently reported barriers to healthy eating.DiscussionResults suggest that directing resources to caregivers struggling emotionally, economically, or transactionally could support pediatric patients undergoing HSCT in maintaining optimal nutritional status

Promoting Recovery from Mental Illness: Consumer, Staff, and Program Level Interventions

poster abstractThe ACT Center of Indiana is a research and training center devoted to helping promote recovery from severe mental illnesses like schizophrenia and bipolar disorder. We focus on interventions that are based on the best research evidence, and we emphasize ways to translate research into actual practice. We have current research projects that target different levels of the mental health service system. Here we present research focused on 1) the consumer with mental illness - identifying ways that consumers set treatment goals related to recovery; 2) the staff who work with people with severe mental illness – helping staff stay healthy and engaged in their work; and 3) the programs that support recovery – identifying cost-effective ways to ensure high quality services

MERIT, a cellular system coordinating lysosomal repair, removal and replacement

Membrane integrity is essential for cellular survival and function. The spectrum of mechanisms protecting cellular and intracellular membranes is not fully known. Our recent work has uncovered a cellular system termed MERIT for lysosomal membrane repair, removal and replacement. Specifically, lysosomal membrane damage induces, in succession, ESCRT-dependent membrane repair, macroautophagy/autophagy-dominant removal of damaged lysosomes, and initiation of lysosomal biogenesis via transcriptional programs. The MERIT system is governed by galectins, a family of cytosolically synthesized lectins recognizing β-galactoside glycans. We found in this study that LGALS3 (galectin 3) detects membrane damage by detecting exposed lumenal glycosyl groups, recruits and organizes ESCRT components PDCD6IP/ALIX, CHMP4A, and CHMPB at damaged sites on the lysosomes, and facilitates ESCRT-driven repair of lysosomal membrane. At later stages, LGALS3 cooperates with TRIM16, an autophagy receptor-regulator, to engage autophagy machinery in removal of excessively damaged lysosomes. In the absence of LGALS3, repair and autophagy are less efficient, whereas TFEB nuclear translocation increases to compensate lysosomal deficiency via de novo lysosomal biogenesis. The MERIT system protects endomembrane integrity against a broad spectrum of agents damaging the endolysosomal network including lysosomotropic drugs, Mycobacterium tuberculosis, or neurotoxic MAPT/tau. Abbreviations: AMPK: AMP-activated protein kinase; APEX2: engineered ascorbate peroxidase 2; ATG13: autophagy related 13; ATG16L1: autophagy related 16 like 1; BMMs: bone marrow-derived macrophages; ESCRT: endosomal sorting complexes required for transport; GPN: glycyl-L-phenylalanine 2-naphthylamide; LLOMe: L-leucyl-L-leucine methyl ester; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MERIT: membrane repair, removal and replacement; MTOR: mechanistic target of rapamycin kinase; TFEB: transcription factor EB; TFRC: transferrin receptor; TRIM16: tripartite motif-containing 16

Galectin-3 Coordinates a Cellular System for Lysosomal Repair and Removal

Jia et al. show that Galectin-3 recruits ESCRT components to damaged lysosomes for repair and restoration of their function. During sustained lysosomal injury, galectins induce autophagy and lysosomal biogenesis for a staged repair, removal, and replacement program. This response is deployed during damage with neurotoxic tau or Mycobacterium tuberculosis infection

Structure of the γ-D-glutamyl-L-diamino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-γ-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases.

Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific γ-D-glutamyl-L-diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (L-Ala-γ-D-Glu) enabled the identification of conserved sequence and structural signatures for recognition of L-Ala and γ-D-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial L-alanine-γ-D-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site

The structure of BVU2987 from Bacteroides vulgatus reveals a superfamily of bacterial periplasmic proteins with possible inhibitory function.

Proteins that contain the DUF2874 domain constitute a new Pfam family PF11396. Members of this family have predominantly been identified in microbes found in the human gut and oral cavity. The crystal structure of one member of this family, BVU2987 from Bacteroides vulgatus, has been determined, revealing a β-lactamase inhibitor protein-like structure with a tandem repeat of domains. Sequence analysis and structural comparisons reveal that BVU2987 and other DUF2874 proteins are related to β-lactamase inhibitor protein, PepSY and SmpA_OmlA proteins and hence are likely to function as inhibitory proteins

Engineering hemoglobin to enable homogenous PEGylation without modifying protein functionality

In order to infuse hemoglobin into the vasculature as an oxygen therapeutic or blood substitute, it is necessary to increase the size of the molecule to enhance vascular retention. This aim can be achieved by PEGylation. However, using non-specific conjugation methods creates heterogenous mixtures and alters protein function. Site-specific PEGylation at the naturally reactive thiol on human hemoglobin (βCys93) alters hemoglobin oxygen binding affinity and increases its autooxidation rate. In order to avoid this issue, new reactive thiol residues were therefore engineered at sites distant to the heme group and the α/β dimer/dimer interface. The two mutants were βCys93Ala/αAla19Cys and βCys93Ala/βAla13Cys. Gel electrophoresis, size exclusion chromatography and mass spectrometry revealed efficient PEGylation at both αAla19Cys and βAla13Cys, with over 80% of the thiols PEGylated in the case of αAla19Cys. For both mutants there was no significant effect on the oxygen affinity or the cooperativity of oxygen binding. PEGylation at αAla19Cys had the additional benefit of decreasing the rates of autoxidation and heme release, properties that have been considered contributory factors to the adverse clinical side effects exhibited by previous hemoglobin based oxygen carriers. PEGylation at αAla19Cys may therefore be a useful component of future clinical products