Screening for Diguanylate Cyclase (DGC) Inhibitors Mitigating Bacterial Biofilm Formation.

The majority of bacteria in the natural environment organize themselves into communal biofilms. Biofilm formation benefits bacteria conferring resistance to harmful molecules (e.g., antibiotics, disinfectants, and host immune factors) and coordinating their gene expression through quorum sensing (QS). A primary signaling molecule promoting bacterial biofilm formation is the universal second messenger cyclic di-GMP. This dinucleotide predominantly controls the gene expression of motility, adhesins, and capsule production to coordinate biofilm formation. Cyclic di-GMP is synthesized by diguanylate cyclases (DGCs) that have a GGDEF domain and is degraded by phosphodiesterases (PDEs) containing either an EAL or an HD-GYP domain. Since high cellular c-di-GMP concentrations are correlated with promoting the ability of bacteria to form biofilms, numerous research endeavors to identify chemicals capable of inhibiting the c-di-GMP synthesis activity of DGCs have been performed in order to inhibit bacterial biofilm formation. This review describes currently identified chemical inhibitors that disturb the activity of DGCs and the methods of screening and assay for their discovery.

Bone marrow transplant with post-transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe systemic genodermatosis lacking therapies beyond supportive care for its extensive, life-limiting manifestations. OBJECTIVES: To report the safety and preliminary responses of 10 patients with RDEB to bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy BMT) after reduced-intensity conditioning with infusions of immunomodulatory donor-derived mesenchymal stromal cells (median follow-up 16 months). METHODS: BMT toxicities, donor blood and skin engraftment, skin biopsies, photographic and dynamic assessments of RDEB disease activity were obtained at intervals from pre-BMT to 1 year post-BMT. RESULTS: Related donors varied from haploidentical (n = 6) to human leucocyte antigen (HLA)-matched (n = 3), with one HLA-matched unrelated donor. Transplant complications included graft failure (n = 3; two pursued a second PTCy BMT), veno-occlusive disease (n = 2), posterior reversible encephalopathy (n = 1) and chronic graft-versus-host disease (n = 1; this patient died). In the nine ultimately engrafted patients, median donor chimerism at 180 days after transplant was 100% in peripheral blood and 27% in skin. Skin biopsies showed stable (n = 7) to improved (n = 2) type VII collagen protein expression by immunofluorescence and gain of anchoring fibril components (n = 3) by transmission electron microscopy. Early signs of clinical response include trends toward reduced body surface area of blisters/erosions from a median of 49·5% to 27·5% at 100 days after BMT (P = 0·05), with parental measures indicating stable quality of life. CONCLUSIONS: PTCy BMT in RDEB provides a means of attaining immunotolerance for future donor-derived cellular grafts (ClinicalTrials.gov identifier NCT02582775). What's already known about this topic? Severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) is marked by great morbidity and early death. No cure currently exists for RDEB. Bone marrow transplant (BMT) is the only described systemic therapy for RDEB. What does this study add? The first description of post-transplant cyclophosphamide (PTCy) BMT for RDEB. PTCy was well tolerated and provided excellent graft-versus-host disease prophylaxis, replacing long courses of calcineurin inhibitors in patients receiving human leucocyte antigen-matched sibling BMT. What is the translational message? The PTCy BMT platform permits identification of a suitable related donor for most patients and for subsequent adoptive transfer of donor nonhaematopoietic cells after establishment of immunological tolerance.

Resiliency, social support, and coping in rural low-income Appalachian adolescents from two racial groups.

In this study an attempt was made to examine social support and coping in relation to resiliency among a sample of rural, low-income Appalachian adolescents of African-American and White races. Fifty-three African-American and 60 White 10th grade students completed the Perceived Social Support Scale for Family and Friends, the Ways of Coping Checklist, and Psychosocial Inventory of Ego Strengths. Utilizing regression analyses, it was shown that social support from family and problem-focused, avoidance, and wishful-thinking forms of coping significantly predicted resiliency. Race and gender distinctions were minimal in respect to the measured variables in the study. Research in the future should include continued examination of rural and diverse samples, the use of various sampling procedures, and longitudinal assessments of resiliency.

BASIC UNPREDICTABILITY OF INDIVIDUAL RESPONSES TO DISCRETE STIMULUS PRESENTATIONS.

A common assertion of psychologists is that the objeotive of psychology .is to predict and control behavior. The assertion springs from the belief that psychologists will learn enough about general stimulus-raponse laws and underlying factors' of behavior to predict how a given individual will react in a given discrete stim- ulus situation, and we will be able to arrange situations in a fashion that will control what the individual does.

GENERALITY AND RELIABILITY OF INDIVIDUAL SITUATIONS DIFFERENCES IN DISCRETE STIMULUS-ITEM.

The basic data with which psychologists commonly deal are the dichotomous responses of individuals t o stimulus presentations. The stimulus situations studied range from those presented in psychophysical brass instrument experiments .to items printed in tests of ability and personality.

Comparative Cluster Analysis Of Social Areas.

Three demographic dimensions previously isolated by cluster analysis procedures (using BC TRY System computer analyses) were compared in different metropolitan areas for their stability over time and place. Also, the social areas discovered within the communities were studied for their stability over time and place. The three demographic dimensions (socio-economic independence, family life, and assimilation) accounted for the generality of 33 census tract (1940) characteristics in two communities. It was also shown that the three basic dimensions were essentially unchanged during the decade which included World War 11. The stability of these dimensions was retained even though there was considerable change in residents in each metropolitan area during the decade. The validity of cluster-search procedures is demonstrated by the stability of the three demographic dimensions.

PERSON-CLUSTERS ON INTELLECTUAL ABILITIES AND ON MMPI ATTRIBUTES.

When persons are observed on multiple dimensions discovered by the objective procedures of the cluster analysis of variables (V-analysis), they can then be allocated to person-clusters by the equally-objective procedures of object-clustering (O-analysis). These procedures, called the Condensation Method, are completely worked out on two empirical studies. In the first study on intellectual abilities (the Holzinger Problem) 301 children are assigned to 15 O-types. In the second study on self-conceptions (the MMPI), 310 psychiatric patients and normals are allocated to 14 O-types. The means of assigning new individuals to these master types are described. All procedures are executed by computer programs of the BC TRY System, in particular the components FACS, OTYPE, and OSTAT. The logic of the methods is fully developed.

Predicting Individual Differences By Cluster Analysis : Holzinger Abilities And MMPI Personality Attributes.

Prediction of individual differences by cluster analysis procedures is described for the case of Holzinger's 24-variable problem and the case of MMPI item-clusters. Comparisons are made between univariate, multiple regression, and person-cluster predictions. The best prediction is from person- clusters, whose score patterns are objectively isolated by BC TRY Computer System programs. The role of chance is objectively assessed by program 4CAST and not by estimation formulations.

Predicting Group Differences In Cluster Analysis: The Social Area Problem.

Prediction of group differences by cluster analysis procedures is described for the case of neighborhoods (tracts) of a metropolitan area. Social areas of homogeneous neighborhoods are isolated by objective "O-analysis" procedures of the BC TRY Computer System. The predictor attributes are pre-war demographic features from which high predictions both of demographic and voting-attitudes are made up to 15 years, despite the social disruptions of a great war. Three basic dimensions, Conservatism, Territoriality, and Exclusiveness are found to predict all demographic and attitudinal characteristics of neighborhoods over a decade and a half.

Unrestricted Cluster And Factor Analysis, With Applications To The MMPI And Holzinger-Harman Problems.

A solution is provided for the problem of large numbers of variables in V-analysis and of large numbers of subjects in 0-analysis. The solution is that of estimating the Structure in the total set from the structures found in manageable samples of the total set. The samples are drawn randomly; structures of each are computed by existing BC TRY programs; finally the structures of the random samples are combined using new BC TRY programs. Examples of the complete analyses in two separate studies are given.