CD4+ T cell memory is impaired by species-specific cytotoxic differentiation, but not by TCF-1 loss.

CD4+ T cells are typically considered as 'helper' or 'regulatory' populations that support and orchestrate the responses of other lymphocytes. However, they can also develop potent granzyme (Gzm)-mediated cytotoxic activity and CD4+ cytotoxic T cells (CTLs) have been amply documented both in humans and in mice, particularly in the context of human chronic infection and cancer. Despite the established description of CD4+ CTLs, as well as of the critical cytotoxic activity they exert against MHC class II-expressing targets, their developmental and memory maintenance requirements remain elusive. This is at least in part owing to the lack of a murine experimental system where CD4+ CTLs are stably induced. Here, we show that viral and bacterial vectors encoding the same epitope induce distinct CD4+ CTL responses in challenged mice, all of which are nevertheless transient in nature and lack recall properties. Consistent with prior reports, CD4+ CTL differentiation is accompanied by loss of TCF-1 expression, a transcription factor considered essential for memory T cell survival. Using genetic ablation of Tcf7, which encodes TCF-1, at the time of CD4+ T cell activation, we further show that, contrary to observations in CD8+ T cells, continued expression of TCF-1 is not required for CD4+ T cell memory survival. Whilst Tcf7-deficient CD4+ T cells persisted normally following retroviral infection, the CD4+ CTL subset still declined, precluding conclusive determination of the requirement for TCF-1 for murine CD4+ CTL survival. Using xenotransplantation of human CD4+ T cells into murine recipients, we demonstrate that human CD4+ CTLs develop and persist in the same experimental conditions where murine CD4+ CTLs fail to persist. These observations uncover a species-specific defect in murine CD4+ CTL persistence with implications for their use as a model system.

Mycobacterium tuberculosis requires glyoxylate shunt and reverse methylcitrate cycle for lactate and pyruvate metabolism.

Bacterial nutrition is an essential aspect of host-pathogen interaction. For the intracellular pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans, fatty acids derived from lipid droplets are considered the major carbon source. However, many other soluble nutrients are available inside host cells and may be used as alternative carbon sources. Lactate and pyruvate are abundant in human cells and fluids, particularly during inflammation. In this work, we study Mtb metabolism of lactate and pyruvate combining classic microbial physiology with a 'multi-omics' approach consisting of transposon-directed insertion site sequencing (TraDIS), RNA-seq transcriptomics, proteomics and stable isotopic labelling coupled with mass spectrometry-based metabolomics. We discovered that Mtb is well adapted to use both lactate and pyruvate and that their metabolism requires gluconeogenesis, valine metabolism, the Krebs cycle, the GABA shunt, the glyoxylate shunt and the methylcitrate cycle. The last two pathways are traditionally associated with fatty acid metabolism and, unexpectedly, we found that in Mtb the methylcitrate cycle operates in reverse, to allow optimal metabolism of lactate and pyruvate. Our findings reveal a novel function for the methylcitrate cycle as a direct route for the biosynthesis of propionyl-CoA, the essential precursor for the biosynthesis of the odd-chain fatty acids.

Does value congruence between nurses and supervisors effect job satisfaction and turnover?

AIM: The purpose of this study was to examine the relationship of congruency of leadership support and value of patient outcomes between nurses and nurse managers and nurses' job satisfaction and turnover intent. BACKGROUND: Turnover most often has a negative effect on an organization. Leadership support and patient outcomes have been identified as important factors, but congruency has not been studied in great detail. METHOD(S): This quantitative non-experimental study included registered nurses (92) and nurse managers (21) in five non-magnet hospitals in the United States. RESULTS: Value congruence on leadership support was correlated with job satisfaction: Satisfaction in Nursing Scale (SINs)-Workload Barriers (r = 0.327, Administrative Support r = 0.544 and Collegiality = 0.920, P < 0.05). Value congruence and leadership support (Leadership Practices Inventory, LPI) was negatively correlated with turnover intent (r = 0.317, P < 0.05). When all variables were combined a correlation of Value of Patient Outcomes (VOPOS) and the Anticipated Turnover Scale (ATS) (r = 0.099, P > 0.05) was noted. CONCLUSION: Value congruence of leadership support is related to job satisfaction and may be a factor in turnover intent. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse Administrators can use these results to develop policies to address the turnover especially in the area of leadership support.

Aberrant retinal projections in congenitally deaf mice: how are phenotypic characteristics specified in development and evolution?

The contribution of sensory input to the formation of sensory system-specific (sensoritopic) connections of the thalamus and midbrain was investigated using mice lacking the Na+-K+-2Cl- cotransporter (NKCC1) or the plasma membrane Ca2+-ATPase isoform2 (PMCA2). Because these mice are congenitally deaf, the developing nervous system has no exposure to sensory-driven neural activity from the auditory system. Here we compared the retinofugal pathway in normal and congenitally deaf mice using intraocular injections of neuroanatomical tracers into each eye, and relating tracer patterns to identified thalamic nuclei and superior colliculus layers. We demonstrate that loss of such activity results in aberrant projections of the retina into nonvisual auditory structures such as the medial geniculate nucleus and the intermediate layers of the superior colliculus. These findings indicate that activity from peripheral sensory receptor arrays is necessary not only for the refinement of developing connections within a unimodal structure, but for the establishment of sensoritopic or sensory-specific connections of unimodal and multimodal structures. We hypothesize that specification of such connections may occur through the modulation of spatial expression patterns of molecules known to be involved in the development of topography of connections between brain structures, such as the ephrins, via activity-dependent, CRE-mediated gene expression.

Application of Fitts' law to individuals with cerebral palsy.

Cerebral palsy is a condition that results in motor abnormalities as a direct consequence of injury to the developing brain. Fitts' law, which describes a speed-accuracy tradeoff in visually guided movements, has been shown to characterize the motor behavior of normal subjects during aiming tasks. To assess whether Fitts' law can also describe the aimed movements of persons with cerebral palsy, eight cerebral palsied adults participated in an aimed movement study. 12 targets were used with Indices of Difficulty ranging from 2.19 to 6.00 bits. The impact of Gan and Hoffmann's 1988 ballistic movement factor, square root(A) , and Fitts' 1954 Index of Difficulty on subject's movement and reaction times was examined using multivariate linear models. The analysis of the full data set yielded a significant effect of square root(A) on movement times and no significant adherence to Fitts' law. However, high error rates that could be the result of oculomotor problems among the subject group were noted, and the method of handling errors had a large effect on the results. Tracking eye position during a Fitts' law task would provide information regarding the effect of oculomotor difficulties on aiming tasks in the cerebral palsied subject group.