A TNF- and c-Cbl-dependent FLIP(S)-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis.

Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIP(S), which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis-triggered macrophage cell death.

Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects.

Oxidative stress in the insulin target tissues has been implicated in the pathophysiology of type 2 diabetes. The study has examined the oxidative stress parameters in the mitochondria of subcutaneous white adipose tissue from obese and non-obese subjects with or without type 2 diabetes. An accumulation of protein carbonyls, fluorescent lipid peroxidation products, and malondialdehyde occurs in the adipose tissue mitochondria of obese type 2 diabetic, non-diabetic obese, and non-obese diabetic subjects with the maximum increase noticed in the obese type 2 diabetes patients and the minimum in non-obese type 2 diabetics. The mitochondria from obese type 2 diabetics, non-diabetic obese, and non-obese type 2 diabetics also produce significantly more reactive oxygen species (ROS) in vitro compared to those of controls, and apparently the mitochondrial ROS production rate in each group is proportional to the respective load of oxidative damage markers. Likewise, the mitochondrial antioxidant enzymes like superoxide dismutase and glutathione peroxidase show decreased activities most markedly in obese type 2 diabetes subjects and to a lesser degree in non-obese type 2 diabetes or non-diabetic obese subjects in comparison to control. The results imply that mitochondrial dysfunction with enhanced ROS production may contribute to the metabolic abnormality of adipose tissue in obesity and diabetes.

Microbiome systems biology advancements for natural well-being.

Throughout the years all data from epidemiological, physiological and omics have suggested that the microbial communities play a considerable role in modulating human health. The population of microorganisms residing in the human intestine collectively known as microbiota presents a genetic repertoire that is higher in magnitude than the human genome. They play an essential role in host immunity and neuronal signaling. Rapid enhancement of sequence based screening and development of humanized gnotobiotic model has sparked a great deal of interest among scientists to probe the dynamic interactions of the commensal bacteria. This review focuses on systemic analysis of the gut microbiome to decipher the complexity of the host-microbe intercommunication and gives a special emphasis on the evolution of targeted precision medicine through microbiome engineering. In addition, we have also provided a comprehensive description of how interconnection between metabolism and biochemical reactions in a specific organism can be obtained from a metabolic network or a flux balance analysis and combining multiple datasets helps in the identification of a particular metabolite. The review highlights how genetic modification of the critical components and programming the resident microflora can be employed for targeted precision medicine. Inspite of the ongoing debate on the utility of gut microbiome we have explored on the probable new therapeutic avenues like FMT (Fecal microbiota transplant) can be utilized. This review also recapitulates integrating human-relevant 3D cellular models coupled with computational models and the metadata obtained from interventional and epidemiological studies may decipher the complex interactome of diet-microbiota-disease pathophysiology. In addition, it will also open new avenues for the development of therapeutics derived from microbiome or implementation of personalized nutrition. In addition, the identification of biomarkers can also help towards the development of new diagnostic tools and eventually will lead to strategic management of the disease. Inspite of the ongoing debate on the utility of the gut microbiome we have explored how probable new therapeutic avenues like FMT (Fecal microbiota transplant) can be utilized. This review also summarises integrating human-relevant 3D cellular models coupled with computational models and the metadata obtained from interventional and epidemiological studies may decipher the complex interactome of diet- microbiota-disease pathophysiology. In addition, it will also open new avenues for the development of therapeutics derived from the microbiome or implementation of personalized nutrition. In addition, the identification of biomarkers can also help towards the development of new diagnostic tools and eventually will lead to strategic management of disease.

The essentials of nursing leadership: A systematic review of factors and educational interventions influencing nursing leadership.

BACKGROUND: Nursing leadership plays a vital role in shaping outcomes for healthcare organizations, personnel and patients. With much of the leadership workforce set to retire in the near future, identifying factors that positively contribute to the development of leadership in nurses is of utmost importance. OBJECTIVES: To identify determining factors of nursing leadership, and the effectiveness of interventions to enhance leadership in nurses. DESIGN: We conducted a systematic review, including a total of nine electronic databases. DATA SOURCES: Databases included: Medline, Academic Search Premier, Embase, PsychInfo, Sociological Abstracts, ABI, CINAHL, ERIC, and Cochrane. REVIEW METHODS: Studies were included if they quantitatively examined factors contributing to nursing leadership or educational interventions implemented with the intention of developing leadership practices in nurses. Two research team members independently reviewed each article to determine inclusion. All included studies underwent quality assessment, data extraction and content analysis. RESULTS: 49,502 titles/abstracts were screened resulting in 100 included manuscripts reporting on 93 studies (n=44 correlational studies and n=49 intervention studies). One hundred and five factors examined in correlational studies were categorized into 5 groups experience and education, individuals' traits and characteristics, relationship with work, role in the practice setting, and organizational context. Correlational studies revealed mixed results with some studies finding positive correlations and other non-significant relationships with leadership. Participation in leadership interventions had a positive impact on the development of a variety of leadership styles in 44 of 49 intervention studies, with relational leadership styles being the most common target of interventions. CONCLUSIONS: The findings of this review make it clear that targeted educational interventions are an effective method of leadership development in nurses. However, due to equivocal results reported in many included studies and heterogeneity of leadership measurement tools, few conclusions can be drawn regarding which specific nurse characteristics and organizational factors most effectively contribute to the development of nursing leadership. Contextual and confounding factors that may mediate the relationships between nursing characteristics, development of leadership and enhancement of leadership development programs also require further examination. Targeted development of nursing leadership will help ensure that nurses of the future are well equipped to tackle the challenges of a burdened health-care system.

Leadership styles and outcome patterns for the nursing workforce and work environment: A systematic review.

BACKGROUND: Leadership is critical in building quality work environments, implementing new models of care, and bringing health and wellbeing to a strained nursing workforce. However, the nature of leadership style, how leadership should be enacted, and its associated outcomes requires further research and understanding. We aimed to examine the relationships between various styles of leadership and outcomes for the nursing workforce and their work environments. METHODS: The search strategy of this systematic review included 10 electronic databases. Published, quantitative studies that examined the correlations between leadership behaviours and nursing outcomes were included. Quality assessments, data extractions and analysis were completed on all included studies by independent reviewers. RESULTS: A total of 50,941 titles and abstracts were screened resulting in 129 included studies. Using content analysis, 121 outcomes were grouped into six categories: 1) staff satisfaction with job factors, 2) staff relationships with work, 3) staff health & wellbeing, 4) relations among staff, 5) organizational environment factors and 6) productivity & effectiveness. Our analysis illuminated patterns between relational and task focused leadership styles and their outcomes for nurses and nursing work environments. For example, 52 studies reported that relational leadership styles were associated with higher nurse job satisfaction, whereas 16 studies found that task-focused leadership styles were associated with lower nurse job satisfaction. Similar trends were found for each category of outcomes. CONCLUSIONS: The findings of this systematic review provide strong support for the employment of relational leadership styles to promote positive nursing workforce outcomes and related organizational outcomes. Leadership focused solely on task completion is insufficient to achieve optimum outcomes for the nursing workforce. Relational leadership practices need to be encouraged and supported by individuals and organizations to enhance nursing job satisfaction, retention, work environment factors and individual productivity within healthcare settings.

Genistein, the Isoflavone in Soybean, Causes Amyloid Beta Peptide Accumulation in Human Neuroblastoma Cell Line: Implications in Alzheimer's Disease.

The isoflavone, genistein, present in soybean is being actively investigated for its potential beneficial effect against Alzheimer's disease. Our data, however, show that in SHSY5Y cells genistein causes increased expression (mRNA and protein) of amyloid precursor protein (APP), increased mRNA expression and activity of ß-secretase and diminished level of insulin degrading enzyme (IDE) which also degrades amyloid beta peptide. These effects of genistein lead to enhanced accumulation of amyloid beta peptide (Aß42) in SHSY5Y cells. The results do not support the view that genistein could be a putative drug against AD and instead strengthen the epidemiological study which implies that genistein content of soybean food product (Tofu) leads to cognitive impairment.

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment.

Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.

Helicobacter pylori protein HP0175 transactivates epidermal growth factor receptor through TLR4 in gastric epithelial cells.

The pathophysiology of Helicobacter pylori-associated gastroduodenal diseases, ulcerogenesis, and carcinogenesis is intimately linked to activation of epidermal growth factor receptor (EGFR) and production of vascular endothelial growth factor (VEGF). Extracellular virulence factors, such as CagA and VacA, have been proposed to regulate EGFR activation and VEGF production in gastric epithelial cells. We demonstrate that the H. pylori secretory protein, HP0175, by virtue of its ability to bind TLR4, transactivates EGFR and stimulates EGFR-dependent VEGF production in the gastric cancer cell line AGS. Knock-out of the hp0175 gene attenuates the ability of the resultant H. pylori strain to activate EGFR or to induce VEGF production. HP0175-induced activation of EGFR is preceded by translocation of TLR4 into lipid rafts. In lipid rafts, the Src kinase family member Lyn interacts with TLR4, leading to tyrosine phosphorylation of TLR4. Knockdown of Lyn prevents HP0175-induced activation of EGFR and VEGF production. Tyrosine-phosphorylated TLR4 interacts with EGFR. This interaction is necessary for the activation of EGFR. Disruption of lipid rafts with methyl beta-cyclodextrin prevents HP0175-induced tyrosine phosphorylation of TLR4 and activation of EGFR. This mechanism of transactivation of EGFR is novel and distinct from that of metalloprotease-dependent shedding of EGF-like ligands, leading to autocrine activation of EGFR. It provides new insight into our understanding of the receptor cross-talk network.