Garcinolic Acid Distinguishes Between GACKIX Domains and Modulates Interaction Networks

Natural products are often uniquely suited to modulate protein-protein interactions (PPIs) due to their architectural and functional group complexity relative to synthetic molecules. Here we demonstrate that the natural product garcinolic acid allosterically blocks the CBP/p300 KIX PPI network and displays excellent selectivity over related GACKIX motifs. It does so via a strong interaction (KD 1 μM) with a non-canonical binding site containing a structurally dynamic loop in CBP/p300 KIX. Garcinolic acid engages full-length CBP in the context of the proteome and in doing so effectively inhibits KIX-dependent transcription in a leukemia model. As the most potent small-molecule KIX inhibitor yet reported, garcinolic acid represents an important step forward in the therapeutic targeting of CBP/p300

Recognition, Perceptions and Treatment Practices for Severe Malaria in Rural Tanzania: Implications for Accessing Rectal Artesunate as a Pre-Referral

OBJECTIVES: Preparatory to a community trial investigating how best to deliver rectal artesunate as pre-referral treatment for severe malaria; local understanding, perceptions of signs/symptoms of severe malaria and treatment-seeking patterns for and barriers to seeking biomedical treatment were investigated. METHODOLOGY/PRINCIPAL FINDINGS: 19 key informant interviews, 12 in-depth interviews and 14 focus group discussions targeting care-givers, opinion leaders, and formal and informal health care providers were conducted. Monthly fever episodes and danger signs or symptoms associated with severe malaria among under-fives were recorded. Respondents recognized convulsions, altered consciousness and coma, and were aware of their risks if not treated. But, these symptoms were perceived to be caused by supernatural forces, and traditional healers were identified as primary care providers. With some delay, mothers eventually visited a health facility when convulsions were part of the illness, despite pressures against this. Although vomiting and failure to eat/suck/drink were associated with malaria, they were not considered as indicators of danger signs unless combined with another more severe symptom. Study communities were familiar with rectal application of medicines. CONCLUSIONS/SIGNIFICANCE: Communities' recognition and awareness of major symptoms of severe malaria could encourage action, but perceptions of their causes and poor discrimination of other danger signs – vomiting and failure to feed – might impede early treatment. An effective health education targeting parents/guardians, decision-makers/advisors, and formal and informal care providers might be a prerequisite for successful introduction of rectal artemisinins as an emergency treatment. Role of traditional healers in delivering such medication to the community should be explored

Mechanical testing of thin-walled zirconia abutments

Although the use of zirconia abutments for implant-supported restorations has gained momentum with the increasing demand for esthetics, little informed design rationale has been developed to characterize their fatigue behavior under different clinical scenarios. However, to prevent the zirconia from fracturing, the use of a titanium connection in bicomponent aesthetic abutments has been suggested. OBJECTIVE: Mechanical testing of customized thin-walled titanium-zirconia abutments at the connection with the implant was performed in order to characterize the fatigue behavior and the failure modes for straight and angled abutments. MATERIAL AND METHODS: Twenty custom-made bi-component abutments were tested according to ISO 14801:2007 either at a straight or a 25º angle inclination (n=10 each group). Fatigue was conducted at 15 Hz for 5 million cycles in dry conditions at 20ºC±5ºC. Mean values and standard deviations were calculated for each group. All comparisons were performed by t-tests assuming unequal variances. The level of statistical significance was set at p≤0.05. Failed samples were inspected in a polarized-light and then in a scanning electron microscope. RESULTS: Straight and angled abutments mean maximum load was 296.7 N and 1,145 N, the dynamic loading mean F(max) was 237.4 N and 240.7 N, respectively. No significant differences resulted between the straight and angled bi-component abutments in both static (p=0.253) and dynamic testing (p=0.135). A significant difference in the bending moment required for fracture was detected between the groups (p=0.01). Fractures in the angled group occurred mainly at the point of load application, whereas in the straight abutments, fractures were located coronally and close to the thinly designed areas at the cervical region. CONCLUSION: Angled or straight thin-walled zirconia abutments presented similar F(max) under fatigue testing despite the different bending moments required for fracture. The main implication is that although zirconia angled or straight abutments presented similar mechanical behavior, the failure mode tended to be more catastrophic in straight (fracture at the cervical region) compared to angled abutments

Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis.

Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Family Life Education Development, Implementation, and Evaluation in Tanzania

This chapter examines the socioeconomic, historical, and cultural context of the United Republic of Tanzania and how it has shaped the country’s family life and family life education throughout the precolonial, colonial, and postcolonial eras. The context includes social factors such as changes in family structures and functions, emergence of HIV/AIDS, sexuality and family life education programs, and related family and health policies. Utilizing the socio-ecological perspective, the article delineates family strengths, gaps, and opportunities available to key stakeholders to meet the contemporary family life education needs for the Tanzanian families