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An atomic four-helix bundle is constructed for cytoplasmic domain, which is functionally subdivided into the signaling and adaptation subdomains. The proposed four-helix bundle structure of the signaling subdomain, which binds CheA, is fully supported by experimental evidence collected with the help of cysteine and disulfide scanning.

Background: Adolescents living in HIV endemic settings face unique sexual health risks, and in the context of abject poverty, orphanhood, social marginalization, and discrimination, adolescents may be particularly at-risk of horizontal HIV transmission. Street-connected children and youth are a particularly vulnerable and marginalized population and therefore may be a key population at-risk. Methods: We sought to describe the sexual behaviours of street-connected children and youth in order to comprehend their sexual practices and elucidate circumstances that put them at increased risk of contracting HIV utilizing qualitative methods from a sample of street-connected children and youth in Eldoret, Kenya. We recruited participants aged 11-24 years who had lived on the street for ≥ 3 months to participate in 25 in-depth interviews and 5 focus group discussions stratified by age and sex. Results: In total we interviewed 65 street-connected children and youth; 69 % were male with a median age of 18 years (IQR: 14-20.5 years). Participants identified both acceptable and unacceptable sexual acts that occur on the streets between males and females, between males, and between females. We grouped reasons for having sex into four categories based on common themes: pleasure, procreation, transactional, and forced. Transactional sex and multiple concurrent partnerships were frequently described by participants. Rape was endemic to street life for girls. Conclusion: These findings have important policy and programming implications, specifically for the government of Kenya's adolescent reproductive health policy, and highlight the need to target out-of-school youth. There is an urgent need for social protection to reduce transactional sex and interventions addressing the epidemic of sexual and gender-based violence. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to describe the physical, social, and psychological initiation practices of street connected children and youths, in Eldoret, western Kenya. Methods: This qualitative study was conducted from August 2013 to February 2014. A total of 65 SCCY aged 11-24 years were purposively sampled from the three referral points: 1) A dedicated study clinic for vulnerable children and youth atMoi Teaching and Referral Hospital (MTRH); 2) Primary locations in which street children reside "bases/ barracks"; 3) Street youth community-based organizations. In-depth interviews and focus group discussions were used to collect data. All data were audio recorded, transcribed, translated to English, and a content analysis performed. Results: The overall median age was 18 years (IQR 14-20.5 years) and 69.2 % of participants were male. None had gone beyond primary level of education. The majority (81.5 %) reported to be sexually active. The street community had well-defined structures and rules that were protective of members and ensured survival on the streets. To be fully accepted children had to go through an initiation ritual that had important gender differences. Common rituals between males and females included interrogation, smearing of black soot, and payment of tax. Ritual practices unique to boys were physical abuse, theft of personal possessions, volatile substance use, being forced to eat garbage, and sodomy among the physically weak. Rituals unique to girls were being forced to 'become a wife or sexual partner', rape, and gang rape. Physical and psychological abuse during initiation was normalized and there were no clear mechanisms of dealing with these forms of abuse. Conclusion: There were important gender differences in the initiation practices of SCCY. Normalization of physical and psychological abuse during initiation contributes to the high health risks faced by these SCCY. Appropriate interventions need to be developed in collaboration with SCCY. [ABSTRACT FROM AUTHOR]

Background: Street-connected youth are a neglected and vulnerable population, particularly in resource-constrained settings. The development of interventions and supports for this population requires insight into how they live. This study describes the social and economic characteristics of a convenience sample of street youth (SY) in Eldoret, Kenya. Methods: Participants were eligible if they were aged 12–21, living in Eldoret, spending days only (part-time), or nights and days on the street (full-time) and able and willing to consent or assent. Data were collected using a standardized interview conducted in English or Kiswahili. Binary dependent variables were having been arrested and/or jailed, and first priority for spending money (food vs. other). Nominal categorical dependent variables included major source of support, and major reason for being street-involved. Multivariable analysis used logistic regression models to examine the association of gender and level of street-involvement with social and economic factors of interest adjusting for age and length of time on the street. Data were analyzed using SAS 9.3. Results: Of the 200 SY enrolled, 41% were female, mean age of 16.3 years; 71% were on the street full-time, and 29% part-time. Compared with part-time SY, full-time SY were more likely to have been arrested (Adjusted Odds Ratio [AOR]: 2.33, 95% Confidence Interval [95%CI]:1.01–5.35), name food as their first spending priority (AOR: 2.57, 95%CI:1.03–6.45), have left home due to violence (AOR: 5.54, 95%CI: 1.67–18.34), and more likely to report friends on the street as a major source of support (AOR: 3.59, 95% CI: 1.01–12.82). Compared with females, males were more likely to have ever been arrested (AOR: 2.66, 95%CI:1.14–6.18), and to have ever been jailed (AOR: 3.22, 95%CI:1.47–7.02). Conclusions: These results suggest a high degree of heterogeneity and vulnerability among SY in this setting. There is an urgent need for interventions taking into consideration these characteristics. [ABSTRACT FROM AUTHOR]

We have been probing the molecular mechanisms of tumor promoters that stimulate distinct initial signals to define critical downstream biochemical events in carcinogenesis. The action of the novel skin tumor promoter palytoxin on signaling and gene expression in keratinocytes, the primary target cells of tumor promoters, was therefore investigated. Palytoxin stimulated an increase in mRNA for matrix metalloproteinase-13 (MMP-13), an enzyme implicated in carcinogenesis, in a keratinocyte cell line derived from initiated mouse skin (308). Palytoxin stimulated an increase in c-Fos binding to the activator protein-1 (AP-1) site present in the promoter of the mouse MMP-13 gene. This effect was specific because palytoxin had little effect on c-Jun, JunB, JunD, FosB, Fra-1, or Fra-2 binding or on overall levels of transcription factor binding. The increase in c-Fos binding corresponded to a palytoxin-stimulated increase in c-Fos protein levels. Palytoxin stimulated the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase, and p38. The MAPK kinase inhibitor PD 98059 blocked palytoxin-stimulated ERK activation. PD 98059 also blocked the palytoxin-stimulated increases in c-Fos protein levels, c-Fos binding to the AP-1 site, and MMP-13 mRNA. These studies identify important differences between palytoxin-stimulated signaling in keratinocytes derived from initiated mouse skin, the biologically relevant cell type, and other cell lines. Specifically, our data suggest that, in keratinocytes derived from initiated mouse skin, ERK plays an important role in transmitting palytoxin-stimulated signals to three downstream targets that are likely to affect carcinogenesis: c-Fos, AP-1, and MMP-13. [Copyright &y& Elsevier]

In mouse epidermis in vivo, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) increases gene expression of matrix metalloproteinase-13 (MMP-13), an enzyme implicated in carcinogenesis. Here we used a keratinocyte cell line (308) derived from initiated mouse skin to investigate TPA-induced MMP-13 gene expression. Use of a pharmacological inhibitor (U0126) demonstrated that extracellular signal regulated kinase (ERK) plays a major role in TPA-induced MMP-13 gene expression. The 5′-flanking sequences of the MMP-13 gene contain binding sites for activator protein-1 (AP-1) and Runx. Both transcription factor families can be modulated by ERK and have been implicated in MMP-13 gene expression. TPA stimulated ERK-dependent increases in c-Fos protein and the c-Fos content of AP-1 complexes. MMP-13 promoter studies indicated that TPA requires AP-1, but not Runx, to induce MMP-13 gene expression. These studies show that in mouse keratinocytes MMP-13 gene expression can be induced through a Runx-independent pathway that involves the ERK-dependent modulation of AP-1. [Copyright &y& Elsevier]