Rate of environmental change determines stress response specificity

Cells use general stress response pathways to activate diverse target genes in response to a variety of stresses. However, general stress responses coexist with more specific pathways that are activated by individual stresses, provoking the fundamental question of whether and how cells control the generality or specificity of their response to a particular stress. Here we address this issue using quantitative time-lapse microscopy of the Bacillus subtilis environmental stress response, mediated by σ^B. We analyzed σ^B activation in response to stresses such as salt and ethanol imposed at varying rates of increase. Dynamically, σ^B responded to these stresses with a single adaptive activity pulse, whose amplitude depended on the rate at which the stress increased. This rate-responsive behavior can be understood from mathematical modeling of a key negative feedback loop in the underlying regulatory circuit. Using RNAseq we analyzed the effects of both rapid and gradual increases of ethanol and salt stress across the genome. Because of the rate responsiveness of σ^B activation, salt and ethanol regulons overlap under rapid, but not gradual, increases in stress. Thus, the cell responds specifically to individual stresses that appear gradually, while using σ^B to broaden the cellular response under more rapidly deteriorating conditions. Such dynamic control of specificity could be a critical function of other general stress response pathways.     

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several small-molecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)—a bicyclic diterpenoid lactone isolated from Andrographis paniculata—and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP–GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP–GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.     

Psychological defence and nuclear war

Society is influenced by the unconcious aspects of the minds of the member individuals. This paper describes a psychoanalytic approach to some aspects of the social processes that give rise to the attitudes in Western society towards nuclear war and the nuclear threat. It is concluded that there are profound hidden factors that work against changing the current views on war and nuclear war, and that some peace groups are inadvertently recruited into maintaining the status quo.     

Multi-level Factors Associated with Pregnancy among Urban Adolescent Women Seeking Psychological Services

The purpose of this study was to examine the prevalence of pregnancy as well as multi-level factors (i.e., individual, family, and environment) associated with history of pregnancy among a sample of urban adolescent women seeking psychological services. Data were collected from a total of 264 sexually active, 13–18-year-old, adolescent women who participated in a larger HIV prevention study. Adolescents and one participating parent completed an audio computer-assisted self-interviewing survey. A total of 17.4 % of participants reported a history of pregnancy. A multivariable logistic regression model suggests that after controlling for empirically derived sociodemographic and behavioral covariates, absence of father in the home, family support and cohesion, and neighborhood risk were positively related to pregnancy. This study is among the first to examine multi-level factors associated with pregnancy among adolescent women diagnosed with psychological disorders. Consideration of such factors is crucial both in terms of clinical practice and in the design of pregnancy prevention programs. Collaboration between physicians and mental health providers working with adolescent women is crucial and represents an ideal opportunity to promote parental involvement and access to supportive community resources, including pregnancy prevention programs for this vulnerable population of adolescents.     

Grandmothers as gatekeepers? The role of grandmothers in influencing health-seeking for mothers and newborns in rural northern Ghana

Previous research suggests that care-seeking in rural northern Ghana is often governed by a woman's husband or compound head. This study was designed to explore the role grandmothers (typically a woman's mother-in-law) play in influencing maternal and newborn healthcare decisions. In-depth interviews were conducted with 35 mothers of newborns, 8 traditional birth attendants and local healers, 16 community leaders and 13 healthcare practitioners. An additional 18 focus groups were conducted with stakeholders such as household heads, compound leaders and grandmothers. In this region, grandmothers play many roles. They may act as primary support providers to pregnant mothers, care for newborns following delivery, preserve cultural traditions and serve as repositories of knowledge on local medicine. Grandmothers may also serve as gatekeepers for health-seeking behaviour, especially with regard to their daughters and daughters-in-law. This research also sheds light on the potential gap between health education campaigns that target mothers as autonomous decision-makers, and the reality of a more collectivist community structure in which mothers rarely make such decisions without the support of other community members.     

The changing cultural and economic dynamics of polygyny and concurrent sexual partnerships in Iringa,Tanzania

Polygyny has been identified both as a ‘benign’ form of concurrency and as the cultural basis of concurrent partnerships that are considered important drivers of the HIV epidemic in sub-Saharan Africa. This paper investigates the changing cultural and economic dynamics of polygyny in concurrency in Iringa, Tanzania, a region with traditions of polygyny and high prevalence of HIV. Our analysis of focus group discussions, in-depth interviews and key informant interviews indicate that contemporary concurrent partnerships differ from regional traditions of polygyny. Whereas in the past, polygyny reflected men's and their kin group's wealth and garnered additional prestige, polygyny today is increasingly seen as a threat to health, and as leading to poverty. Nevertheless, participants evoked the social prestige of polygyny to explain men's present-day concurrency, even outside the bounds of marriage, and despite continued social prohibitions against extramarital affairs. Difficult economic conditions, combined with this prestige, made it easier for men to engage in concurrency without the considerable obligations to wives and children in polygyny. Local economic conditions also compelled women to seek concurrent partners to meet basic needs and to access consumer goods, but risked greater moral judgement than men, especially if deemed to have excessive ‘desire’ for money.     

STEM DISTRIBUTION IN IRREGULAR FORESTS

The author outlines the fifty years history of national professional forestry education in Canberra by the Australian Forestry School and its successor the Australian National University Department of Forestry.     

Effect of Velocity Profile Skewing on Blood Velocity and Volume Flow Waveforms Derived From Maximum Doppler Spectral Velocity

Given evidence that fully developed axisymmetric flow may be the exception rather than the rule, even in nominally straight arteries, maximum velocity (V_max) can lie outside the Doppler sample volume (SV). The link between V_max and derived quantities, such as volume flow (Q), may therefore be more complex than commonly thought. We performed idealized virtual Doppler ultrasound on data from image-based computational fluid dynamics (CFD) models of the normal human carotid artery and investigated how velocity profile skewing and choice of sample volume affected V_max waveforms and derived Q variables, considering common assumptions about velocity profile shape (i.e., Poiseuille or Womersley). Severe velocity profile skewing caused substantial errors in V_max waveforms when using a small, centered SV, although peak V_max was reliably detected; errors with a long SV covering the vessel diameter were orientation dependent but lower overall. Cycle-averaged Q calculated from V_max was typically within ±15%, although substantial skewing and use of a small SV caused 10%–25% underestimation. Peak Q derived from Womersley's theory was generally accurate to within ±10%. V_max pulsatility and resistance indexes differed from Q-based values, although the Q-based resistance index could be predicted reliably. Skewing introduced significant error into V_max-derived Q waveforms, particularly during mid-to-late systole. Our findings suggest that errors in the V_max and Q waveforms related to velocity profile skewing and use of a small SV, or orientation-dependent errors for a long SV, could limit their use in wave analysis or for constructing characteristic or patient-specific flow boundary conditions for model studies.