Nucleocytoplasmic transport: a thermodynamic mechanism

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.Comment: in press at HFSP Journal, vol 3 16 text pages, 1 table, 4 figures, plus Supplementary Material include

Natural disasters in the history of the eastern Turk empire

This article analyzes the effect of climate extremes on the historical processes that took place (AD 536, 581, 601, 626 and 679) in the Eastern Turk Empire (AD 534–745) in Inner Asia. Climate extremes are sharp, strong and sometimes protracted periods of cooling and drought caused by volcanic eruptions that in this case resulted in a negative effect on the economy of a nomadic society and were often accompanied by famine and illness. In fact, many of these natural catastrophes coincided with the Black Death pandemics among the Eastern Turks and the Chinese living in the north of China. The Turk Empire can be split into several chronological periods during which significant events that led to changes in the course of history of the nomadic state took place: AD 534–545—the rise of the Turk Empire; AD 581–583—the division of the Turk Empire into theWestern and the Eastern Empires; AD 601–603—the rise of Qimin Qaghan; AD 627–630—the Eastern Turks are conquered by China; AD 679–687—the second rise of the Eastern Turk Empire. The research shows that there is clearly-discernable interplay between important historical events and climate extremes in the history of the Turk Empire. This interplay has led us to the conclusion that the climatic factor did have an impact on the historical processes that took place in the eastern part of Inner Asia, especially on the territories with a nomadic economy. © The Author(s) 2019

The Small GTPase RhoA Localizes to the Nucleus and Is Activated by Net1 and DNA Damage Signals

Rho GTPases control many cellular processes, including cell survival, gene expression and migration. Rho proteins reside mainly in the cytosol and are targeted to the plasma membrane (PM) upon specific activation by guanine nucleotide exchange factors (GEFs). Accordingly, most GEFs are also cytosolic or associated with the PM. However, Net1, a RhoA-specific GEF predominantly localizes to the cell nucleus at steady-state. Nuclear localization for Net1 has been seen as a mechanism for sequestering the GEF away from RhoA, effectively rendering the protein inactive. However, considering the prominence of nuclear Net1 and the fact that a biological stimulus that promotes Net1 translocation out the nucleus to the cytosol has yet to be discovered, we hypothesized that Net1 might have a previously unidentified function in the nucleus of cells.Using an affinity precipitation method to pulldown the active form of Rho GEFs from different cellular fractions, we show here that nuclear Net1 does in fact exist in an active form, contrary to previous expectations. We further demonstrate that a fraction of RhoA resides in the nucleus, and can also be found in a GTP-bound active form and that Net1 plays a role in the activation of nuclear RhoA. In addition, we show that ionizing radiation (IR) specifically promotes the activation of the nuclear pool of RhoA in a Net1-dependent manner, while the cytoplasmic activity remains unchanged. Surprisingly, irradiating isolated nuclei alone also increases nuclear RhoA activity via Net1, suggesting that all the signals required for IR-induced nuclear RhoA signaling are contained within the nucleus.These results demonstrate the existence of a functional Net1/RhoA signaling pathway within the nucleus of the cell and implicate them in the DNA damage response

Human resources for health policies: a critical component in health policies

In the last few years, increasing attention has been paid to the development of health policies. But side by side with the presumed benefits of policy, many analysts share the opinion that a major drawback of health policies is their failure to make room for issues of human resources. Current approaches in human resources suggest a number of weaknesses: a reactive, ad hoc attitude towards problems of human resources; dispersal of accountability within human resources management (HRM); a limited notion of personnel administration that fails to encompass all aspects of HRM; and finally the short-term perspective of HRM. There are three broad arguments for modernizing the ways in which human resources for health are managed: • the central role of the workforce in the health sector; • the various challenges thrown up by health system reforms; • the need to anticipate the effect on the health workforce (and consequently on service provision) arising from various macroscopic social trends impinging on health systems. The absence of appropriate human resources policies is responsible, in many countries, for a chronic imbalance with multifaceted effects on the health workforce: quantitative mismatch, qualitative disparity, unequal distribution and a lack of coordination between HRM actions and health policy needs. Four proposals have been put forward to modernize how the policy process is conducted in the development of human resources for health (HRH): • to move beyond the traditional approach of personnel administration to a more global concept of HRM; • to give more weight to the integrated, interdependent and systemic nature of the different components of HRM when preparing and implementing policy; • to foster a more proactive attitude among human resources (HR) policy-makers and managers; • to promote the full commitment of all professionals and sectors in all phases of the process. The development of explicit human resources policies is a crucial link in health policies and is needed both to address the imbalances of the health workforce and to foster implementation of the health services reforms

Runoff variations in Lake Balkhash Basin, Central Asia, 1779-2015, inferred from tree rings

Long highly-resolved proxies for runoff are in high demand for hydrological forecasts and water management in arid Central Asia. An accurate (R2 = 0.53) reconstruction of October-September discharge of the Ili River in Kazakhstan, 1779–2015, is developed from moisture-sensitive tree rings of spruce sampled in the Tian Shan Mountains. The fivefold extension of the gauged discharge record represents the variability of runoff in the Lake Balkhash Basin for the last 235 years. The reconstruction shows a 40 year long interval of low discharge preceded a recent high peak in the first decade of the 2000s followed by a decline to more recent levels of discharge not seen since the start of the gauged record. Most reconstructed flow extremes (± 2σ) occur outside the instrumental record (1936–2015) and predate the start of large dam construction (1969). Decadal variability of the Ili discharge corresponds well with hydrological records of other Eurasian internal drainages modeled with tree rings. Spectral analysis identifies variance peaks (highest near 42 year) consistent with main hemispheric oscillations of the Eurasian climatic system. Seasonal comparison of the Ili discharge with sea-level-pressure and geopotential height data suggests periods of high flow likely result from the increased contribution of snow to runoff associated with the interaction of Arctic air circulation with the Siberian High-Pressure System and North Atlantic Oscillation

Validating the model of predictors of academic self-handicapping behavior

The main aim of the present study is to validate the model of predictors of self-handicapping behavior (POASH) on the data derived from undergraduate students in an ongoing co-curriculum compulsory course. The study adapted and extended the original theory of reciprocal interaction of emotion, cognition and behavior by adding self-handicapping behavior component. In so doing, this study assessed the direct and indirect effects of emotion, cognition and behavior via student engagement on self-handicapping behavior. The second purpose of the study is to evaluate gender and nationality status invariants of the causal structure of POASH. This cross-validation procedure determined whether gender and nationality status moderated the causal structure of the model, and thus the generality of POASH. The data was collected from two self-reported questionnaires administered to 790 undergraduates of an International Islamic University in Malaysia. A confirmatory three-step approach theory testing and development using Maximum Likelihood method was applied. The results of structured equation modeling supported the adequacy of POASH and the causal structure of POASH proved to be applicable to both genders and nationality statuses