Identification of Molecular Pathologies Sufficient to Cause Neuropathic Excitability in Primary Somatosensory Afferents Using Dynamical Systems Theory

Pain caused by nerve injury (i.e. neuropathic pain) is associated with development of neuronal hyperexcitability at several points along the pain pathway. Within primary afferents, numerous injury-induced changes have been identified but it remains unclear which molecular changes are necessary and sufficient to explain cellular hyperexcitability. To investigate this, we built computational models that reproduce the switch from a normal spiking pattern characterized by a single spike at the onset of depolarization to a neuropathic one characterized by repetitive spiking throughout depolarization. Parameter changes that were sufficient to switch the spiking pattern also enabled membrane potential oscillations and bursting, suggesting that all three pathological changes are mechanistically linked. Dynamical analysis confirmed this prediction by showing that excitability changes co-develop when the nonlinear mechanism responsible for spike initiation switches from a quasi-separatrix-crossing to a subcritical Hopf bifurcation. This switch stems from biophysical changes that bias competition between oppositely directed fast- and slow-activating conductances operating at subthreshold potentials. Competition between activation and inactivation of a single conductance can be similarly biased with equivalent consequences for excitability. “Bias” can arise from a multitude of molecular changes occurring alone or in combination; in the latter case, changes can add or offset one another. Thus, our results identify pathological change in the nonlinear interaction between processes affecting spike initiation as the critical determinant of how simple injury-induced changes at the molecular level manifest complex excitability changes at the cellular level. We demonstrate that multiple distinct molecular changes are sufficient to produce neuropathic changes in excitability; however, given that nerve injury elicits numerous molecular changes that may be individually sufficient to alter spike initiation, our results argue that no single molecular change is necessary to produce neuropathic excitability. This deeper understanding of degenerate causal relationships has important implications for how we understand and treat neuropathic pain

Massive stars as thermonuclear reactors and their explosions following core collapse

Nuclear reactions transform atomic nuclei inside stars. This is the process of stellar nucleosynthesis. The basic concepts of determining nuclear reaction rates inside stars are reviewed. How stars manage to burn their fuel so slowly most of the time are also considered. Stellar thermonuclear reactions involving protons in hydrostatic burning are discussed first. Then I discuss triple alpha reactions in the helium burning stage. Carbon and oxygen survive in red giant stars because of the nuclear structure of oxygen and neon. Further nuclear burning of carbon, neon, oxygen and silicon in quiescent conditions are discussed next. In the subsequent core-collapse phase, neutronization due to electron capture from the top of the Fermi sea in a degenerate core takes place. The expected signal of neutrinos from a nearby supernova is calculated. The supernova often explodes inside a dense circumstellar medium, which is established due to the progenitor star losing its outermost envelope in a stellar wind or mass transfer in a binary system. The nature of the circumstellar medium and the ejecta of the supernova and their dynamics are revealed by observations in the optical, IR, radio, and X-ray bands, and I discuss some of these observations and their interpretations.Comment: To be published in " Principles and Perspectives in Cosmochemistry" Lecture Notes on Kodai School on Synthesis of Elements in Stars; ed. by Aruna Goswami & Eswar Reddy, Springer Verlag, 2009. Contains 21 figure

Association Rate Constants of Ras-Effector Interactions Are Evolutionarily Conserved

Evolutionary conservation of protein interaction properties has been shown to be a valuable indication for functional importance. Here we use homology interface modeling of 10 Ras-effector complexes by selecting ortholog proteins from 12 organisms representing the major eukaryotic branches, except plants. We find that with increasing divergence time the sequence similarity decreases with respect to the human protein, but the affinities and association rate constants are conserved as predicted by the protein design algorithm, FoldX. In parallel we have done computer simulations on a minimal network based on Ras-effector interactions, and our results indicate that in the absence of negative feedback, changes in kinetics that result in similar binding constants have strong consequences on network behavior. This, together with the previous results, suggests an important biological role, not only for equilibrium binding constants but also for kinetics in signaling processes involving Ras-effector interactions. Our findings are important to take into consideration in system biology approaches and simulations of biological networks

Metastasis to the breast from an adenocarcinoma of the lung with extensive micropapillary component: a case report and review of the literature

Breast metastasis from extra-mammary malignancy is rare. Based on the literature an incidence of 0.4-1.3% is reported. The primary malignancies most commonly metastasizing to the breast are leukemia-lymphoma, and malignant melanoma. We present a case of metastasis to the breast from a pulmonary adenocarcinoma, with extensive micropapillary component, diagnosed concomitantly with the primary tumor. A 73-year-old female presented with dyspnea and dry cough of 4 weeks duration and a massive pleural effusion was found on a chest radiograph. Additionally, on physical examination a poorly defined mass was noted in the upper outer quadrant of the left breast. The patient underwent bronchoscopy, excisional breast biopsy and medical thoracoscopy. By cytology, histology and immunohistochemistry primary lung adenocarcinoma with metastasis to the breast and parietal pleura was diagnosed. Both the primary and metastatic anatomic sites demonstrated histologically extensive micropapillary component, which is recently recognized as an important prognostic factor. The patient received chemotherapy but passed away within 7 months. Accurate differentiation of metastatic from primary carcinoma is of crucial importance because the treatment and prognosis differ significantly

Lifestyle physical activity among urban Palestinians and Israelis: a cross-sectional comparison in the Palestinian-Israeli Jerusalem risk factor study

<p>Abstract</p> <p>Background</p> <p>Urban Palestinians have a high incidence of coronary heart disease, and alarming prevalences of obesity (particularly among women) and diabetes. An active lifestyle can help prevent these conditions. Little is known about the physical activity (PA) behavior of Palestinians. This study aimed to determine the prevalence of insufficient PA and its socio-demographic correlates among urban Palestinians in comparison with Israelis.</p> <p>Methods</p> <p>An age-sex stratified random sample of Palestinians and Israelis aged 25-74 years living in east and west Jerusalem was drawn from the Israel National Population Registry: 970 Palestinians and 712 Israelis participated. PA in a typical week was assessed by the Multi-Ethnic Study of Atherosclerosis (MESA) questionnaire. Energy expenditure (EE), calculated in metabolic equivalents (METs), was compared between groups for moderate to vigorous-intensity physical activity (MVPA), using the Wilcoxon rank-sum test, and for domain-specific prevalence rates of meeting public health guidelines and all-domain insufficient PA. Correlates of insufficient PA were assessed by multivariable logistic modeling.</p> <p>Results</p> <p>Palestinian men had the highest median of MVPA (4740 METs-min_*wk^-1) compared to Israeli men (2,205 METs-min_*wk^-1<it>p </it>< 0.0001), or to Palestinian and Israeli women, who had similar medians (2776 METs-min_*wk^-1). Two thirds (65%) of the total MVPA reported by Palestinian women were derived from domestic chores compared to 36% in Israeli women and 25% among Palestinian and Israeli men. A high proportion (63%) of Palestinian men met the PA recommendations by occupation/domestic activity, compared to 39% of Palestinian women and 37% of the Israelis. No leisure time PA was reported by 42% and 39% of Palestinian and Israeli men (<it>p </it>= 0.337) and 53% and 28% of Palestinian and Israeli women (<it>p </it>< 0.0001). Palestinian women reported the lowest level of walking. Considering all domains, 26% of Palestinian women were classified as insufficiently active versus 13% of Palestinian men (<it>p </it>< 0.0001) who did not differ from the Israeli sample (14%). Middle-aged and elderly and less educated Palestinian women, and unemployed and pensioned Palestinian men were at particularly high risk of inactivity. Socio-economic indicators only partially explained the ethnic disparity.</p> <p>Conclusions</p> <p>Substantial proportions of Palestinian women, and subgroups of Palestinian men, are insufficiently active. Culturally appropriate intervention strategies are warranted, particularly for this vulnerable population.</p

Diagnostic utility of snail in metaplastic breast carcinoma

Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer characterized by coexistence of carcinomatous and sarcomatous components. Snail is a nuclear transcription factor incriminated in the transition of epithelial to mesenchymal differentiation of breast cancer. Aberrant Snail expression results in lost expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. We aimed to identify the utility of Snail, and of traditional immunohistochemical markers, in accurate MBC classification and to evaluate clinicopathologic characteristics and outcome