Optogenetics and deep brain stimulation neurotechnologies

Brain neural network is composed of densely packed, intricately wired neurons whose activity patterns ultimately give rise to every behavior, thought, or emotion that we experience. Over the past decade, a novel neurotechnique, optogenetics that combines light and genetic methods to control or monitor neural activity patterns, has proven to be revolutionary in understanding the functional role of specific neural circuits. We here briefly describe recent advance in optogenetics and compare optogenetics with deep brain stimulation technology that holds the promise for treating many neurological and psychiatric disorders

Phenology of Scramble Polygyny in a Wild Population of Chrysolemid Beetles: The Opportunity for and the Strength of Sexual Selection

Recent debate has highlighted the importance of estimating both the strength of sexual selection on phenotypic traits, and the opportunity for sexual selection. We describe seasonal fluctuations in mating dynamics of Leptinotarsa undecimlineata (Coleoptera: Chrysomelidae). We compared several estimates of the opportunity for, and the strength of, sexual selection and male precopulatory competition over the reproductive season. First, using a null model, we suggest that the ratio between observed values of the opportunity for sexual selections and their expected value under random mating results in unbiased estimates of the actual nonrandom mating behavior of the population. Second, we found that estimates for the whole reproductive season often misrepresent the actual value at any given time period. Third, mating differentials on male size and mobility, frequency of male fighting and three estimates of the opportunity for sexual selection provide contrasting but complementary information. More intense sexual selection associated to male mobility, but not to male size, was observed in periods with high opportunity for sexual selection and high frequency of male fights. Fourth, based on parameters of spatial and temporal aggregation of female receptivity, we describe the mating system of L. undecimlineata as a scramble mating polygyny in which the opportunity for sexual selection varies widely throughout the season, but the strength of sexual selection on male size remains fairly weak, while male mobility inversely covaries with mating success. We suggest that different estimates for the opportunity for, and intensity of, sexual selection should be applied in order to discriminate how different behavioral and demographic factors shape the reproductive dynamic of populations

Cytotoxic isolates of Helicobacter pylori from Peptic Ulcer Diseases decrease K(+)-dependent ATPase Activity in HeLa cells

BACKGROUND: Helicobacter pylori is a Gram negative bacterium that plays a central role in the etiology of chronic gastritis and peptic ulcer diseases. However, not all H. pylori positive cases develop advanced disease. This discriminatory behavior has been attributed to the difference in virulence of the bacteria. Among all virulence factors, cytotoxin released by H. pylori is the most important factor. In this work, we studied variation in H. pylori isolates from Indian dyspeptic patients on the basis of cytotoxin production and associated changes in K(+)-dependent ATPase (one of its targets) enzyme activity in HeLa cells. METHODS: The patients were retrospectively grouped on the basis of endoscopic and histopathological observation as having gastritis or peptic ulcer. The HeLa cells were incubated with the broth culture filtrates (BCFs) of H. pylori isolates from patients of both groups and observed for the cytopathic effects: morphological changes and viability. In addition, the K(+)-dependent ATPase activity was measured in HeLa cells extracts. RESULTS: The cytotoxin production was observed in 3/7 (gastritis) and 4/4 (peptic ulcer) H. pylori isolates. The BCFs of cytotoxin producing H. pylori strains reduced the ATPase activity of HeLa cells to 40% of that measured with non-cytotoxin producing H. pylori strains (1.33 μmole Pi/mg protein and 3.36 μmole Pi/mg protein, respectively, p < 0.05). The decreased activity of ATPase enzyme or the release of cytotoxin also correlated with the increased pathogenicity indices of the patients. CONCLUSIONS: Our results suggest that the isolation of cytotoxic H. pylori is more common in severe form of acid peptic diseases (peptic ulcer) than in gastritis patients from India. Also the cytotoxin released by H. pylori impairs the ion-transporting ATPase and is a measure of cytotoxicity

Moral Distress Amongst American Physician Trainees Regarding Futile Treatments at the End of Life: A Qualitative Study.

BACKGROUND: Ethical challenges are common in end of life care; the uncertainty of prognosis and the ethically permissible boundaries of treatment create confusion and conflict about the balance between benefits and burdens experienced by patients. OBJECTIVE: We asked physician trainees in internal medicine how they reacted and responded to ethical challenges arising in the context of perceived futile treatments at the end of life and how these challenges contribute to moral distress. DESIGN: Semi-structured in-depth qualitative interviews. PARTICIPANTS: Twenty-two internal medicine residents and fellows across three American academic medical centers. APPROACH: This study uses systematic qualitative methods of data gathering, analysis and interpretation. KEY RESULTS: Physician trainees experienced significant moral distress when they felt obligated to provide treatments at or near the end of life that they believed to be futile. Some trainees developed detached and dehumanizing attitudes towards patients as a coping mechanism, which may contribute to a loss of empathy. Successful coping strategies included formal and informal conversations with colleagues and superiors about the emotional and ethical challenges of providing care at the end of life. CONCLUSIONS: Moral distress amongst physician trainees may occur when they feel obligated to provide treatments at the end of life that they believe to be futile or harmful.This study was funded by the Health Resources and Service Administration T32 HP10025-20 Training Grant, the Gates Cambridge Scholarship, Society of General Internal Medicine Founders Grant, and the Ho-Chiang Palliative Care Research Fellowship at the Johns Hopkins School of Medicine.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11606-015-3505-

Drug Discovery Using Chemical Systems Biology: Weak Inhibition of Multiple Kinases May Contribute to the Anti-Cancer Effect of Nelfinavir

Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent

Metal-responsive gene regulation and metal transport in Helicobacter species

Helicobacter species are among the most successful colonizers of the mammalian gastrointestinal and hepatobiliary tract. Colonization is usually lifelong, indicating that Helicobacter species have evolved intricate mechanisms of dealing with stresses encountered during colonization of host tissues, like restriction of essential metal ions. The recent availability of genome sequences of the human gastric pathogen Helicobacter pylori, the murine enterohepatic pathogen Helicobacter hepaticus and the unannotated genome sequence of the ferret gastric pathogen Helicobacter mustelae has allowed for comparitive genome analyses. In this review we present such analyses for metal transporters, metal-storage and metal-responsive regulators in these three Helicobacter species, and discuss possible contributions of the differences in metal metabolism in adaptation to the gastric or enterohepatic niches occupied by Helicobacter species

A Novel System of Cytoskeletal Elements in the Human Pathogen Helicobacter pylori

Pathogenicity of the human pathogen Helicobacter pylori relies upon its capacity to adapt to a hostile environment and to escape from the host response. Therefore, cell shape, motility, and pH homeostasis of these bacteria are specifically adapted to the gastric mucus. We have found that the helical shape of H. pylori depends on coiled coil rich proteins (Ccrp), which form extended filamentous structures in vitro and in vivo, and are differentially required for the maintenance of cell morphology. We have developed an in vivo localization system for this pathogen. Consistent with a cytoskeleton-like structure, Ccrp proteins localized in a regular punctuate and static pattern within H. pylori cells. Ccrp genes show a high degree of sequence variation, which could be the reason for the morphological diversity between H. pylori strains. In contrast to other bacteria, the actin-like MreB protein is dispensable for viability in H. pylori, and does not affect cell shape, but cell length and chromosome segregation. In addition, mreB mutant cells displayed significantly reduced urease activity, and thus compromise a major pathogenicity factor of H. pylori. Our findings reveal that Ccrp proteins, but not MreB, affect cell morphology, while both cytoskeletal components affect the development of pathogenicity factors and/or cell cycle progression

Prenatal Diagnosis of Oculocutaneous Albinism by Electron Microscopy of Fetal Skin

Oculocutaneous albinism was diagnosed prenatally by electron microscopic examination of fetal skin samples taken during fetoscopy at 20 weeks of gestation. Melanosome development in hair bulb melanocytes progressed no further than stage II, indicating a lack of melanin synthesis. In 4 age-matched control fetuses, numerous stage IV melanosomes, signifying active melanin synthesis, were identified. The diagnosis was confirmed after the pregnancy was terminated at 22 weeks. Examination of the fetal eye showed absence of pigment in the retinal epithelium and uvea at a stage when ocular melanogenesis would normally be active. This study shows that oculocutaneous albinism can be detected in the second trimester using similar techniques to those employed in the prenatal diagnosis of epidermolysis bullosa and ichthyosis