Derivation of Human Differential Photoreceptor-like Cells from the Iris by Defined Combinations of CRX, RX and NEUROD

Examples of direct differentiation by defined transcription factors have been provided for beta-cells, cardiomyocytes and neurons. In the human visual system, there are four kinds of photoreceptors in the retina. Neural retina and iris-pigmented epithelium (IPE) share a common developmental origin, leading us to test whether human iris cells could differentiate to retinal neurons. We here define the transcription factor combinations that can determine human photoreceptor cell fate. Expression of rhodopsin, blue opsin and green/red opsin in induced photoreceptor cells were dependent on combinations of transcription factors: A combination of CRX and NEUROD induced rhodopsin and blue opsin, but did not induce green opsin; a combination of CRX and RX induced blue opsin and green/red opsin, but did not induce rhodopsin. Phototransduction-related genes as well as opsin genes were up-regulated in those cells. Functional analysis; i.e. patch clamp recordings, clearly revealed that generated photoreceptor cells, induced by CRX, RX and NEUROD, responded to light. The response was an inward current instead of the typical outward current. These data suggest that photosensitive photoreceptor cells can be generated by combinations of transcription factors. The combination of CRX and RX generate immature photoreceptors: and additional NEUROD promotes maturation. These findings contribute substantially to a major advance toward eventual cell-based therapy for retinal degenerative diseases

HFE C282Y and H63D in adults with malignancies in a community medical oncology practice

BACKGROUND: We sought to compare frequencies of HFE C282Y and H63D alleles and associated odds ratios (OR) in 100 consecutive unrelated white adults with malignancy to those in 318 controls. METHODS: Data from patients with more than one malignancy were analyzed according to each primary malignancy. For the present study, OR ≥2.0 or ≤0.5 was defined to be increased or decreased, respectively. RESULTS: There were 110 primary malignancies (52 hematologic neoplasms, 58 carcinomas) in the 100 adult patients. Allele frequencies were similar in patients and controls (C282Y: 0.0850 vs. 0.0896, respectively (OR = 0.9); H63D: 0.1400 vs. 0.1447, respectively (OR = 0.9)). Two patients had hemochromatosis and C282Y homozygosity. With C282Y, increased OR occurred in non-Hodgkin lymphoma, myeloproliferative disorders, and adenocarcinoma of prostate (2.0, 2.8, and 3.4, respectively); OR was decreased in myelodysplasia (0.4). With H63D, increased OR occurred in myeloproliferative disorders and adenocarcinomas of breast and prostate (2.4, 2.0, and 2.0, respectively); OR was decreased in non-Hodgkin lymphoma and B-chronic lymphocytic leukemia (0.5 and 0.4, respectively). CONCLUSIONS: In 100 consecutive adults with malignancy evaluated in a community medical oncology practice, frequencies of HFE C282Y or H63D were similar to those in the general population. This suggests that C282Y or H63D is not associated with an overall increase in cancer risk. However, odds ratios computed in the present study suggest that increased (or decreased) risk for developing specific types of malignancy may be associated with the inheritance of HFE C282Y or H63D. Study of more patients with these specific types of malignancies is needed to determine if trends described herein would remain and yield significant differences

Using breath carbon monoxide to validate self-reported tobacco smoking in remote Australian Indigenous communities

Background: This paper examines the specificity and sensitivity of a breath carbon monoxide (BCO) test and\ud optimum BCO cutoff level for validating self-reported tobacco smoking in Indigenous Australians in Arnhem Land,\ud Northern Territory (NT).\ud \ud Methods: In a sample of 400 people (≥16 years) interviewed about tobacco use in three communities, both selfreported\ud smoking and BCO data were recorded for 309 study participants. Of these, 249 reported smoking tobacco\ud within the preceding 24 hours, and 60 reported they had never smoked or had not smoked tobacco for ≥6\ud months. The sample was opportunistically recruited using quotas to reflect age and gender balances in the\ud communities where the combined Indigenous populations comprised 1,104 males and 1,215 females (≥16 years).\ud Local Indigenous research workers assisted researchers in interviewing participants and facilitating BCO tests using\ud a portable hand-held analyzer.\ud \ud Results: A BCO cutoff of ≥7 parts per million (ppm) provided good agreement between self-report and BCO\ud (96.0% sensitivity, 93.3% specificity). An alternative cutoff of ≥5 ppm increased sensitivity from 96.0% to 99.6% with no change in specificity (93.3%). With data for two self-reported nonsmokers who also reported that they smoked\ud cannabis removed from the analysis, specificity increased to 96.6%.\ud \ud Conclusion: In these disadvantaged Indigenous populations, where data describing smoking are few, testing for\ud BCO provides a practical, noninvasive, and immediate method to validate self-reported smoking. In further studies\ud of tobacco smoking in these populations, cannabis use should be considered where self-reported nonsmokers\ud show high BCO

An ecological future for weed science to sustain crop production and the environment. A review

Sustainable strategies for managing weeds are critical to meeting agriculture's potential to feed the world's population while conserving the ecosystems and biodiversity on which we depend. The dominant paradigm of weed management in developed countries is currently founded on the two principal tools of herbicides and tillage to remove weeds. However, evidence of negative environmental impacts from both tools is growing, and herbicide resistance is increasingly prevalent. These challenges emerge from a lack of attention to how weeds interact with and are regulated by the agroecosystem as a whole. Novel technological tools proposed for weed control, such as new herbicides, gene editing, and seed destructors, do not address these systemic challenges and thus are unlikely to provide truly sustainable solutions. Combining multiple tools and techniques in an Integrated Weed Management strategy is a step forward, but many integrated strategies still remain overly reliant on too few tools. In contrast, advances in weed ecology are revealing a wealth of options to manage weedsat the agroecosystem levelthat, rather than aiming to eradicate weeds, act to regulate populations to limit their negative impacts while conserving diversity. Here, we review the current state of knowledge in weed ecology and identify how this can be translated into practical weed management. The major points are the following: (1) the diversity and type of crops, management actions and limiting resources can be manipulated to limit weed competitiveness while promoting weed diversity; (2) in contrast to technological tools, ecological approaches to weed management tend to be synergistic with other agroecosystem functions; and (3) there are many existing practices compatible with this approach that could be integrated into current systems, alongside new options to explore. Overall, this review demonstrates that integrating systems-level ecological thinking into agronomic decision-making offers the best route to achieving sustainable weed management

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib plus docetaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Forty-eight patients received up to eight 21-day cycles of docetaxel (60–100 mg m−2 on day 1) plus bortezomib (1.0–1.5 mg m−2 on days 1, 4, 8, and 11). Pharmacodynamic and pharmacokinetic analyses were performed in a subset of patients. Five patients experienced DLTs: grade 3 bone pain (n=1) and febrile neutropenia (n=4). The MTD was bortezomib 1.5 mg m−2 plus docetaxel 75 mg m−2. All 48 patients were assessable for safety and efficacy. The most common adverse events were diarrhoea, nausea, alopecia, asthenia, and vomiting. The most common grade 3/4 toxicities were neutropenia (44%), and febrile neutropenia and diarrhoea (each 19%). Overall patient response rate was 29%. Median time to progression was 5.4 months. In patients with confirmed response, median time to response was 1.3 months and median duration of response was 3.2 months. At the MTD, response rate was 38%. Pharmacokinetic characteristics of bortezomib/docetaxel were comparable with single-agent data. Addition of docetaxel appeared not to affect bortezomib inhibition of 20S proteasome activity. Mean alpha-1 acid glycoprotein concentrations increased from baseline at nearly all time points across different bortezomib dose levels. Bortezomib plus docetaxel is an active combination for anthracycline-pretreated advanced/metastatic breast cancer. The safety profile is manageable and consistent with the side effects of the individual agents

Orbital interactions and chemical reactivity of metal particles and metal surfaces

A review is presented with 101 refs. on chem. bonding to metal surfaces and small metal particles demonstrating the power of symmetry concepts to predict changes in chem. bonding. Ab-initio calcns. of chemisorption to small particles, as well as semiempirical extended Hueckel calcns. applied to the study of the reactivity of metal slabs are reviewed. On small metal particles, classical notions of electron promotion and hybridization are found to apply. The surroundings of a metal atom (ligands in complexes, other metal atoms at surfaces), affect bonding and reactivity through the prehybridization they induce. A factor specific for large particles and surfaces is the required localization of electrons on the atoms involved in the metal surface bond. At the surface, the bond energy is found to relate to the grou8p orbital local d. of states at the Fermi level. The use of this concept is extensively discussed and illustrated for chemisorption of CO and dissocn. of NO on metal surfaces. A discussion is given of the current decompn. schemes of bond energies and related concepts (exchange (Pauli)-repulsion, polarization, charge transfer). The role of non-orthogonality of fragment orbitals and of kinetic and potential energy for Pauli repulsion and (orbital) polarization is analyzed. Numerous examples are discussed to demonstrate the impact of those concepts on chem. bonding theor

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion