Paleo-Environment and C-14 Dating: The Key to the Depositional Age of the Tha Chang and Related Sand Pits, Northeastern Thailand

Tha Chang sand pits, Nakhon Ratchasima Province and many other sand pits in the area adjacent to the Mun River are characterized by their fluviatile environment in association with mass wasting deposits, along the paleo-river channel and the flood plain of the Mun River. Sediments of these deposits are characterized by clasts of various rock types especially the resistant ones with frequent big tree trunks, logs and wood fragments in different sizes and various stages of transformation from moldering stage to lignification and petrification. Widespread pyritization of the lower horizon suggests strongly reducing environment during burial. The Tha Chang deposits have been received much attention from geoscientists especially paleontologist communities, as they contain fragments of some distinct vertebrate species such as Stegadon sp., hominoid primate, rhinoceros Aceratherium and others. Based on the associated mammal fauna and hominoid fossils, the late Miocene ( 9 - 6 Ma) was given for the time of deposition of this sand and gravel unit. Some other reports believed that sediments and materials of these sand and gravel quarries (pits) were deposited by high-energy flood pulses contemporaneous with the tektites forming event during mid-Pleistocene at c. 0.8 Ma. Interpretation from Palynostratigraphical study suggested that the lower horizon of Tha Chang sand pit was deposited during Pliocene/Pleistocene period and the upper horizons are Pleistoncene/Holocene. It is crystal clear that all the fluviatile sediments including tektites and almost all fossil fragments being deposited in these sand pits were, likely a multiple times reworked materials. Only some old bamboo trees, some old crowling trees and fossils grasses observed on the old river bank are considered in situ. C-14 dating of 5 old wood specimens from Tha Chang Sand Pits, 15 old wood specimens from Chumpuang Sand Pits and one sample of old pottery from a Chumpuang Sand Pit were carried out in the NSF- Arizona AMS Laboratory. Although, there is no sharp boundary between the unconsolidated sedimentary horizons in the pits, C-14 ages obtained from the Tha Chang vary from 34,340 BP at the middle horizon (approx 10 m below ground zero) to >49,900 BP at the lower horizon with unknown basal formation (highly pyritized zone approx 20 - 25 m below ground zero). The ages for the Chumpuang vary from 41,700 BP, >45,900 BP and >49,900 BP from the upper most to the lower most of a broad horizon (approx 8 m to approx 12 m below ground zero). The C-14 age of the pottery collected from layer approximately 5 m below ground zero is 2,514 BP. The nature of fluviatile together with occasional mass wasting characteristics of all sand pits studies suggest the relatively faster depositional rate of the lower horizon which involved more flooding and mass wasting deposits than those of the upper horizons. The apparent of some mixing of the wood ages may indicate reworking and lag deposits nature of the area. The depositional rate of the upper most sand and soil horizon (5 m thick) is approximately 1 m per 500 years which mean both erosion and deposition had played a significant role during that time period. In term of the true age of the formation, we argue that since most of the materials deposited are reworked materials, all ages obtained from fossil fragments could not be the age of sand and gravel formation. Furthermore, the maximum age of all the tektite bearing horizons cannot be older than 0.8 Ma. The oldest C-14 age of 49,900 BP is interpreted as the minimum age of the Tha Chang and related sand pits formation when geomorphology of the area was a lot more hilly and much higher gradient than that of the present day

Oxidative Coupling as a Biomimetic Approach to the Synthesis of Scytonemin

The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations In Its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki-Miyaura cross-coupling, orchestrated In a stereospecific tandem fashion, followed by a biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4-dihydrocyclopenta[b]indol-2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin

Deriving and critiquing an empirically-based framework for pharmaceutical ethics.

Background: The pharmaceutical industry has been responsible for major medical advances, but the industry has also been heavily criticized. Such criticisms, and associated regulatory responses, are no doubt often warranted, but do not provide a framework for those who wish to reason systematically about the moral dimensions of drug development. We set out to develop such a framework using Beauchamp and Childress’s “four principles” as organizing categories. Methods: We conducted a qualitative interview study of people working in the “medical affairs” departments of pharmaceutical companies to determine: (1) whether our data could meaningfully be organized under the headings of “autonomy,” “beneficence,” “nonmaleficence,” and “justice”; (2) how principles might be expressed in this particular commercial setting; and (3) if these principles are expressed, whether and how competing principles are balanced. We then critiqued these findings using existing normative theory. Results: Our interviews demonstrated that three of Beauchamp and Childress’ four principles were salient to our participants: beneficence, non-maleficence, and justice. Within each of these principles, participants had two broad ethical orientations: an altruistic public focus (“other-ness”) and a commitment to their companies (“firm-ness”). Our participants also demonstrated efforts to balance these principles and highlighted the importance of phronesis (or practical wisdom) in balancing and enacting principles. Notably, however, our participants did not spontaneously emphasize the importance of autonomy. Conclusions: It is possible to use qualitative empirical research, together with normative analysis, to derive a framework for pharmaceutical ethics. We suggest that our framework would be useful for those who wish to reason ethically within, or in collaboration with, the pharmaceutical industry. Keywords: Empirical ethics, principle-based ethics, pharmaceutical industry, pharmaceutical ethics, qualitative researchNHMRC Career Development Fellowship APP106356

A multi-institutional experience in adventitial cystic disease

AbstractBackgroundAdventitial cystic disease (ACD) is an unusual arteriopathy; case reports and small series constitute the available literature regarding treatment. We sought to examine the presentation, contemporary management, and long-term outcomes using a multi-institutional database.MethodsUsing a standardized database, 14 institutions retrospectively collected demographics, comorbidities, presentation/symptoms, imaging, treatment, and follow-up data on consecutive patients treated for ACD during a 10-year period, using Society for Vascular Surgery reporting standards for limb ischemia. Univariate and multivariate analyses were performed comparing treatment methods and factors associated with recurrent intervention. Life-table analysis was performed to estimate the freedom from reintervention in comparing the various treatment modalities.ResultsForty-seven patients (32 men, 15 women; mean age, 43 years) were identified with ACD involving the popliteal artery (n = 41), radial artery (n = 3), superficial/common femoral artery (n = 2), and common femoral vein (n = 1). Lower extremity claudication was seen in 93% of ACD of the leg arteries, whereas patients with upper extremity ACD had hand or arm pain. Preoperative diagnosis was made in 88% of patients, primarily using cross-sectional imaging of the lower extremity; mean lower extremity ankle-brachial index was 0.71 in the affected limb. Forty-one patients with lower extremity ACD underwent operative repair (resection with interposition graft, 21 patients; cyst resection, 13 patients; cyst resection with bypass graft, 5 patients; cyst resection with patch, 2 patients). Two patients with upper extremity ACD underwent cyst drainage without resection or arterial reconstruction. Complications, including graft infection, thrombosis, hematoma, and wound dehiscence, occurred in 12% of patients. Mean lower extremity ankle-brachial index at 3 months postoperatively improved to 1.07 (P < .001), with an overall mean follow-up of 20 months (range, 0.33-9 years). Eight patients (18%) with lower extremity arterial ACD required reintervention (redo cyst resection, one; thrombectomy, three; redo bypass, one; balloon angioplasty, three) after a mean of 70 days with symptom relief in 88%. Lower extremity patients who underwent cyst resection and interposition or bypass graft were less likely to require reintervention (P = .04). One patient with lower extremity ACD required an above-knee amputation for extensive tissue loss.ConclusionsThis multi-institutional, contemporary experience of ACD examines the treatment and outcomes of ACD. The majority of patients can be identified preoperatively; surgical repair, consisting of cyst excision with arterial reconstruction or bypass alone, provides the best long-term symptomatic relief and reduced need for intervention to maintain patency

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4-8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions

Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling

Aims Under hypoxic conditions, nitrite (NO2-) can be reduced to nitric oxide (NO) eliciting vasorelaxation. However, nitrite also exerts vasorelaxant effects of potential therapeutic relevance under normal physiological conditions via undetermined mechanisms. We, therefore, sought to investigate the mechanism(s) by which nitrite regulates the vascular system in normoxia and, specifically, whether the biological effects are a result of NO generation (as in hypoxia) or mediated via alternative mechanisms involving classical downstream targets of NO [e.g. effects on protein kinase G1 alpha (PKG1 alpha)]. Methods and results Ex vivo myography revealed that, unlike in thoracic aorta (conduit vessels), the vasorelaxant effects of nitrite in mesenteric resistance vessels from wild-type (WT) mice were NO-independent. Oxidants such as H2O2 promote disulfide formation of PKG1 alpha, resulting in NO- cyclic guanosine monophosphate (cGMP) independent kinase activation. To explore whether the microvascular effects of nitrite were associated with PKG1 alpha oxidation, we used a Cys42Ser PKG1 alpha knock-in (C42S PKG1 alpha KI; 'redox-dead') mouse that cannot transduce oxidant signals. Resistance vessels from these C42S PKG1 alpha KI mice were markedly less responsive to nitrite-induced vasodilation. Intraperitoneal (i.p.) bolus application of nitrite in conscious WT mice induced a rapid yet transient increase in plasma nitrite and cGMP concentrations followed by prolonged hypotensive effects, as assessed using in vivo telemetry. In the C42S PKG1 alpha KI mice, the blood pressure lowering effects of nitrite were lower compared to WT. Increased H2O2 concentrations were detected in WT resistance vessel tissue challenged with nitrite. Consistent with this, increased cysteine and glutathione persulfide levels were detected in these vessels by mass spectrometry, matching the temporal profile of nitrite's effects on H2O2 and blood pressure. Conclusion Under physiological conditions, nitrite induces a delayed and long-lasting blood pressure lowering effect, which is NO-independent and occurs via a new redox mechanism involving H2O2, persulfides, and PKG1 alpha oxidation/activation. Targeting this novel pathway may provide new prospects for anti-hypertensive therapy

Barriers to women entrepreneurship. Different methods, different results?

Building on research by Akehurst et al. (Serv Ind J 32:2489-2505, 2012), this study analysed internal and external factors in women entrepreneurship and linked these factors to the barriers that women face when starting businesses. To do so, two contrasting statistical techniques were used: PLS and QCA. After analysing results from each of these techniques, we observed that family duties and difficulties in obtaining financing (both internal and external) were the main factors related to barriers faced by women entrepreneurs

Tyrosine Nitration of PA700 Links Proteasome Activation to Endothelial Dysfunction in Mouse Models with Cardiovascular Risk Factors

Oxidative stress is believed to cause endothelial dysfunction, an early event and a hallmark in cardiovascular diseases (CVD) including hypertension, diabetes, and dyslipidemia. However, the targets for oxidative stress-mediated endothelial dysfunction in CVD have not been completely elucidated. Here we report that 26S proteasome activation by peroxynitrite (ONOO−) is a common pathway for endothelial dysfunction in mouse models of diabetes, hypertension, and dyslipidemia. Endothelial function, assayed by acetylcholine-induced vasorelaxation, was impaired in parallel with significantly increased 26S proteasome activity in aortic homogenates from streptozotocin (STZ)-induced type I diabetic mice, angiotensin-infused hypertensive mice, and high fat-diets -fed LDL receptor knockout (LDLr−/−) mice. The elevated 26S proteasome activities were accompanied by ONOO−-mediated PA700/S10B nitration and increased 26S proteasome assembly and caused accelerated degradation of molecules (such as GTPCH I and thioredoxin) essential to endothelial homeostasis. Pharmacological (administration of MG132) or genetic inhibition (siRNA knockdown of PA700/S10B) of the 26S proteasome blocked the degradation of the vascular protective molecules and ablated endothelial dysfunction induced by diabetes, hypertension, and western diet feeding. Taken together, these results suggest that 26S proteasome activation by ONOO−-induced PA700/S10B tyrosine nitration is a common route for endothelial dysfunction seen in mouse models of hypertension, diabetes, and dyslipidemia