Adaptive designs are increasingly developed and used to improve all phases of clinical trials and in biomedical studies in various ways to address different statistical issues. We first present an ...overview of adaptive designs and note their numerous advantages over traditional clinical trials. In particular, we provide a concrete demonstration that shows how recent adaptive design strategies can further improve an adaptive trial implemented 13 years ago. Despite their usefulness, adaptive designs are still not widely implemented in clinical trials. We offer a few possible reasons and propose some ways to use them more broadly in practice, which include greater availability of software tools and interactive websites to generate optimal adaptive trials freely and effectively, including the use of metaheuristics to facilitate the search for an efficient trial design. To this end, we present several web-based tools for finding various adaptive and nonadaptive optimal designs and discuss nature-inspired metaheuristics. Metaheuristics are assumptions-free general purpose optimization algorithms widely used in computer science and engineering to tackle all kinds of challenging optimization problems, and their use in designing clinical trials is just emerging. We describe a few recent such applications and some of their capabilities for designing various complex trials. Particle swarm optimization is an exemplary nature-inspired algorithm, and similar to others, it has a simple definition but many moving parts, making it hard to study its properties analytically. We investigated one of its hitherto unstudied issues on how to bring back out-of-range candidates during the search for the optimum of the search domain and show that different strategies can impact the success and time of the search. We conclude with a few caveats on the use of metaheuristics for a successful search.
Here, a novel mycovirus, Botryosphaeria dothidea mitovirus 1 (BdMV1), was isolated from a phytopathogenic fungus,
Botryosphaeria dothidea
, and its molecular characteristics were determined. BdMV1 ...has a genome of 2,667 nt that contains a single large open reading frame (ORF) using the fungal mitochondrial genetic code. The ORF encodes an RNA-dependent RNA polymerase (RdRp) of 727 amino acids with a molecular mass of 81.64 kDa. BLASTp analysis revealed that the RdRp domain of BdMV1 has 39.59% and 39.18% sequence identity to Plasmopara viticola associated mitovirus 43 and Setosphaeria turcica mitovirus 1, respectively. Phylogenetic analysis further suggested that BdMV1 is a new member of the genus
Mitovirus
within the family
Mitoviridae
. To the best of our knowledge, this is the first report of a mitovirus in
B. dothidea
.
During the Meso-Cenozoic, the eastern Ordos Basin (EOB) underwent a complex tectonothermal process influenced by the destruction of North China Craton, significantly affecting the thermal maturation ...of the Late Paleozoic source rocks. Tectonothermal modeling and maturation of coal-bearing shales were performed in the EOB to reveal the geological process of shale gas generation. Organic geochemical data for shales show that TOC values vary from 0.96 wt% to 21.36 wt% and Ro values range from 1.56% to 2.47%, as well as that organic matter mainly consists of type III kerogen—indicating excellent potential, and sufficient maturity, for gas generation. Thermal modeling suggests that heat flow in the EOB significantly increased as a result of intense magmatic activities during the Yanshanian orogeny, with peak values of 108 and 128 mW/m2 in the northern and southern regions, respectively. Consequently, great variations in maturation history are seen in different regions of the EOB, with the Taiyuan and Shanxi shales reaching the wet gas and dry gas stages, respectively, in the northern region and all shales reaching the dry gas stage in the southern region. Hydrocarbons were generated at 237 Ma and peaked around 162 Ma, whereas hydrocarbon expulsion began at 230 Ma and peaked at 131 Ma. Rapid subsidence in the Triassic brought the shales to the oil generation window and Early Cretaceous magmatic activities led to rapid maturation of shales, again reaching the gas generation stage. Accordingly, extremely high levels of thermal maturity are well documented in hydrocarbons' alkane composition and stable carbon isotope ratio. Gas geochemical data (δ13C1 vs. C1/C2+3, δ13C1 vs. C2+) imply that that hydrocarbons are from highly mature thermogenic gas generated mainly from humus, and this offers great support for thermal maturation modeling. Regionally, coal-bearing shales have been steadily uplifted and eroded since the Late Cretaceous, causing partial destruction of gas reservoirs. The tectonothermal evolution and hydrocarbon generation of EOB were controlled primarily by magmatic thermal effects resulting from the westward subduction of the Pacific plate.
•Tectonothermal modeling and maturation of coal-bearing shales were studied in the EOB to reveal the geological process of shale gas generation.•Hydrocarbons were generated at 237 Ma and peaked around 162 Ma, whereas hydrocarbon expulsion began at 230 Ma and peaked at 131 Ma.•Extremely high levels of thermal maturity are well documented in hydrocarbons' alkane composition and stable carbon isotope ratio.•The tectonothermal evolution and hydrocarbon generation of EOB were controlled primarily by magmatic thermal effects resulting from the westward subduction of the Pacific plate.
Gas shales contain a variety of clay-rich materials with multifarious pore networks. Clay-hosted porosity is an essential component and considered to play a crucial role in establishing the original ...hydrocarbon molecules in place and transport characteristics of the shale gas reservoir. To better understand the petrophysical basis of gas storage and migration mechanisms, we aim to visualize and quantify the nature of the clay-hosted pore networks and across micrometer and nanometer length scales. Core and outcrop samples are provided of various clay-rich shales (Qiongzhusi, Longmaxi, Wufeng, and Shihezi Formation), which are characterized using a synergistic multi-scale multi-dimensional workflow by FIBSEM, TEM, and X-ray micro-tomography (mCT). Clay-hosted pores are observed in three significant modes of occurrence depending on imaging of pores at the 2D-FIBSEM/TEM level. The first pore type is found between clay domains in clay matrix as interparticle pore, with pore size smaller than 1 μm, and includes six subtypes: type a, type b, type c, type d, type e, and type f. The second associated with the admixture belongs to inter-aggregate pore that can be further sub-divided into three classes: type g (organic-clay), type h (pyrite-clay), and type I (organic-pyrite-clay), with pore size above 50 up to 500 nm. The third associated with the clay nanoplatelets is intraparticle pore. The upper pore-size range of such pores is generally less than 1 nm, with most pores being less than 0.4 nm. Using 3D-mCT and 3D-FIBSEM, the data sets were reconstructed, clay structures were segmented and visualized, revealing the well-connected clay-hosted pore networks within the heterogeneous clay matrix and quantitatively computing pore size, pore volume, and porosity at micrometer and nanometer scales. These visual results highlight the significance of clay-hosted pore networks in shale gas reservoirs because they are the dominant controls on the petrophysical properties. The application of this workflow to worldwide clay-rich shale deposits will allow essential insights into estimating porosity and permeability of shale formations and provide insight to the storage and transport of hydrocarbon molecules from shale matrix to predict total gas resources.
•We provide a synergistic workflow for clay microstructural characterization.•Gas shales contain a variety of clay-rich materials with multifarious pore networks.•Three major clay-hosted pore types are identified and classified.•Clay pores and their related capacities of storage and transport for gas are studied.
Cyclothems, composed of interbedded mudstone, coal and sandstone layers, make up the Taiyuan and Shanxi Formations in the Late Carboniferous to Early Permian in North China under a ...marine-to-continental depositional environment. The cyclothems act as important fossil energy hosts, such as coalbeds, hydrocarbon source rocks and unconventional natural gas reservoirs. Organic geochemistry and petrology of mudstones and coals in the Taiyuan and Shanxi Formations in the eastern Ordos Basin were studied to reveal the organic matter sources and paleoenvironments. Total organic carbon (TOC) contents vary from 1.1 wt% (mudstone) to 72.6 wt% (coal). The samples are mainly within the oil window, with the Tmax values ranging from 433 to 469 °C. Organic petrology and source biomarkers indicate that the mudstones were sourced from a mixed organic matter input, and terrigenous organic matter predominates over aquatic organic matter. The coals are mostly sourced by terrigenous organic matter inputs. High concentrations of hopanes argue for a strong bacterial input. Some m/z 217 mass chromatograms have peaks at the hopanes' retention times as a result of high hopane to sterane ratios. These hopane-derived peaks do not interfere the identification of the steranes because the hopanes and the steranes have different retention times. Maturity-dependent biomarkers demonstrate that the samples have been thermally mature, which agree with the Tmax values. Anomalously low C29 20S/(20S + 20R) and C29 ββ/(ββ + αα) sterane ratios are present in all the samples, and are interpreted as due to the terrigenous organic matter input or the coal-related depositional environment. In addition, biomarkers and iron sulfide morphology indicate that the organic matter of the mudstones deposited in a proximal setting with shallow, brackish/fresh water bodies. With consideration of preservation of organic matter, the redox conditions are dysoxic. Redox oscillations resulted in the records of oxic conditions in some samples. Finally, the coals and the mudstones mainly generate gas and have poor oil generative potential.
•Terrigenous organic matter dominates the coals and predominates over aquatic organic matter in the mudstones.•High hopane to sterane ratios result in fragment peaks of hopanes on m/z 217 mass chromatograms.•The fragments derived from the hopanes on m/z 217 mass chromatograms do not interfere identification of the steranes.•The redox condition is dysoxic and the oxic records of geochemical parameters result from redox oscillations.
Marine shale gas exploration targets are reaching into shallow to deep or ultradeep burial depths. Rock microstructure and reservoir quality emerge as the main risk considerations for a profitable ...reservoir at these large depths. Shallow to deep marine shales occur in the Silurian Longmaxi Formation of the Weiyuan Block, which is located on the southwestern margin of the Sichuan Basin. However, few details of the characteristics of the Longmaxi shales in this Block have been reported. In this study, five wells approximately 3500 m deep were drilled. Field emission scanning electron microscopy, low-pressure gas adsorption and core plug porosity-permeability measurements are conducted on 6 shallow (2651–2940 m) and 11 deep (3539–3575 m) Longmaxi samples to obtain the organic geochemical characteristics, mineral constitutions, pore structures and petrophysical properties, and they are the major controls on reservoir quality. The results show similar mineralogical and organic geochemical characteristics in all samples from the various depths. Both shallow and deep shales are mainly composed of quartz, carbonate and clays and have a total organic carbon (TOC) content more than 2 wt.% and a mean S1 + S2 value more than 52 mg/g. Source rock quality criteria using the TOC and S1 + S2 suggest most shale samples fall excellent source rocks. The samples are mostly siliceous rocks that contain organic pores, intraparticle dissolution pores, interparticle quartz pores and interparticle clay pores and they play a positive role in improving reservoir quality. Pore surface area and pore volume increase with increasing TOC, indicating that the porous organic fraction is a major control on pore structure and porosity. We suggested that siliceous deep Longmaxi formation in Weiyuan Block belongs to a high-quality shale with an average TOC value of 3.9 wt.% and well-developed pore networks, which should be the important target for deep shale gas exploration.
A novel mycovirus belonging to the proposed family “
Fusariviridae
” was discovered in
Alternaria solani
by sequencing a cDNA corresponding to double-stranded RNA extracted from this phytopathogenic ...fungus. The virus was tentatively named “Alternaria solani fusarivirus 1” (AsFV1). AsFV1 has a single-stranded positive-sense (+ssRNA) genome of 6845 nucleotides containing three open reading frames (ORFs) and a poly(A) tail. The largest ORF, ORF1, encodes a large polypeptide of 1,556 amino acids (aa) with conserved RNA-dependent RNA polymerase and helicase domains. The ORF2 and ORF3 have overlapping regions, encoding a putative protein of 522 amino acids (aa) and a putative protein of 105 amino acids (aa), respectively, both of unknown function. A multiple sequence alignment and phylogenetic analysis revealed that AsFV1 could be a new member of the “
Fusariviridae
”. This is the first report of the full-length nucleotide sequence of a fusarivirus that infects
Alternaria solani
.
Over 80% of women diagnosed with advanced-stage ovarian cancer die as a result of disease recurrence due to failure of chemotherapy treatment. In this study, using two distinct ovarian cancer cell ...lines (epithelial OVCA 433 and mesenchymal HEY) we demonstrate enrichment in a population of cells with high expression of CSC markers at the protein and mRNA levels in response to cisplatin, paclitaxel and the combination of both. We also demonstrate a significant enhancement in the sphere forming abilities of ovarian cancer cells in response to chemotherapy drugs. The results of these in vitro findings are supported by in vivo mouse xenograft models in which intraperitoneal transplantation of cisplatin or paclitaxel-treated residual HEY cells generated significantly higher tumor burden compared to control untreated cells. Both the treated and untreated cells infiltrated the organs of the abdominal cavity. In addition, immunohistochemical studies on mouse tumors injected with cisplatin or paclitaxel treated residual cells displayed higher staining for the proliferative antigen Ki67, oncogeneic CA125, epithelial E-cadherin as well as cancer stem cell markers such as Oct4 and CD117, compared to mice injected with control untreated cells. These results suggest that a short-term single treatment of chemotherapy leaves residual cells that are enriched in CSC-like traits, resulting in an increased metastatic potential. The novel findings in this study are important in understanding the early molecular mechanisms by which chemoresistance and subsequent relapse may be triggered after the first line of chemotherapy treatment.
Bone marrow-derived mononuclear cells (BMMNCs) offer the promise of augmenting poststroke recovery. There is mounting evidence of safety and efficacy of BMMNCs from preclinical studies of ischemic ...stroke; however, their pooled effects have not been described.
Using Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, we conducted a systematic review of preclinical literature for intravenous use of BMMNCs followed by meta-analyses of histological and behavioral outcomes. Studies were selected based on predefined criteria. Data were abstracted by 2 independent investigators. After quality assessment, the pooled effects were generated using mixed-effect models. Impact of possible biases on estimated effect size was evaluated.
Standardized mean difference and 95% confidence interval for reduction in lesion volume was significantly beneficial for BMMNC treatment (standardized mean difference: -3.3; 95% confidence interval, -4.3 to -2.3). n=113 each for BMMNC and controls. BMMNC-treated animals (n=161) also had improved function measured by cylinder test (standardized mean difference: -2.4; 95% confidence interval, -3.1 to -1.6), as compared with controls (n=205). A trend for benefit was observed for adhesive removal test and neurological deficit score. Study quality score (median: 6; Q1-Q3: 5-7) was correlated with year of publication. There was funnel plot asymmetry; however, the pooled effects were robust to the correction of this bias and remained significant in favor of BMMNC treatment.
BMMNCs demonstrate beneficial effects across histological and behavioral outcomes in animal ischemic stroke models. Although study quality has improved over time, considerable degree of heterogeneity calls for standardization in the conduct and reporting of experimentation.
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