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Textbook outcome (TBO) has been proposed as a composite measure of quality in esophagogastric surgery, and achieving a TBO has been associated with improved overall survival (OS). The Dutch Upper Gastrointestinal Cancer Audit group determined their TBO rate for gastrectomy to be 32.1%, using 10 parameters. Our study aimed to assess the TBO rate in patients who had a gastrectomy for cancer in an Australian Upper GI unit, allowing for comparisons with international specialist centers.

Connecting earthquake nucleation in basement rock to fluid injection in basal, sedimentary reservoirs, depends heavily on choices related to the poroelastic properties of the fluid‐rock system, thermo‐chemical effects notwithstanding. Direct constraints on these parameters outside of laboratory settings are rare, and it is commonly assumed that the rock layers are isotropic. With the Arbuckle wastewater disposal reservoir in Osage County, Oklahoma, high‐frequency formation pressure changes and collocated broadband ground velocities measured during the passing of large teleseismic waves show a poroelastic response of the reservoir that is both azimuthally variable and anisotropic; this includes evidence of static shifts in pressure that presumably relate to changes in local permeability. The azimuthal dependence in both the static response and shear coupling appears related to tectonic stress and strain indicators such as the orientations of the maximum horizontal stress and faults and fractures. Using dynamic strains from a nearby borehole strainmeter, we show that the ratio of shear to volumetric strain coupling is ~0.41 which implies a mean Skempton's coefficient ofA= 0.24 over the plausible range of the undrained Poisson's ratio. Since these observations are made at relatively low confining pressure and differential stress, we suggest that the hydraulically conductive fracture network is a primary control on the coupling between pore pressure diffusion and elastic stresses in response to natural or anthropogenic sources. Direct measurements of reservoir pressure and strain are used to investigate the poroelastic response of the Arbuckle wastewater disposal reservoir in Oklahoma, USA.The response to teleseismic waves includes an anisotropic dynamic response, with shear strain coupling observed, and static shifts.Systematic azimuthal variability in this response implicates the hydraulically conductive fracture network as a primary control on the poroelastic response of the reservoir. Direct measurements of reservoir pressure and strain are used to investigate the poroelastic response of the Arbuckle wastewater disposal reservoir in Oklahoma, USA. The response to teleseismic waves includes an anisotropic dynamic response, with shear strain coupling observed, and static shifts. Systematic azimuthal variability in this response implicates the hydraulically conductive fracture network as a primary control on the poroelastic response of the reservoir.

ABSTRACTIntroduction: Glioblastoma (GBM) is a highly aggressive brain tumor and is one of the most lethal human cancers. Chimeric antigen receptor (CAR) T cell therapy has markedly improved survival in previously incurable disease; however, this vanguard treatment still faces challenges in GBM. Likewise, checkpoint blockade therapies have not enjoyed the same victories against GBM. As it becomes increasingly evident that a mono-therapeutic approach is unlikely to provide anti-tumor efficacy, there evolves a critical need for combined treatment strategies.Areas covered: This review highlights the clinical successes observed with CAR T cell therapy as well the current efforts to overcome its perceived limitations. The review also explores employed combinations of CAR T cell approaches with immune checkpoint blockade strategies, which aim to potentiate immunotherapeutic benefits while restricting the impact of tumor heterogeneity and T cell exhaustion.Expert opinion: Barriers such as tumor heterogeneity and T cell exhaustion have exposed the weaknesses of various mono-immunotherapeutic approaches to GBM, including CAR T cell and checkpoint blockade strategies. Combining these potentially complementary strategies, however, may proffer a rational means of mitigating these barriers and advancing therapeutic successes against GBM and other solid tumors.

Earthquakes caused by human activities have been observed for decades. Often these are related to industrial activities pumping fluids into deep geologic formations, like with wastewater disposal. The simplest theory connecting these processes to earthquakes is straightforward: injection leads to fluid pressure changes that either reduce the strength of preexisting faults or generate new faults. In practice, the conditions that lead to induced earthquakes are not always clear in ways that can be generalized. Kao et al. (2018, https://doi.org/10.1029/2018GL079288) show how the distribution of induced earthquakes in Western Canada relate to natural rates of deformation in the crust. Using these new results, they discuss an intriguing paradox: induced seismicity can cause short‐term increases in the seismic hazard that are followed by a period of reduced seismic hazard. Such hazard‐reducing scenarios are plausible but hinge upon simplifying assumptions about how the crust stores and releases strain energy in the form of earthquakes. Geodetic data indicate a close relationship between crustal strain rates and induced earthquakesInduced earthquakes might reduce the seismic hazard in the long runHazard‐reducing scenarios hinge critically on a few major assumptions

The Arbuckle Group is the principal reservoir used for wastewater disposal in Oklahoma. In Osage County—a seismically quiet part of the state—continuous measurements of fluid pressure reveal that pressure in the reservoir is increasing by at least 5 kPa annually and sometimes at a much higher rate. Tidal analysis reveals that fluid level changes lead the local strain tides, with no apparent influence from transient permeability changes; this indicates a response that is inconsistent with flow in a radially extensive, confined reservoir. We investigate whether this is due to vertical flow to the water table, vertical flow within the Arbuckle, or local distortions from fractures. While none of these alternative models can fully explain both the observed tidal phases and amplitude ratios, the observed response to teleseismic waves supports a mechanism related to leakage rather than fracture effects. At this location fluid influx associated with wastewater disposal is offset by migration into surrounding layers, which include the Precambrian basement below. Thus, our findings suggest the need to monitor for changes in the induced seismicity hazard, while pore pressures increase in a leaky disposal reservoir. There is consensus among earthquake scientists that subsurface fluid pressure changes are the principal cause of the manmade (or "induced") earthquakes occurring in Oklahoma and around the globe. This is because greater fluid pressures reduce the clamping pressure that would otherwise prevent a fault from having an earthquake. The leading cause of pressure changes on faults in Oklahoma is the disposal of wastewater related to production of oil and natural gas. Disposing of wastewater is generally done by pumping fluid down boreholes into deep, highly permeable reservoirs, like the Arbuckle. One way for scientists to measure water pressure changes is by lowering specially designed instruments down unused wastewater disposal wells. The paper presents continuous measurements of fluid pressure at an Arbuckle well located in Osage County, Oklahoma. Our findings show an overall trend of fluid pressures increasing over time. The only conceivable source of this increase is due to the injection of wastewater. Furthermore, our findings show evidence that fluids are leaking out of the reservoir at a significant rate. The tidal response of the Arbuckle reservoir in Oklahoma is inconsistent with confined, radial flow and shows evidence of leakageTime series show additional signals unrelated to tides and atmospheric pressure, including a robust teleseismic response and long‐term trendsFluid pressure in the Arbuckle is steadily increasing, presumably related to high volume wastewater disposal

This paper reports independent cohort validation of previously discovered esophageal adenocarcinoma (EAC) serum diagnostic glycoprotein biomarker candidates. To demonstrate their potential clinical application in evaluating patients during endoscopy-biopsy surveillance, we developed a panel of 10 biomarker candidates (AUC 0.93) to discriminate Barrett's esophagus (BE) patients not requiring intervention [BE+/− low-grade dysplasia] from those requiring intervention [BE with high-grade dysplasia or EAC]. Complement pathway proteins appear to be dysregulated during EAC, with C9 detected in BE and EAC tissue.

Quantitative interpretation of the tidal response of water levels measured in wells has long been made either with a model for perfectly confined aquifers or with a model for purely unconfined aquifers. However, many aquifers may be neither totally confined nor purely unconfined at the frequencies of tidal loading but behave somewhere between the two end‐members. Here we present a more general model for the tidal response of groundwater in aquifers with both horizontal flow and vertical leakage. The model has three independent parameters: the transmissivity (T) and storativity (S) of the aquifer and the specific leakage (K′/b′) of the leaking aquitard, where K′and b′are the hydraulic conductivity and the thickness of the aquitard, respectively. If Tand Sare known independently, this model may be used to estimate aquitard leakage from the phase shift and amplitude ratio of water level in wells obtained from tidal analysis. We apply the model to interpret the tidal response of water level in a US Geological Survey (USGS) deep monitoring well installed in the Arbuckle aquifer in Oklahoma, into which massive amount of wastewater coproduced from hydrocarbon exploration has been injected. The analysis shows that the Arbuckle aquifer is leaking significantly at this site. We suggest that the present method may be effective and economical for monitoring leakage in groundwater systems, which bears on the safety of water resources, the security of underground waste repositories, and the outflow of wastewater during deep injection and hydrocarbon extraction. Quantitative interpretation of the tidal response of the hydraulic head of an aquifer has been made either with a model for perfectly confined aquifers or with that for purely unconfined aquifers. However, many aquifers may neither be totally confined nor purely unconfined at the frequencies of tidal loading but behave somewhere between the two end‐members. A model for the interpretation of the tidal response of such aquifers, however, is currently lacking. Here we derive a new model for the tidal response of a leaky aquifer and apply the model to interpret the tidal response of water level in a USGS Oklahoma deep monitoring well installed in the Arbuckle aquifer, into which a massive amount of wastewater coproduced from hydrocarbon exploration has been injected. The analysis suggests that the Arbuckle aquifer is leaking significantly at this site. It also shows that Earth tide analysis of water level in wells may be useful for continuous monitoring of leakage of groundwater system, which bears on the safety of water resources, the security of underground waste repositories, and the outflow of wastewater during hydrocarbons extraction. Most confined aquifers may be leaking to some extent; here we derive a new model for the tidal response of a leaky aquiferLeakage may be estimated from Earth tide analysis if the transmissivity and storativity of the aquifer are known independentlyApplying the model to interpret the water level tides in an Oklahoma deep well shows that the Arbuckle aquifer may be leaking significantly

The cumulative seismic moment is a robust measure of the earthquake response to fluid injection for injection volumes ranging from 3,100 to about 12 million m3. Over this range, the moment release is limited to twice the product of the shear modulus and the volume of injected fluid. This relation also applies at the much smaller injection volumes of the field experiment in France reported by Guglielmi et al. (2015, https://doi.org/10.1126/science.aab0476) and laboratory experiments to simulate hydraulic fracturing described by Goodfellow et al. (2015, https://doi.org/10.1002/2015GL063093). In both of these studies, the relevant moment release for comparison with the fluid injection was aseismic and consistent with the scaling that applies to the much larger volumes associated with injection‐induced earthquakes with magnitudes extending up to 5.8. Neither the microearthquakes, at the site in France, nor the acoustic emission in the laboratory samples contributed significantly to the deformation due to fluid injection. Injection of fluid into the Earth's crust sometimes results in a sequence of earthquakes. The deformation associated with these earthquakes is proportional to the volume of injected fluid. This relationship between injected volume and induced earthquakes applies for volumes ranging from 3,100 m3up to volumes exceeding 10 million m3, for induced earthquakes with magnitudes as high as 5.8. It turns out that this simple relationship is also useful at much smaller injected volumes. At a field experiment in southern France, injection of 0.95 m3of water into a preexisting fault zone, cutting through a limestone terrain, caused a “slow earthquake” with a magnitude of 1.17. At a much smaller scale, laboratory experiments to simulate hydraulic fracturing revealed that injection of approximately 1 ml of water into samples of granite resulted in slow sample expansion equivalent to the deformation of earthquakes with magnitudes of about minus 3. Crustal deformation in response to fluid injection can be seismic or aseismicCumulative moment release, a measure of deformation, varies linearly with injected volumeThe range of linearity extends from volumes of 1 ml in the laboratory up to more than 10 million m3for sequences of induced earthquakes

Each of the three earthquake sequences in Oklahoma in 2016—Fairview, Pawnee, and Cushing—appears to have been induced by high‐volume wastewater disposal within 10 km. The Fairview M5.1 main shock was part of a 2 year sequence of more than 150 events of M3, or greater; the main shock accounted for about half of the total moment. The foreshocks and aftershocks of the M5.8 Pawnee earthquake were too small and too few to contribute significantly to the cumulative moment; instead, nearly all of the moment induced by wastewater injection was focused on the main shock. The M5.0 Cushing event is part of a sequence that includes 48 earthquakes of M3, or greater, that are mostly foreshocks. The cumulative moment for each of the three sequences during 2016, as well as that for the 2011 Prague, Oklahoma, and nine other sequences representing a broad range of injected volume, are all limited by the total volumes of wastewater injected locally. Cumulative seismic moment for each of the three sequences is within the limit imposed by injected volume within 10 kmFor the Pawnee sequence, nearly all of the injection‐induced seismic moment was focused on the M5.8 main shockCumulative seismic moments of injection‐induced earthquake sequences scale linearly with injected volume

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The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

For patients with BRAF wild-type stage III and IV melanoma, there is an urgent clinical need to identify prognostic biomarkers and biomarkers predictive of treatment response. Circulating tumor DNA (ctDNA) is emerging as a blood-based biomarker and has shown promising results for many cancers, including melanoma. The purpose of this study was to identify targetable, tumor-derived mutations in patient blood that may lead to treatment alternatives and improved outcomes for patients with BRAF-negative melanoma. Using a CAPP-seq pan-cancer gene panel, ctDNA from 150 plasma samples (n = 106 patients) was assessed, including serial blood collections for a subset of patients (n = 16). ctDNA variants were detected in 85% of patients, all in targetable pathways, such as vascular endothelial growth factor receptor, epidermal growth factor receptor, phosphatidylinositol 3-kinase/AKT, Bcl2/mammalian target of rapamycin, ALK/MET, and cyclin-dependent kinase 4/6. Patients with stage IV melanoma with low ctDNA concentrations, <10 ng/mL, had significantly better disease-specific survival and progression-free survival. Patients with both a high concentration of ctDNA and any detectable ctDNA variants had the worst prognosis. In addition, these results indicated that longitudinal changes in ctDNA correlated with treatment response and disease progression determined by radiology. This study confirms that ctDNA has potential to be used as a noninvasive liquid biopsy to identify recurrent disease and detect targetable variants in patients with late-stage melanoma.

Direct pyrolysis of self-assembled block copolymers (BCPs) is a resource-efficient method for synthesizing ordered mesoporous carbons (OMCs), through which the resulting pore textures and properties are often collectively determined by the precursor identity and processing pathways. Previous works in this area heavily rely on the use of polyacrylonitrile-based BCP systems, which employ a high-temperature cross-linking reaction that can impact the degree of ordering in their nanostructures. Recently, thermoplastic elastomers have been employed as an emerging OMC precursor, demonstrated by commodity grade polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS). This method requires solid-state, sulfonation-induced cross-linking, involving simultaneous reactions with both the majority poly(ethylene-ran-butylene) phase and the polystyrene segments. This work elucidates the fundamentals of how the reaction mechanism and condition govern SEBS nanostructure development, which deconvolutes distinct contributions from sulfonation and cross-linking. Specifically, small-angle X-ray scattering results, in conjunction with chemical evolution investigations, indicate that polystyrene sulfonation is primarily responsible for increased domain spacing that is mediated through competition between thermodynamically driven nanostructure rearrangement and kinetic trapping from cross-linking. The conversion of cross-linked SEBS, obtained from varying reaction conditions, to OMCs is also studied for establishing critical process–structure relationship. These fundamental understandings provide key insights about rational system design of SEBS-derived OMCs, prepared through two steps of sulfonation-induced cross-linking and direct pyrolysis.

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLITsignalling, G1/Stransition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53and KDM6Amutations, upregulation of the TP63∆Ntranscriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRASactivation, exocrine (NR5A2and RBPJL), and endocrine differentiation (NEUROD1and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Size-at-age information is critical in estimating growth parameters (e.g., the von Bertalanffy growth function [VBGF]) that are used to assess fish populations. Due to gear selectivity, single sampling methods rarely sample all ages or all sizes equally well. Most growth estimates rely on samples from a single gear or a haphazard combination of gears, potentially leading to biased and imprecise growth parameter estimates. We evaluated the efficacy of combining samples from two gears with different size selectivity to estimate VBGF parameters; we then applied that approach to a case study on the Lochloosa Lake (Florida) population of Black Crappies Pomoxis nigromaculatus. Simulated age- and size-structured populations were randomly sampled with two gears characterized by different size-selectivity curves (one gear was selective for smaller fish; the other was selective for larger fish). Maximum likelihood VBGF estimates obtained for each gear separately were compared with estimates from a combined VBGF fitted to data from both gears. In every simulated scenario, a combined-gear approach reduced bias and increased precision for estimating the VBGF, but the gear-specific proportions that improved VBGF estimates depended on size selectivity. The VBGF estimates for the Black Crappie population showed that the combined-gear method yielded intermediate parameter values relative to single-gear approaches based on (1) trawl sampling (fishery-independent survey) and (2) angler harvest (as determined from carcass collections; fishery-dependent data). Furthermore, the combined-gear approach had greater precision in individual parameter estimates and much less variance than single-gear approaches when estimating the VBGF. Combining data from two gears can increase sample representativeness, leading to improvements in VBGF estimation. Such approaches can reduce uncertainty in VBGF estimation and can provide insight into key demographic processes occurring in fish populations for which ontogeny and gear selectivity lead to imperfect sampling. Received January 22, 2015; accepted July 30, 2015

AbstractSize-at-age information is critical in estimating growth parameters (e.g., the von Bertalanffy growth function [VBGF]) that are used to assess fish populations. Due to gear selectivity, single sampling methods rarely sample all ages or all sizes equally well. Most growth estimates rely on samples from a single gear or a haphazard combination of gears, potentially leading to biased and imprecise growth parameter estimates. We evaluated the efficacy of combining samples from two gears with different size selectivity to estimate VBGF parameters; we then applied that approach to a case study on the Lochloosa Lake (Florida) population of Black Crappies Pomoxis nigromaculatus. Simulated age- and size-structured populations were randomly sampled with two gears characterized by different size-selectivity curves (one gear was selective for smaller fish; the other was selective for larger fish). Maximum likelihood VBGF estimates obtained for each gear separately were compared with estimates from a combined VBGF fitted to data from both gears. In every simulated scenario, a combined-gear approach reduced bias and increased precision for estimating the VBGF, but the gear-specific proportions that improved VBGF estimates depended on size selectivity. The VBGF estimates for the Black Crappie population showed that the combined-gear method yielded intermediate parameter values relative to single-gear approaches based on (1) trawl sampling (fishery-independent survey) and (2) angler harvest (as determined from carcass collections; fishery-dependent data). Furthermore, the combined-gear approach had greater precision in individual parameter estimates and much less variance than single-gear approaches when estimating the VBGF. Combining data from two gears can increase sample representativeness, leading to improvements in VBGF estimation. Such approaches can reduce uncertainty in VBGF estimation and can provide insight into key demographic processes occurring in fish populations for which ontogeny and gear selectivity lead to imperfect sampling.Received January 22, 2015; accepted July 30, 2015

We report an integrated pipeline for efficient serum glycoprotein biomarker candidate discovery and qualification that may be used to facilitate cancer diagnosis and management. The discovery phase used semi-automated lectin magnetic bead array (LeMBA)-coupled tandem mass spectrometry with a dedicated data-housing and analysis pipeline; GlycoSelector (http://glycoselector.di.uq.edu.au). The qualification phase used lectin magnetic bead array-multiple reaction monitoring-mass spectrometry incorporating an interactive web-interface, Shiny mixOmics (http://mixomics-projects.di.uq.edu.au/Shiny), for univariate and multivariate statistical analysis. Relative quantitation was performed by referencing to a spiked-in glycoprotein, chicken ovalbumin. We applied this workflow to identify diagnostic biomarkers for esophageal adenocarcinoma (EAC), a life threatening malignancy with poor prognosis in the advanced setting. EAC develops from metaplastic condition Barrett's esophagus (BE). Currently diagnosis and monitoring of at-risk patients is through endoscopy and biopsy, which is expensive and requires hospital admission. Hence there is a clinical need for a noninvasive diagnostic biomarker of EAC. In total 89 patient samples from healthy controls, and patients with BE or EAC were screened in discovery and qualification stages. Of the 246 glycoforms measured in the qualification stage, 40 glycoforms (as measured by lectin affinity) qualified as candidate serum markers. The top candidate for distinguishing healthy from BE patients' group was Narcissus pseudonarcissuslectin (NPL)-reactive Apolipoprotein B-100 (pvalue = 0.0231; AUROC = 0.71); BE versusEAC, Aleuria aurantialectin (AAL)-reactive complement component C9 (pvalue = 0.0001; AUROC = 0.85); healthy versusEAC, Erythroagglutinin Phaseolus vulgaris(EPHA)-reactive gelsolin (pvalue = 0.0014; AUROC = 0.80). A panel of 8 glycoforms showed an improved AUROC of 0.94 to discriminate EAC from BE. Two biomarker candidates were independently verified by lectin magnetic bead array-immunoblotting, confirming the validity of the relative quantitation approach. Thus, we have identified candidate biomarkers, which, following large-scale clinical evaluation, can be developed into diagnostic blood tests. A key feature of the pipeline is the potential for rapid translation of the candidate biomarkers to lectin-immunoassays.

Triggered seismicity arising from dynamic stresses is often explained by the Mohr‐Coulomb failure criterion, where elevated pore pressures reduce the effective strength of faults in fluid‐saturated rock. The seismic response of a fluid‐rock system naturally depends on its hydromechanical properties, but accurately assessing how pore fluid pressure responds to applied stress over large scales in situ remains a challenging task; hence, spatial variations in response are not well understood, especially around active faults. Here I analyze previously unutilized records of dynamic strain and pore pressure from regional and teleseismic earthquakes at Plate Boundary Observatory (PBO) stations from 2006 to 2012 to investigate variations in response along the Pacific/North American tectonic plate boundary. I find robust scaling response coefficients between excess pore pressure and dynamic strain at each station that are spatially correlated: around the San Andreas and San Jacinto fault systems, the response is lowest in regions of the crust undergoing the highest rates of secular shear strain. PBO stations in the Parkfield instrument cluster are at comparable distances to the San Andreas Fault (SAF), and spatial variations there follow patterns in dextral creep rates along the fault, with the highest response in the actively creeping section, which is consistent with a narrowing zone of strain accumulation seen in geodetic velocity profiles. At stations in the San Juan Bautista (SJB) and Anza instrument clusters, the response depends nonlinearly on the inverse fault‐perpendicular distance, with the response decreasing toward the fault; the SJB cluster is at the northern transition from creeping‐to‐locked behavior along the SAF, where creep rates are at moderate to low levels, and the Anza cluster is around the San Jacinto Fault, where to date there have been no statistically significant creep rates observed at the surface. These results suggest that the strength of the pore pressure response in fluid‐saturated rock near active faults is controlled by shear strain accumulation associated with tectonic loading, which implies a strong feedback between fault strength and permeability: dynamic triggering susceptibilities may vary in space and also in time. I have quantified the response of pore pressure signals from seismic wavesThis response varies systematically in spaceSpatial variations are linked to strain rates around active faults

The North Brawley Geothermal Field, located within the Brawley Seismic Zone of Southern California, presents a case study for understanding seismic hazards linked to fluid injection and geothermal energy extraction. An earthquake swarm near the geothermal field in 2012 included two earthquakes with magnitudes greater than 5 and was potentially preceded by a years‐long aseismic slip transient. To better understand ground deformation around the geothermal field, including its evolution with time and its physical mechanisms, we analyze deformation before, during, and after the swarm using ground‐ and satellite‐based geodetic techniques between 2009 and 2019. We integrate observations from GNSS, Sentinel‐1, TerraSAR‐X, UAVSAR, and leveling surveys into a single deformation history. Modeling of this new collection of observations at the North Brawley Geothermal Field provides evidence for 80% more pre‐swarm aseismic slip than previously recognized from 2009 to 2012. During the 2012 Brawley swarm, our geodetic slip inversions closely match the results of seismic waveform inversions from the swarm events. After the 2012 swarm, surface deformation is dominated by poroelastic deformation of a shallow fluid reservoir at <1 km depth rather than fault slip. The deformation history and seismicity catalogs at North Brawley suggest a cessation of fault‐related slip during the ∼7 years after the 2012 earthquake swarm. It is well known that seismicity around geothermal fields is a major concern for the energy industry and for the public, but there is another potential source of concern from faults that slip without generating seismic waves. Silent slip may play a role in controlling the location and duration of earthquake swarms. The processes behind silent or aseismic slip at geothermal fields are not well understood, largely because they are difficult to measure. The North Brawley Geothermal Field in Southern California provides an opportunity to learn about these processes in a region prone to natural earthquake swarms: after a few years of geothermal operations, several magnitude 4–5 earthquakes occurred in 2012, followed by a long period of few earthquakes. We study this area by combining radar images, GPS, and leveling to reveal how the ground moved before, during, and after the 2012 events, with centimeter‐scale accuracy. We show that signals in these data come from aseismic fault slip in 2009–2013 and underground pressure changes in 2014–2019. The patterns preceding the 2012 earthquakes did not continue afterward, suggesting that aseismic slip controlled the timing and location of the 2012 events, and that the seismic and aseismic slip released tectonically accumulated strain. Geodetic measurements reveal a time series of deformation at the North Brawley Geothermal Field from 2009 to 2019Before and during the 2012 Brawley swarm, deformation can be modeled by seismic slip and a growing aseismic slip featureAfter 2012, deformation can be modeled by a poroelastic pressure source from fluid injection and production in the geothermal reservoir Geodetic measurements reveal a time series of deformation at the North Brawley Geothermal Field from 2009 to 2019 Before and during the 2012 Brawley swarm, deformation can be modeled by seismic slip and a growing aseismic slip feature After 2012, deformation can be modeled by a poroelastic pressure source from fluid injection and production in the geothermal reservoir

Strainmeters can be subject to hydrologic effects from pumping of nearby water wells, depending on the state of the local rock. Strain signals associated with hydrology are generally not used and regarded as troublesome because they are much larger than most tectonic signals (e.g., tides or slow slip episodes in Cascadia), but here we show that fluid extraction leads to detectable strain and pore pressure signals, which we use to constrain valuable material properties of the rock, namely the hydraulic diffusivity and elastic shear modulus. We collected multiple years of pump activity at two active water wells near a pair of Plate Boundary Observatory borehole strainmeters in southern California. These data demonstrate clearly the connection between fluid extraction and deformation: the onset of transient strains and pore pressures is strongly correlated with both the onset of fluid extraction, and the sizes of the transient signals are strongly correlated with cumulative extraction volumes. These data also suggest that the instruments are a possible tool for remote monitoring of fluid injection and withdrawal. Based on poroelastic modeling, we find estimates of hydraulic diffusivity (0.061 m2s−1to 0.126 m2s−1) which are consistent with data for fractured igneous rock, and estimates of shear modulus (39.7 MPa to 101 MPa) which are comparable to data for shallow granodiorite—expected to be weak from weathering, and other sources of damage (e.g., faulting). We infer that crustal rock in this region is drained at shallow depths by pervasive, hydraulically conductive fractures: as a result of changes in applied stress, fluid flow will occur rather than a sustained change in pore fluid pressure. Strain and pressure signals linked to measured fluid extractionPoroelastic models constrain rock propertiesRock is relatively weak and fluids flow easily

From 2017 to 2019, three destructive earthquakes (27 January 2017 Mw 4.7, 16 December 2018 Mw 5.2, and 3 January 2019 Mw 4.8) occurred in the Changning shale gas field in the southwest Sichuan Basin, China. Previous seismological studies attributed these events to hydraulic fracturing (HF), but were unable to identify the causative seismogenic faults and their slip behaviors. Here, we use Sentinel‐1 synthetic aperture radar data to measure surface deformation triggered by the three events and conduct geodetic inversions to characterize their rupture models. The resulting coseismic interferograms show prominent surface deformation with the maximum line‐of‐sight displacements of up to 4 cm. The inversion results show that all three earthquakes mainly ruptured sedimentary formations above the shale gas bed, in the upper 3 km of the crust, with slip magnitudes ranging from 8.5 to 15 cm, and stress drops ranging from ∼1.8 to ∼3.3 MPa. Their source faults intersect with horizontal HF wells, but do not root in the crystalline basement. Combined with the reported difficulty of increasing HF operation pressures prior to the three events, we argue that they were most likely induced by direct injection of pressurized fluids into the fault zones. Crustal deformation patterns inferred from regional topography and GPS velocities highlight that the Changning field is located within a triple junction region near the southeastern margin of the Tibetan Plateau with large deformation gradients; such conditions are not only favorable to the development of critically stressed faults, but also facilitate the occurrence of at least moderate magnitude earthquakes. The number of earthquakes induced by the process of shale gas extraction through hydraulic fracturing (HF) has been increasing across the globe, with dozens of M> 4 events reported by the end of August 2021. Although most case studies on HF‐induced seismicity are from the United States and Canada, the southwestern Sichuan Basin (China), located to the southeast of the Tibetan Plateau, is another region with notable seismicity linked to HF operations, including dozens of moderate‐to‐large earthquakes. We here focus on the three largest Mw ≥ 4.7 earthquakes that occurred within the Changning shale gas field up to now. We use geodetic techniques to measure ground deformation caused by the three earthquakes and to further infer their ruptures at depth. Our results reveal that the three earthquakes occurred on shallow faults intersecting with horizontal HF wells, with little‐to‐no slip in the crystalline basement below the depth of 3 km. These questions the common theme of HF‐induced earthquakes having hypocenters proximal to basement rock, presumably associated with basement‐rooted faults, and suggests that the potential for ground shaking of HF‐induced earthquakes is more significant than previously understood. The three events ruptured shallow faults within sedimentary formations above the shale gas bed rather than basement‐rooted faultsThe faults of the three events intersect with horizontal hydraulic fracturing wells and were likely reactivated by direct fault‐zone pressurizationHigh HF‐induced seismicity rate in the Changning area links to the proximity to a triple junction region with relatively high tectonic strain accumulation rates The three events ruptured shallow faults within sedimentary formations above the shale gas bed rather than basement‐rooted faults The faults of the three events intersect with horizontal hydraulic fracturing wells and were likely reactivated by direct fault‐zone pressurization High HF‐induced seismicity rate in the Changning area links to the proximity to a triple junction region with relatively high tectonic strain accumulation rates

In order to develop a better understanding of the evolutionary dynamics of HIV drug resistance, it is necessary to quantify accurately the in vivo fitness costs of resistance mutations. However, the reliable estimation of such fitness costs is riddled with both theoretical and experimental difficulties. Experimental fitness assays typically suffer from the shortcoming that they are based on in vitro data. Fitness estimates based on the mathematical analysis of in vivodata, however, are often questionable because the underlying assumptions are not fulfilled. In particular, the assumption that the replication rate of the virus population is constant in time is frequently grossly violated. By extending recent work of Marée and colleagues, we present here a new approach that corrects for time–dependent viral replication in time–series data for growth competition of mutants. This approach allows a reliable estimation of the relative replicative capacity (with confidence intervals) of two competing virus variants growing within the same patient, using longitudinal data for the total plasma virus load, the relative frequency of the two variants and the death rate of infected cells. We assess the accuracy of our method using computer–generated data. An implementation of the developed method is freely accessible on the Web (http://www.eco.ethz.ch/fitness.html).

We study the variance-to-mean ratio of the distributions of parasites among hosts for some models of parasite infection, using the cohort approach. We consider a model with density dependence in parasite mortality, and two different formulations of disease induced host mortality. We show that the distributions of parasites, conditional on host survival, converge to quasi-stationary distributions as host age increases. When there is density dependence in parasite mortality, the limiting variance-to-mean ratio is less than 1 (an ‘under-dispersed’ distribution). In contrast, the two modes of disease induced host mortality show that either over- or underdispersed distributions may result.

Family profile analysis (FPA), described in this paper, compares all available homologous amino acid sequences of a target family with the profile of a probe family while conventional sequence profile analysis (Gribskov M, Lüthy R, Eisenberg D. Meth Enzymol 1990;183:146–159) considers only a single target sequence in comparison with the probe family. The increased input of sequence information in FPA expands the range for sequence‐based recognition of structural relationships. In the FPA algorithm, Zscores of each of the target sequences, obtained from a probe profile search over all known amino acid sequences, are averaged and then compared with the scores for sequences of 100 reference families in the same probe family search. The resulting F‐Zscore of the target family, expressed in “effective standard deviations” of the mean Zscores of the reference families, with value above a threshold of 3.5 indicates a statistically significant evolutionary relationship between the target and probe families. The sensitivity of FPA to sequence information was tested with several protein families where distant relationships have been verified from known tertiary protein architectures, which included vitamin B6‐dependent enzymes, (β/α)8‐barrel proteins, β‐trefoil proteins, and globins. In comparison to other methods, FPA proved to be significantly more sensitive, finding numerous new homologies. The FPA technique is not only useful to test a suspected relationship between probe and target families but also identifies possible target families in profile searches over all known primary structures. Proteins 1999;35:387–400. © 1999 Wiley‐Liss, Inc.

Stein's method is used to prove approximations in total variation to the distributions of integer valued random variables by (possibly signed) compound Poisson measures. For sums of independent random variables, the results obtained are very explicit, and improve upon earlier work of Kruopis (1983) and Čekanavičius (1997); coupling methods are used to derive concrete expressions for the error bounds. An example is given to illustrate the potential for application to sums of dependent random variables.

Family profile analysis (FPA), described in this paper, compares all available homologous amino acid sequences of a target family with the profile of a probe family while conventional sequence profile analysis (Gribskov M, Lüthy R, Eisenberg D. Meth Enzymol 1990;183:146–159) considers only a single target sequence in comparison with the probe family. The increased input of sequence information in FPA expands the range for sequence-based recognition of structural relationships. In the FPA algorithm, Zscores of each of the target sequences, obtained from a probe profile search over all known amino acid sequences, are averaged and then compared with the scores for sequences of 100 reference families in the same probe family search. The resulting F-Zscore of the target family, expressed in “effective standard deviations” of the mean Zscores of the reference families, with value above a threshold of 3.5 indicates a statistically significant evolutionary relationship between the target and probe families. The sensitivity of FPA to sequence information was tested with several protein families where distant relationships have been verified from known tertiary protein architectures, which included vitamin B6-dependent enzymes, (β/α)8-barrel proteins, β-trefoil proteins, and globins. In comparison to other methods, FPA proved to be significantly more sensitive, finding numerous new homologies. The FPA technique is not only useful to test a suspected relationship between probe and target families but also identifies possible target families in profile searches over all known primary structures. Proteins 1999;35:387–400. © 1999 Wiley-Liss, Inc.

Let X(t) be a continuous time Markov process on the integers such that, if sis a time at which Xmakes a jump, X(s)– X(s–) is distributed independently of X(s–), and has finite mean µand variance. Let q(j) denote the residence time parameter for the state j.If tndenotes the time of the nth jump and Xn= X(tb), it is easy to deduce limit theorems for from those for sums of independent identically distributed random variables. In this paper, it is shown how, for µ> 0 and for suitable q(·), these theorems can be translated into limit theorems for X(t), by using the continuous mapping theorem.

Let {XN(t)} be a sequence of continuous time Markov population processes on an n-dimensional integer lattice, such that XNhas initial state Nx(0) and has a finite number of possible transitions Jfrom any state X: let the transition X? X + Jhave rate NgJ(N–1X), and let gJ(x) and x(0) be fixed as Nvaries. The rate of convergence of vN(N–1XN(t) — ?(t)) to a Gaussian diffusion is investigated, where ?(t) is the deterministic approximation to N–1XN(t), and a method of deriving higher order asymptotic expansions for its distribution is justified. The methods are applied to two birth and death processes, and to the closed stochastic epidemic.

In a recent article, Kelly [4] has been able to exhibit interesting equilibrium properties for a wide class of ‘quasi-reversible’ queue networks. The assumption of quasi-reversibility puts restrictions on queue discipline, but not on the distributions of the service requirements of customers: however, because of the method of proof he employed, Kelly was forced to impose the condition that the service requirements were finite mixtures of gamma distributions. The form of the results he obtained led him to conjecture that this condition was in fact unnecessary, as is shown to be the case in this paper. The method used to prove the conjecture is of potentially wide application, in problems where the ‘method of stages' leads to useful simplification.

One way of analysing complicated Markov population processes is to approximate them by a diffusion about the deterministic path. This approximation alone may not, however, answer all the questions which might reasonably be asked. Many processes have phases, for example near boundaries, where a different approximation is required; such processes are better described by a succession of diffusion and special approximations alternately.This paper looks at the special treatment required near a point where the deterministic equations are in equilibrium. When the equilibrium is unstable, the process will eventually wander off, and possibly follow a diffusion around another deterministic path. If the equilibrium is stable, the process will behave as if in stable equilibrium about it for a very much longer time, but may at last be trapped away from it, for instance in an absorbing state. The results presented describe the distributions of the time and place of leaving neighbourhoods of the equilibrium point. The neighbourhoods considered are large enough, in the unstable case, to make possible the link with the next phase of motion. In the stable case, exit times are shown to be so long that the possibility of exit can often be ignored in practice, and the quasi-equilibrium distribution treated as a true equilibrium. A more detailed result, showing how closely the normal approximation holds in this situation, is also provided.