Search Results (25)

Molecular diagnostics has the potential to revolutionise the field of clinical microbiology. Microbial identification and nomenclature have, for too long, been restricted to phenotypic characterisation. However, this species-level view fails to wholly account for genetic heterogeneity, a result of lateral gene transfer, mediated primarily by mobile genetic elements. This genetic promiscuity has helped to drive virulence development, stress adaptation, and antimicrobial resistance in several important bacterial pathogens, complicating their detection and frustrating our ability to control them. We argue that, as clinical microbiologists at the front line, we must embrace the molecular technologies that allow us to focus specifically on the genetic elements that cause disease rather than the bacterial species that express them. This review focuses on the evolution of microbial taxonomy since the introduction of molecular sequencing, the role of mobile genetic elements in antimicrobial resistance, the current and emerging assays in clinical laboratories, and the comparison of phenotypic versus genotypic analyses. In essence, it is time now to refocus from species to genes as part of a new diagnostic paradigm. Full article

This study proposes a new computational framework for the multi-objective topology optimization of conjugate heat transfer systems using a continuous adjoint approach. It relies on a monolithic solver for the coupled steady-state Navier–Stokes and heat equations, which combines finite elements stabilized by the variational multi-scale method, level set representations of the fluid–solid interfaces and immersed modeling of heterogeneous materials (fluid–solid) to ensure that the proper amount of heat is exchanged to the ambient fluid by solid objects in arbitrary geometry. At each optimization iteration, anisotropic mesh adaptation is applied in near-wall regions automatically captured by the level set. This considerably cuts the computational effort associated with calling the finite element solver, in comparison to traditional topology optimization algorithms operating on isotropic grids with a comparable refinement level. Given that we operate within the constraint of a specified number of nodes in the mesh, this allows not only to improve the accuracy of interface representation and motion but also to retain the high fidelity of the numerical solutions at the grid points just adjacent to the interface. Finally, the remeshing and resolution steps both run within a highly parallel environment, which makes it possible for the proposed algorithm to tackle large-scale problems in three dimensions with several tens of millions of state degrees of freedom. The developed solver is validated first by minimizing dissipation in a flow splitter device, for which the method delivers relevant optimal designs over a wide range of volume constraints and flow rate distributions over the multiple outlet orifices but yields better accuracy compared to reference data from literature obtained using uniform meshes (in the sense that the layouts are more smooth, and the solutions are better resolved). The scheme is then applied to a two-dimensional heat transfer problem, using bi-objective cost functionals combining flow resistance and thermal recoverable power. A comprehensive parametric study reveals a complex arrangement of optimal solutions on the Pareto front, with multiple branches of symmetric and asymmetric designs, some of them previously unreported. Finally, the algorithmic developments are substantiated with several three-dimensional numerical examples tackled under fixed weights for heat transfer and flow resistance, for which we show that the optimal layouts computed at low Reynolds number, that are intrinsically relevant to a broad range of microfluidic application, can also serve as smooth solutions to high-Reynolds-number engineering problems of practical interest. Full article

The heterogeneity and intricate cellular architecture of complex cellular ecosystems play a crucial role in the progression and therapeutic response of cancer. Understanding the regulatory relationships of malignant cells at the invasive front of the tumor microenvironment (TME) is important to explore the heterogeneity of the TME and its role in disease progression. In this study, we inferred malignant cells at the invasion front by analyzing single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data of ER-positive (ER+) breast cancer patients. In addition, we developed a software pipeline for constructing intercellular gene regulatory networks (IGRNs), which help to reduce errors generated by single-cell communication analysis and increase the confidence of selected cell communication signals. Based on the constructed IGRN between malignant cells at the invasive front of the TME and the immune cells of ER+ breast cancer patients, we found that a high expression of the transcription factors FOXA1 and EZH2 played a key role in driving tumor progression. Meanwhile, elevated levels of their downstream target genes (ESR1 and CDKN1A) were associated with poor prognosis of breast cancer patients. This study demonstrates a bioinformatics workflow of combining scRNA-seq and ST data; in addition, the study provides the software pipelines for constructing IGRNs automatically (cIGRN). This strategy will help decipher cancer progression by revealing bidirectional signaling between invasive frontline malignant tumor cells and immune cells, and the selected signaling molecules in the regulatory network may serve as biomarkers for mechanism studies or therapeutic targets. Full article

Municipal solid waste (MSW) landfill slope failures can have significant consequences for the economy, environment, and human health. One potential cause of slope failure is insufficient reliability, resulting from inadequate design. The usual practice in the design of MSW landfills involves utilizing established geotechnical codes, such as Eurocode 7 (EC7), to perform slope stability assessments. Considering the substantial heterogeneity of MSW relative to soil, questions arise regarding the justification of such an approach in the design of MSW landfills. This study examines the suitability of applying EC7 in MSW landfill design, analyzing the stability and reliability of landfill slopes across various heights, front slope angles, design approaches, and consequence classes. This study finds that, in most cases considered, EC7 does not ensure an adequate level of reliability for MSW landfill slopes. Therefore, it is suggested that EC7 should be complemented with specific guidelines for incorporating MSW in geotechnical analyses to achieve the desired structural reliability. Adopting this strategy will not only enhance the reliability of landfill design but also promote the development of solutions that are economically and environmentally sustainable. Full article

Deep-sea benthic fauna is vital for a well-functioning marine ecosystem but is increasingly under threat from a changing environment. To monitor and conserve this fauna, an understanding of their large-scale spatial and bathymetric distribution and their environmental drivers is necessary. In this study, we conduct a multivariate analysis on abundance benthic fauna data collected at the phylum and multitaxon levels using an epibenthic sledge (EBS) across the Atlantic, and identify the environmental factors that affect such data. Our findings show a decrease in abundance with depth in most of the Atlantic but find relatively heterogeneous abundances with depth within the Southern Ocean. Principal component analyses indicate differences in environmental conditions south of the Antarctic Polar Front (~52° S), outlining contrasts in the quantities of macronutrients and physical factors. Despite this, community composition seemed markedly similar throughout the Atlantic with the Antarctic Circumpolar Current seemingly not affecting benthic community composition for higher taxonomic levels. Those differences that did occur were largely caused by benthic chlorophyll, benthic iron, and surface silicate through a Bio-ENV. Overall, we argue that further large-scale spatial and bathymetric distribution studies are important amid environmental changes that are driving shifts in benthic community abundance and composition. Full article

The heterogeneity of the fractured-basalt and interbedded-sediment aquifer along the eastern margin of the Columbia Plateau Regional Aquifer System has presented challenges to resource managers in quantifying recharge and estimating sustainable withdrawals. Previous studies indicated recharge pathways in alluvial sediments atop a mountain–front interface upgradient of the basalt flows. In this sedimentary zone, six seismic stations were deployed for one year to detect velocity changes in low-frequency seismic waves that could be correlated to changes in groundwater recorded by a well transducer near the center of the seismic station network. Waveforms in the 1−5 Hz range were recorded at each station to determine changes in wave velocities between station pairs and correlate these velocity changes to changes in groundwater levels. The velocity–groundwater relation allowed for estimation of daily groundwater levels beneath the seismic station network. Existing hydrogeologic information was used to estimate hydraulic gradients and hydraulic conductivities, which allowed for the calculation of the daily volume of recharge passing beneath the seismic stations and into the confined aquifer system. The daily recharge volumes across the seismic station network were summed for comparison of the total annual recharge calculated from the change in seismic wave velocities (154,660 m³) to a flow model calculation of recharge based on areal precipitation and infiltration (26,250 m³). The 6× greater recharge estimated from the seismic wave velocity changes for this portion of the recharge zone is attributed to preferential pathways of high hydraulic conductivity and greater depth associated with paleochannels beneath the seismic station network. Full article

Two commercially important scallop species of the genus Pecten are found in Europe: the north Atlantic Pecten maximus and the Mediterranean Pecten jacobaeus whose distributions abut at the Almeria–Orán front. Whilst previous studies have quantified genetic divergence between these species, the pattern of differentiation along the Pecten genome is unknown. Here, we mapped RADseq data from 235 P. maximus and 27 P. jacobaeus to a chromosome-level reference genome, finding a heterogeneous landscape of genomic differentiation. Highly divergent genomic regions were identified across 14 chromosomes, while the remaining five showed little differentiation. Demographic and comparative genomics analyses suggest that this pattern resulted from an initial extended period of isolation, which promoted divergence, followed by differential gene flow across the genome during secondary contact. Single nucleotide polymorphisms present within highly divergent genomic regions were located in areas of low recombination and contrasting patterns of LD decay were found between the two species, hinting at the presence of chromosomal inversions in P. jacobaeus. Functional annotations revealed that highly differentiated regions were enriched for immune-related processes and mRNA modification. While future work is necessary to characterize structural differences, this study provides new insights into the speciation genomics of P. maximus and P. jacobaeus. Full article

The green finance policy is crucial for enterprises to participate in environmental governance actively. Taking the “Green Credit Guidelines” issued by China in 2012 as a quasi-natural experiment, this study investigated the impact of green finance policies on corporate environmental, social, and governance (ESG) performance by using a continuous Difference-in-Differences (DID) model based on the data of listed companies from 2006 to 2020. The conclusions are: (1) The green finance policy significantly improves corporate ESG, but the effects vary across enterprises. (2) The policy has encouraged enterprises to develop and adopt green products and technologies. Still, it has not had a positive effect on the treatment of enterprise pollutant emissions because the implementation of the policy makes enterprises pay more attention to front-end risk control than pollution treatment after production. (3) Research results have heterogeneity. The impact of green finance policies on enterprises at different levels of environmental regulation is different. Enterprises in areas with high intensity of environmental regulation are more vulnerable to green credit. The conclusion of this paper helps improve the green finance policy system, enhance the awareness and level of corporate ESG, and strengthen the collaborative governance of policies and enterprises on environmental issues in combination with the mandatory environmental regulations and incentive mechanisms to promote the green development of enterprises and realize the goal of carbon neutrality. Full article

The therapeutic landscape for metastatic renal cell carcinoma has rapidly evolved over the years, and we are now in an era of combination therapy strategies employing immune checkpoint blockade and anti-angiogenesis targeted therapy. Since 2018, we have gained regulatory approval for four distinct combination therapies, all with survival benefits, and with guideline recommendation for use in the front-line setting. As such, treatment selection has become increasingly complex with a myriad of treatment choices but little high-level head-to-head data to guide treatment selection. Heterogeneity in tumor biology further complicates treatment selection as tumors vary in behavior and treatment responsiveness. Ongoing development of biomarkers will certainly assist in this setting, and validation of predictive markers represents an unmet need. In their absence, we highlight features of disease and nuances to datasets from landmark prospective clinical trials to help inform treatment selection. There is growing evidence to support deferring upfront systemic therapy in some patients, with opportunities for active surveillance or metastasis-directed therapy. In others, upfront systemic therapy is warranted and necessitates thoughtful consideration of multiple clinicopathologic parameters to inform optimal patient-centered decision making. Full article

Excessive average daily pork intake of Chinese residents increases the risk of obesity and related chronic diseases. Understanding consumers’ preference for the Front-of-Package (FOP) labeling on fresh pork is of practical significance for designing an FOP labeling scheme that meets market demand and effectively guides moderate pork consumption. This study used the conditional logit model to reveal the stated preferences of 930 nationally representative respondents in China for FOP labeling attributes elicited by a choice experiment approach. The results indicated that respondents preferred the nutritional information to be printed in Chinese characters, the label size to be a quarter of the front package surface, the label color to be green, and the label price to account for 10% of the retail price of 500 g standard fresh pork. Moreover, these preferences were heterogeneous across the sample population due to respondents’ different levels of education and trust in labeling. People with primary and junior high school education preferred nutritional information in Chinese characters, while those with junior high education and above preferred green labeling. The higher the respondents’ trust in the labeling, the stronger their willingness to accept the appropriate FOP labeling price. Information campaigns and educational programs can be used to increase the acceptance of FOP labelling, particularly among consumers with low education levels and distrust of FOP labeling. Full article

Accessibility to transportation is a crucial factor for economic growth. Transportation land, defined as the land used to support transportation infrastructure, such as city and inter-city rail, ports, and air travel, is a critical element for constructing transportation facilities and has attracted increasing attention from researchers and policy makers. Transportation land transfer (TLT) is defined as the act by which the state transfers transportation land-use rights to a land user (collective or individual) within a certain period of time as the land owner (all land in China is owned by the state). The land user pays a land-use right transfer fee to the state. This article first reveals the multidimensional effect between TLT and economic growth based on data from China’s 30 provinces for 2007–2019. The study found the following. (1) A continuous increase in the availability of transportation land is vital to ensure sustainable economic growth, and the construction of transportation land between adjacent areas has positive spatial spillover effects. (2) These positive effects work through three mechanisms, i.e., increased employment, industrial interactions, and improvements in economic operational efficiency, with a time lag. (3) The positive effects of TLT on economic growth have significant heterogeneous moderating effects on the differences in the economic development stage, the level of industrial structure, and urbanization rate. The study expands the front-end to back-end analysis of land use, provides a reference for countries and regions at different stages of development to promote economic growth using transportation land construction, and presents beneficial insights for governments to efficiently avoid the mismatch of transportation land resources. Full article

In this paper, a three-dimensional heterogenous-integrated (3DHI) wafer-level packaging (WLP) process is proposed, and a radio frequency (RF) front-end module with two independent ultra-high frequency (UHF) receiving channels are designed and implemented, which covers 400 MHz–600 MHz and 2050 MHz–2200 MHz respectively for unmanned aerial vehicle (UAV) applications. The module is formed by wafer-to-wafer (W2W) bonding of two high-resistivity silicon (HR-Si) interposers with embedded bare dies and through silicon via (TSV) interconnections. Double-sided deep reactive ion etching (DRIE) and conformal electroplating process are introduced to realize the high-aspect-ratio TSV connection within 290 µm-thick cap interposer. Co-plane waveguide (CPW) transmission lines are fabricated as the process control monitor (PCM), the measured insertion loss of which is less than 0.18 dB/mm at 35 GHz. The designed RF front-end module is fabricated and measured. The measured return loss and gain of each RF channel is better than 13 dB and 21 dB, and the noise figure is less than 1.5 dB. In order to evaluate the capability of the 3DHI process for multi-layer interposers, the module is re-designed and fabricated with four stacked high-resistivity silicon interposers. After W2W bonding of two pairs of interposers and wafer slicing, chip-to chip (C2C) bonding is applied to form a four-layer module with operable temperature gradient. Full article

Grain growth is a well-known and complex phenomenon occurring during annealing of all polycrystalline materials. Its numerical modeling is a complex task when anisotropy sources such as grain orientation and grain boundary inclination have to be taken into account. This article presents the application of a front-tracking methodology to the context of anisotropic grain boundary motion at the mesoscopic scale. The new formulation of boundary migration can take into account any source of anisotropy both at grain boundaries as well as at multiple junctions (MJs) (intersection point of three or more grain boundaries). Special attention is given to the decomposition of high-order MJs for which an algorithm is proposed based on local grain boundary energy minimisation. Numerical tests are provided using highly heterogeneous configurations, and comparisons with a recently developed Finite-Element Level-Set (FE-LS) approach are given. Finally, the computational performance of the model will be studied comparing the CPU-times obtained with the same model but in an isotropic context. Full article

Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line. Full article

The lopolithic Pados-Tundra layered complex, the largest member of the Serpentinite belt–Tulppio belt (SB–TB) megastructure in the Fennoscandian Shield, is characterized by (1) highly magnesian compositions of comagmatic dunite–harzburgite–orthopyroxenite, with primitive levels of high-field-strength elements; (2) maximum values of Mg# in olivine (Ol, 93.3) and chromian spinel (Chr, 57.0) in the Dunite block (DB), which exceed those in Ol (91.7) and Chr (42.5) in the sills at Chapesvara, and (3) the presence of major contact-style chromite–IPGE-enriched zones hosted by the DB. A single batch of primitive, Al-undepleted komatiitic magma crystallized normally as dunite close to the outer contact, then toward the center. A similar magma gave rise to Chapesvara and other suites of the SB–TB megastructure. Crystallization proceeded from the early Ol + Chr cumulates to the later Ol–Opx and Opx cumulates with accessory Chr in the Orthopyroxenite zone. The accumulation of Chr resulted from efficient cooling along boundaries of the Dunite block. The inferred front of crystallization advanced along a path traced by vectors of Ol and Chr compositions. Grains and aggregates of Chr were mainly deposited early after the massive crystallization of olivine. Chromium, Al, Zn and H₂O, all incompatible in Ol, accumulated to produce podiform segregations or veins of chromitites. This occurred episodically along the moving front of crystallization. Crystallization occurred rapidly owing to heat loss at the contact and to a shallow level of emplacement. The Chr layers are not continuous but rather heterogeneously distributed pods or veins of Chr–Ol–clinochlore segregations. Isolated portions of melt enriched in H₂O and ore constituents accumulated during crystallization of Ol. Levels of fO₂ in the melt and, consequently, the content of ferric iron in Chr, increased progressively, as in other intrusions of the SB–TB megastructure. The komatiitic magma vesiculated intensely, which led to a progressive loss of H₂ and buildup in fO₂. In turn, this led to the appearance of anomalous Chr–Ilm parageneses. Diffuse rims of Chr grains, abundant in the DB, contain elevated levels of Fe³⁺ and enrichments in Ni and Mn. In contrast, Zn is preferentially partitioned into the core, leading to a decoupling of Zn from Mn, also known at Chapesvara. The sulfide species display a pronounced Ni-(Co) enrichment in assemblages of cobaltiferous pentlandite, millerite (and heazlewoodite at Khanlauta), deposited at ≤630 °C. The oxidizing conditions have promoted the formation of sulfoselenide phases of Ru in the chromitites. The attainment of high degrees of oxidation during crystallization of a primitive parental komatiitic magma accounts for the key characteristics of Pados-Tundra and related suites of the SB–TB megastructure. Full article