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ABSTRACT Candida auris is a yeast pathogen causing nosocomial outbreaks of candidemia. Its ability to adhere to inert surfaces and to be transmitted from one patient to another via medical devices is of particular concern. Like other Candida spp., C. auris has the ability to transition from the yeast form to pseudohyphae and to build biofilms. Moreover, some isolates have a unique capacity to form aggregates. These morphogenetic changes may impact virulence. In this study, we demonstrated the role of the transcription factor Ume6 in C. auris morphogenesis. Genetic hyperactivation of Ume6 induced filamentation and aggregation. The Ume6-hyperactivated strain (UME6HA) also exhibited increased adhesion to inert surface and formed biofilms of higher biomass compared to the parental strain. Transcriptomic analyses of UME6HA revealed enrichment of genes encoding for adhesins, proteins involved in cell wall organization, sterol biosynthesis, and aspartic protease activities. The three most upregulated genes compared to wild-type were those encoding for the agglutin-like sequence adhesin Als4498, the C. auris-specific adhesin Scf1, and the hypha-specific G1 cyclin-related protein Hgc1. The deletion of these genes in the UME6HA background showed that Ume6 controls filamentation via Hgc1 and aggregation via Als4498 and Scf1. Adhesion to inert surface was essentially triggered by Scf1. However, Als4498 and Hgc1 were also crucial for biofilm formation. Our data show that Ume6 is a universal regulator of C. auris morphogenesis via distinct modulators.IMPORTANCEC. auris represents a public health threat because of its ability to cause difficult-to-treat infections and hospital outbreaks. The morphogenetic plasticity of C. auris, including its ability to filament, to form aggregates or biofilms on inert surfaces, is important to the fungus for interhuman transmission, skin or catheter colonization, tissue invasion, antifungal resistance, and escape of the host immune system. This work deciphered the importance of Ume6 in the control of distinct pathways involved in filamentation, aggregation, adhesion, and biofilm formation of C. auris. A better understanding of the mechanisms of C. auris morphogenesis may help identify novel antifungal targets.

Abstract A virus infection can be initiated with very few or even a single infectious virion, and as such can become extinct, i.e. stochastically fail to take hold or spread significantly. There are many ways that a fully competent infectious virion, having successfully entered a cell, can fail to cause a productive infection, i.e. one that yields infectious virus progeny. Though many stochastic models (SMs) have been developed and used to estimate a virus infection’s establishment probability, these typically neglect infection failure post virus entry. The SM presented herein introduces parameter $$\gamma \in (0,1]$$ γ ∈ ( 0 , 1 ] which corresponds to the probability that a virion’s entry into a cell will result in a productive cell infection. We derive an expression for the likelihood of infection establishment in this new SM, and find that prophylactic therapy with an antiviral reducing $$\gamma$$ γ is at least as good or better at decreasing the establishment probability, compared to antivirals reducing the rates of virus production or virus entry into cells, irrespective of the SM parameters. We investigate the difference in the fraction of cells consumed by so-called extinct versus established virus infections, and find that this distinction becomes biologically meaningless as the probability of establishment approaches zero. We explain why the release of virions continuously over an infectious cell’s lifespan, rather than as a single burst at the end of the cell’s lifespan, does not result in an increased risk of infection extinction. We show, instead, that the number of virus released, not the timing of the release, affects infection establishment and associated critical antiviral efficacy.

ABSTRACTCandida auris is an emerging yeast pathogen of major concern because of its ability to cause hospital outbreaks of invasive candidiasis and to develop resistance to antifungal drugs. A majority of C. auris isolates are resistant to fluconazole, an azole drug used for the treatment of invasive candidiasis. Mechanisms of azole resistance are multiple, including mutations in the target gene ERG11 and activation of the transcription factors Tac1b and Mrr1, which control the drug transporters Cdr1 and Mdr1, respectively. We investigated the role of the transcription factor Upc2, which is known to regulate the ergosterol biosynthesis pathway and azole resistance in other Candida spp. Genetic deletion and hyperactivation of Upc2 by epitope tagging in C. auris resulted in drastic increases and decreases in susceptibility to azoles, respectively. This effect was conserved in strains with genetic hyperactivation of Tac1b or Mrr1. Reverse transcription PCR analyses showed that Upc2 regulates ERG11 expression and also activates the Mrr1/Mdr1 pathway. We showed that upregulation of MDR1 by Upc2 could occur independently from Mrr1. The impact of UPC2 deletion on MDR1 expression and azole susceptibility in a hyperactive Mrr1 background was stronger than that of MRR1 deletion in a hyperactive Upc2 background. While Upc2 hyperactivation resulted in a significant increase in the expression of TAC1b, CDR1 expression remained unchanged. Taken together, our results showed that Upc2 is crucial for azole resistance in C. auris, via regulation of the ergosterol biosynthesis pathway and activation of the Mrr1/Mdr1 pathway. Notably, Upc2 is a very potent and direct activator of Mdr1.IMPORTANCECandida auris is a yeast of major medical importance causing nosocomial outbreaks of invasive candidiasis. Its ability to develop resistance to antifungal drugs, in particular to azoles (e.g., fluconazole), is concerning. Understanding the mechanisms of azole resistance in C. auris is important and may help in identifying novel antifungal targets. This study shows the key role of the transcription factor Upc2 in azole resistance of C. auris and shows that this effect is mediated via different pathways, including the regulation of ergosterol biosynthesis and also the direct upregulation of the drug transporter Mdr1.

In order to accurately monitor the fuel consumption of hybrid diesel engine, a new key technology for monitoring abnormal fuel consumption of hybrid diesel engine was proposed. According to the structure of the hybrid diesel engine, the data sampling interval is set to collect information and synthesize the driving conditions of the hybrid diesel engine under different working conditions. The equivalent relationship between fuel consumption and electric energy of hybrid diesel engine is established, the equivalent fuel consumption rate of hybrid diesel engine is calculated, and the distribution power of diesel engine and motor is determined according to the abnormal fuel consumption value, and the instantaneous fuel consumption of hybrid diesel engine is obtained. On this basis, the output power sequence of APU and battery is analyzed, and the abnormal fuel consumption of hybrid diesel engine is monitored. The experimental results show that compared with the traditional fuel consumption monitoring technology, this technology can accurately detect the abnormal fuel consumption of hybrid diesel engine, and the energy recovery rate is high.

Summary: With the rapid emergence and spread of SARS-CoV-2 variants, development of vaccines with broad and potent protectivity has become a global priority. Here, we designed a lipid nanoparticle-encapsulated, nucleoside-unmodified mRNA (mRNA-LNP) vaccine encoding the trimerized receptor-binding domain (RBD trimer) and showed its robust capability in inducing broad and protective immune responses against wild-type and major variants of concern (VOCs) in the mouse model of SARS-CoV-2 infection. The protectivity was correlated with RBD-specific B cell responses especially the long-lived plasma B cells in bone marrow, strong ability in triggering BCR clustering, and downstream signaling. Monoclonal antibodies isolated from vaccinated animals demonstrated broad and potent neutralizing activity against VOCs tested. Structure analysis of one representative antibody identified a novel epitope with a high degree of conservation among different variants. Collectively, these results demonstrate that the RBD trimer mRNA vaccine serves as a promising vaccine candidate against SARS-CoV-2 variants and beyond.

Developing understanding of degradation phenomena in nickel rich cathodes is under intense investigation. Here the authors use learning-assisted statistical analysis and experiment-informed mathematical modelling to resolve the microstructure of a Ni-rich NMC composite cathode.

Summary: The electrification revolution in the automobile and other industries demands annual production capacity of batteries of at least 102 GWh, which presents a twofold challenge: supply of key materials such as cobalt and nickel and recycling when batteries are retired from use. Pyrometallurgical and hydrometallurgical recycling are currently used in industry but suffer from complexity, high costs, and secondary pollution. Here we report a molten-salt-based method for direct recycling (MSDR) that is environmentally benign and creates value on the basis of a techno-economic analysis using real-world data and price information. We also experimentally demonstrate the feasibility of MSDR by upcycling a low-nickel polycrystalline LiNi0.5Mn0.3Co0.2O2 (NMC) cathode material into Ni-rich (Ni > 65%) single-crystal NMCs with increased energy density (>10% increase) and outstanding electrochemical performance (>94% capacity retention after 500 cycles). This work may open opportunities for closed-loop recycling of electric vehicle batteries and manufacturing of next-generation NMC cathode materials.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge and spread around the world, antibodies and vaccines to confer broad and potent neutralizing activity are urgently needed. Through the isolation and characterization of monoclonal antibodies (mAbs) from individuals infected with SARS-CoV-2, we identified one antibody, P36-5D2, capable of neutralizing the major SARS-CoV-2 variants of concern. Crystal and electron cryo-microscopy (cryo-EM) structure analyses revealed that P36-5D2 targeted to a conserved epitope on the receptor-binding domain of the spike protein, withstanding the three key mutations—K417N, E484K, and N501Y—found in the variants that are responsible for escape from many potent neutralizing mAbs, including some already approved for emergency use authorization (EUA). A single intraperitoneal (IP) injection of P36-5D2 as a prophylactic treatment completely protected animals from challenge of infectious SARS-CoV-2 Alpha and Beta. Treated animals manifested normal body weight and were devoid of infection-associated death up to 14 days. A substantial decrease of the infectious virus in the lungs and brain, as well as reduced lung pathology, was found in these animals compared to the controls. Thus, P36-5D2 represents a new and desirable human antibody against the current and emerging SARS-CoV-2 variants.

ABSTRACT Candida auris is an emerging yeast pathogen of candidemia with the ability to develop resistance to all current antifungal drug classes. Novel antifungal therapies against C. auris are warranted. NSC319726 is a thiosemicarbazone with an inhibitory effect on fungal ribosome biogenesis that has demonstrated some antifungal activity. In this study, we assessed the in vitro activity and in vivo efficacy of NSC319726 against C. auris. NSC319726 was active in vitro against 22 C. auris isolates from different clades, with MICs ranging from 0.125 to 0.25 mg/liter. Despite complete visual growth inhibition, the effect was described as fungistatic in time-kill curves. Interactions with fluconazole, amphotericin B, and micafungin, as tested by the checkerboard dilution method, were described as indifferent. NSC319726 demonstrated significant effects in rescuing G. mellonella larvae infected with two distinct C. auris isolates, compared to the untreated group. In conclusion, NSC319726 demonstrated in vitro activity against C. auris and in vivo efficacy in an invertebrate model of infection. Its potential role as a novel antifungal therapy in humans should be further investigated. IMPORTANCE Candida auris is emerging as a major public health threat because of its ability to cause nosocomial outbreaks of severe invasive candidiasis. Management of C. auris infection is difficult because of its frequent multidrug-resistant profile for currently licensed antifungals. Here, we show that the thiosemicarbazone NSC319726 was active in vitro against a large collection of C. auris isolates from different clades. Moreover, the drug was well tolerated and effective for the treatment of C. auris infection in an invertebrate model of Galleria mellonella. We conclude that NSC319726 might represent an interesting drug candidate for the treatment of C. auris infection.

Summary: The manufacturing of commercial lithium-ion batteries (LIBs) involves a number of sophisticated production processes. Various cell defects can be induced, and, depending on their structural and chemical characteristics, they could lead to acute failure and/or chronic degradation. Although tremendous efforts have been devoted to develop a robust quality control (QC) procedure, the functional role of the cell defects is not well understood. Here, we address this question through a systematic experimental study of commercial 18650-type LIBs that have failed the QC inspection due to a self-discharging effect. We identify and recover the defective regions from the cell and conduct a comprehensive investigation from the chemical, structural, and morphological perspectives. Our results reveal how the structural defects affect the cell performance, which is highly important to industry-scale battery production.

ABSTRACT Fungal cell wall mannans are complex carbohydrate polysaccharides with different structures in yeasts and molds. In contrast to yeasts, their biosynthetic pathway has been poorly investigated in filamentous fungi. In Aspergillus fumigatus, the major mannan structure is a galactomannan that is cross-linked to the β-1,3-glucan-chitin cell wall core. This polymer is composed of a linear mannan with a repeating unit composed of four α1,6-linked and α1,2-linked mannoses with side chains of galactofuran. Despite its use as a biomarker to diagnose invasive aspergillosis, its biosynthesis and biological function were unknown. Here, we have investigated the function of three members of the Ktr (also named Kre2/Mnt1) family (Ktr1, Ktr4, and Ktr7) in A. fumigatus and show that two of them are required for the biosynthesis of galactomannan. In particular, we describe a newly discovered form of α-1,2-mannosyltransferase activity encoded by the KTR4 gene. Biochemical analyses showed that deletion of the KTR4 gene or the KTR7 gene leads to the absence of cell wall galactomannan. In comparison to parental strains, the Δktr4 and Δktr7 mutants showed a severe growth phenotype with defects in polarized growth and in conidiation, marked alteration of the conidial viability, and reduced virulence in a mouse model of invasive aspergillosis. In yeast, the KTR proteins are involved in protein 0- and N-glycosylation. This study provided another confirmation that orthologous genes can code for proteins that have very different biological functions in yeasts and filamentous fungi. Moreover, in A. fumigatus, cell wall mannans are as important structurally as β-glucans and chitin. IMPORTANCE The fungal cell wall is a complex and dynamic entity essential for the development of fungi. It allows fungal pathogens to survive environmental challenge posed by nutrient stress and host defenses, and it also is central to polarized growth. The cell wall is mainly composed of polysaccharides organized in a three-dimensional network. Aspergillus fumigatus produces a cell wall galactomannan whose biosynthetic pathway and biological functions remain poorly defined. Here, we described two new mannosyltransferases essential to the synthesis of the cell wall galactomannan. Their absence leads to a growth defect with misregulation of polarization and altered conidiation, with conidia which are bigger and more permeable than the conidia of the parental strain. This study showed that in spite of its low concentration in the cell wall, this polysaccharide is absolutely required for cell wall stability, for apical growth, and for the full virulence of A. fumigatus.

Thin, flexible silicon crystals are starting up applications such as light-weighted flexible solar cells, SOI, flexible IC chips, 3D ICs imagers and 3D CMOS imagers on the demand of high performance with low cost. Kerfless wafering technology by direct conversion of source gases into mono-crystalline wafers on reusable substrates is highly cost-effective and feedstock-effective route to cheap wafers with the thickness down to several microns. Here we show a prototype for direct conversion of silicon source gases to wafers by using the substrate with protruded seeds. A reliable and controllable method of wafer-scaled preparation of protruded seed patterns has been developed by filling liquid wax into a rod array as the mask for the selective removal of oxide layer on the rod head. Selectively epitaxial growth is performed on the protruded seeds, and the voidless film is formed by the merging of neighboring seeds through growing. And structured hollows are formed between the grown film and the substrate, which would offer the transferability of the grown film and the reusability of the protruded seeds.

Glycosylphosphatidylinositols (GPIs) are lipid anchors allowing the exposure of proteins at the outer layer of the plasma membrane. In fungi, a number of GPI-anchored proteins (GPI-APs) are involved in the remodeling of the cell wall polymers. GPIs follow a specific biosynthetic pathway in the endoplasmic reticulum. After the transfer of the protein onto the GPI-anchor, a lipid remodeling occurs to substitute the diacylglycerol moiety by a ceramide. In addition to GPI-APs, A. fumigatus produces a GPI-anchored polysaccharide, the galactomannan (GM), that remains unique in the fungal kingdom. To investigate the role of the GPI pathway in the biosynthesis of the GM and cell wall organization, the deletion of PER1—coding for a phospholipase required for the first step of the GPI lipid remodeling—was undertaken. Biochemical characterization of the GPI-anchor isolated from GPI-APs showed that the PER1 deficient mutant produced a lipid anchor with a diacylglycerol. The absence of a ceramide on GPI-anchors in the Δper1 mutant led to a mislocation of GPI-APs and to an alteration of the composition of the cell wall alkali-insoluble fraction. On the other hand, the GM isolated from the Δper1 mutant membranes possesses a ceramide moiety as the parental strain, showing that GPI anchor of the GM follow a distinct unknown biosynthetic pathway.

High-resolution imaging with compositional and chemical sensitivity is crucial for a wide range of scientific and engineering disciplines. Although synchrotron X-ray imaging through spectromicroscopy has been tremendously successful and broadly applied, it encounters challenges in achieving enhanced detection sensitivity, satisfactory spatial resolution, and high experimental throughput simultaneously. In this work, based on structured illumination, we develop a single-pixel X-ray imaging approach coupled with a generative image reconstruction model for mapping the compositional heterogeneity with nanoscale resolvability. This method integrates a full-field transmission X-ray microscope with an X-ray fluorescence detector and eliminates the need for nanoscale X-ray focusing and raster scanning. We experimentally demonstrate the effectiveness of our approach by imaging a battery sample composed of mixed cathode materials and successfully retrieving the compositional variations of the imaged cathode particles. Bridging the gap between structural and chemical characterizations using X-rays, this technique opens up vast opportunities in the fields of biology, environmental, and materials science, especially for radiation-sensitive samples. [ABSTRACT FROM AUTHOR]

Spatial transcriptomics technology has revolutionized our understanding of cell types and tissue organization, opening possibilities for researchers to explore transcript distributions at subcellular levels. However, existing methods have limitations in resolution, sensitivity, or speed. To overcome these challenges, we introduce SPRINTseq (Spatially Resolved and signal-diluted Next-generation Targeted sequencing), an innovative in situ sequencing strategy that combines hybrid block coding and molecular dilution strategies. Our method enables fast and sensitive high-resolution data acquisition, as demonstrated by recovering over 142 million transcripts using a 108-gene panel from 453,843 cells from four mouse brain coronal slices in less than 2 d. Using this advanced technology, we uncover the cellular and subcellular molecular architecture of Alzheimer's disease, providing additional information into abnormal cellular behaviors and their subcellular mRNA distribution. This improved spatial transcriptomics technology holds great promise for exploring complex biological processes and disease mechanisms. [ABSTRACT FROM AUTHOR]

This study proposes a model for simulating the dynamics of electric bicycle flow in isolated non-motorized lanes. The model is an extension of the conventional social force model with an additional rotational degree of freedom that describes the steering angle of electric bicycles. In this model, two corrective relaxation terms are included in the driving force for the rotational degree of freedom: one on the steering angle and another on the angular velocity. Stability analysis shows that an appropriate amount of correction on the angular velocity helps to avoid oscillation and overshoots of the turning angle. The proposed model is validated both macroscopically and microscopically, and the agreement of the simulated fundamental diagram with that in the literature demonstrates the rationality of the model in characterizing the collective motions of electric bicycles. Comparison of simulated and observed trajectories confirms that the proposed model could reproduce electric bicycle motions with a certain accuracy at the microscopic level. Finally, predictions based on the validated model are provided. According to the simulation results, congestion starts to occur when the inlet flow rate of the lane reaches 1500–1750 ebike/h/m. For a mixed configuration, the maximum allowed flow rate in the lane is 2350–2400 ebike/h/m, and this value depends on the proportion of fast electric bicycles and the riding style in the flow.

This paper proposes and validates the application of a two-dimensional Social Force Model to simulate the lane-disciplined vehicular flow on roads. In detail, a lane-wise lane-keeping force field is established along the lateral direction of the road. This force, with a magnitude quadratic to the lateral displacement of the vehicle to the lane centerline, confines the lateral movement of the vehicle to form a laned pattern on the road. To realize the overtaking maneuvers and avoid collisions, the distance-dependent overtaking force and repulsive forces are also defined in the model. The parameters in the proposed model are calibrated by comparing with the fundamental diagram collected in the literature (GA400 dataset). The comparison shows that the proposed model could provide a good prediction in terms of average speed and speed range up to 80 veh/km/lane. However, for very high-density flows, the model is likely to overpredict the flow speed, possibly owing to a fixed target speed in the model. After the validation step, the model is employed to simulate traffic flows on a segment of 4-lane freeway in Nanjing, China. The comparison of the simulated and measured trajectories demonstrates that, except for very abnormal behaviors, the proposed model could predict most car-following and lane-changing behaviors based on relative velocity and inter-vehicle gaps at the microscopic level.

Lithium-ion battery (LIB) is a broadly adopted technology for energy storage. With increasing demands to improve the rate capability, cyclability, energy density, safety, and cost efficiency, it is crucial to establish an in-depth understanding of the detailed structural evolution and cell-degradation mechanisms during battery operation. Here, we present a laboratory-based high-resolution and high-throughput X-ray micro-computed laminography approach, which is capable of in situ visualizing of an industry-relevant lithium-ion (Li-ion) pouch cell with superior detection fidelity, resolution, and reliability. This technique enables imaging of the pouch cell at a spatial resolution of 0.5 µm in a laboratory system and permits the identification of submicron features within cathode and anode electrodes. We also demonstrate direct visualization of the lithium plating in the imaged pouch cell, which is an important phenomenon relevant to battery fast charging and low-temperature cycling. Our development presents an avenue toward a thorough understanding of the correlation among multiscale structures, chemomechanical degradation, and electrochemical behavior of industry-scale battery pouch cells. [ABSTRACT FROM AUTHOR]

Air-gap eccentricity is one of the common faults of typical rotating machine, which results in a dynamic instability state of multi-physical fields. To investigate the muti-physical instabilities of rotating machine under air–gap eccentricity fault, combining numerical and experimental methods were applied. The electromagnetism simulations were conducted to calculate magnetic flux density and unbalanced magnetic pull. The signal acquisition including magnetic flux density, vibration acceleration, and pressure fluctuation were conducted to muti-physical coupling experiment. The modulation characteristics caused by air–gap eccentricity were extracted with a signal demodulation method based on principle component analysis. The results indicate that modulation effects of the rotating frequency (fs) and twice the rotating frequency (2 fs) generated by the magnetic field were transmitted to the structure field and flow field. In the demodulation results of pressure pulsation, the modulation effect of blade passing frequency near the pump inlet was enhanced. Correlations between the instability of magnetic field, structure field, and flow field are determined to develop monitoring, detection, and diagnosis for rotating machine system, while the modulation characteristics of muti-physical field signals can serve as indicators of instabilities.

Rationale: Alteration of human respiratory microbiota had been observed in coronavirus disease (COVID-19). How the microbiota is associated with the prognosis in COVID-19 is unclear. Objectives: To characterize the feature and dynamics of the respiratory microbiota and its associations with clinical features in patients with COVID-19. Methods: We conducted metatranscriptome sequencing on 588 longitudinal oropharyngeal swab specimens collected from 192 patients with COVID-19 (including 39 deceased patients) and 95 healthy controls from the same geographic area. Meanwhile, the concentration of 27 cytokines and chemokines in plasma was measured for patients with COVID-19. Measurements and Main Results: The upper respiratory tract (URT) microbiota in patients with COVID-19 differed from that in healthy controls, whereas deceased patients possessed a more distinct microbiota, both on admission and before discharge/death. The alteration of URT microbiota showed a significant correlation with the concentration of proinflammatory cytokines and mortality. Specifically, Streptococcus-dominated microbiota was enriched in recovered patients, and showed high temporal stability and resistance against pathogens. In contrast, the microbiota in deceased patients was more susceptible to secondary infections and became more deviated from the norm after admission. Moreover, the abundance of S. parasanguinis on admission was significantly correlated with prognosis in nonsevere patients (lower vs. higher abundance, odds ratio, 7.80; 95% CI, 1.70--42.05). Conclusions: URT microbiota dysbiosis is a remarkable manifestation of COVID-19; its association with mortality suggests it may reflect the interplay between pathogens, symbionts, and the host immune status. Whether URT microbiota could be used as a biomarker for diagnosis and prognosis of respiratory diseases merits further investigation. [ABSTRACT FROM AUTHOR]

Background and aimLithium is considered to be the first-line treatment for bipolar disorder, and paliperidone was approved for the treatment of schizophrenia and acute bipolar manic/mixed episodes. However, both agents have been associated with thyroid dysfunction and cardiovascular adverse effects like subclinical hypothyroidism, bradycardia, and sinus arrest, even at therapeutic doses.Case presentationHere, we reported a case of a 17-year-old Han Chinese female who developed symptomatic hypothyroidism, sinus bradycardia, and sinus arrest while being treated with lithium and paliperidone for bipolar disorder with psychotic features including auditory hallucinations. Her workup suggested that these adverse effects might be related to the combined lithium and paliperidone treatment, although other causes could not be ruled out. After discontinuing both medications, her thyroid function and heart rhythm normalized over 20 days.ConclusionTo our knowledge, hypothyroidism, sinus bradycardia, and sinus arrest associated with the combined use of lithium and paliperidone had not been reported previously. Further research is warranted to elucidate the potential risks and benefits of this combination therapy for bipolar disorder with psychotic symptoms.

Microchannel heat sinks play a crucial role in dissipating heat in microelectronic systems in computer data centers. To enhance their thermal performance, this study proposes a combined microchannel design consisting of various cavity shapes and straight ribs, and analyzes its heat transfer and flow performance through numerical simulation. The heat transfer characteristics of microchannel heat sink with different straight rib structures are compared. Moreover, the four parameters including the relative length (α), relative width of the cavity (β), relative length of straight ribs (γ) and relative width of straight ribs (λ) are investigated, and the effects of Reynolds number variation on heat sink Nusselt number (Nu), friction coefficient (f) and thermal enhancement efficiency (η) are studied. The optimization process employs an artificial neural network and a multi-objective genetic algorithm to determine the optimal compromise solution and heat sink model, utilizing the Nusselt number and friction coefficient as evaluation indices. The results show that rectangular rounded straight rib is the straight rib structures with the best comprehensive thermal performance, with an average η approximately 9.7 % higher than that of the non-straight ribbed heat sink model. Furthermore, the variation in the four studied parameters yields distinct effects on the Nusselt number, friction coefficient, and thermal enhancement efficiency. Notably, the optimal performance is achieved when Nu = 13.59679 and f = 0.11855, with corresponding parameter values of α = 0.1575, β = 0.3931, γ = 0.0714, and λ = 1.2149. Ultimately, these results provide valuable insights into the structural optimization of microchannel heat sink cavity and straight rib combination models.

The overall research methods were applied to understand geochemical partition process and assess ecological risk of heavy metals in river network in Changjiang River Delta. The type of river water was identified as Ca-HCO3, due to Ca2+ and HCO3· accounting for ~40% of cation and anion, respectively. All heavy metals except Cd in most river water samples were below standard and 22.6% of Cd in samples were at contaminated level. Cd was the most mobilizing metal with more than 50% of weak-acid extractable fraction in sediment. Hierarchical cluster analysis and PCA results showed that water Pb and Cr concentration in rivers were influenced by pH while As and Cd could be associated with dissolved organic matter., Speciation of As and Cd were associated with organic matter except for the residual fraction. Speciation distribution of Cr, Pb and Hg were mainly influenced by iron oxides and clay minerals. Results of multivariable linear regression showed that partition of As, Cr and Pb were mainly influenced by iron oxides and clay minerals, Hg partition was controlled by pH while Cd partition could be related to fine particle. In overall ecological risk assessment, As was thought as the biggest polluted factor for water, due to contributing 52.37% of total hazard quotient (THQ)(>1) and 65.49% of carcinogenic risk (RISK) which was at unacceptable level in 82.26% of samples. Human health risk assessment for water samples results showed that almost all HQ values of individual metal were below 1. And 37.10% of THQ was above 1, which indicated that a potential adverse non-carcinogenic risk in sediment caused by heavy metals. Arsenic and Pb were the biggest two contributors with accounting for 52.37% and 46.82% of THQ respectively. For carcinogenic risk, 64.52% of As and 22.58% of Cr fell into unacceptable level. Cd and Pb in all samples were under the acceptable level. Arsenic and Cr accounted for 65.49% and 32.37% of 9708 total RISK. RISK in 82.26% of samples was unacceptable. This implied As and Cr had great carcinogenic risk to human health through drinking water. Totally, As was the main pollution factor in river network in Changjiang River Delta with the biggest health risk potentially through water drinking. Ecological contamination index (ECI) showed sediment Cr and Pb possessed great ecological risk. [ABSTRACT FROM AUTHOR]

Abstract Background Immune checkpoint inhibitors (ICIs) have elicited durable antitumor responses in multiple types of cancers. However, ICIs could also induce potential toxicities that involve all organs, including renal system. In this study, we aimed to conduct a comprehensive description of the ICIs‐induced renal toxicities and the potential effects of chemotherapy. Methods We conducted a pharmacovigilance study based on US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database between 01 January 2014 and 30 June 2019. Disproportionality analysis was used to assess the association between ICIs and renal adverse events (AEs), including reporting odds ratio (ROR) and information component (IC). ROR025 and IC025 are, respectively, 95% confidence interval lower end of ROR and IC. If the value of ROR025 exceeding one or IC025 higher than zero, then a signal was considered statistically significant. Results A total of 30,602,758 reports were extracted from the database, with 4578 reports for ICIs‐associated renal AEs. Renal AEs were more frequently reported in anti‐PD‐1/PD‐L1 versus anti‐CTLA‐4 monotherapy group (ROR: 1.75, 95% CI: 1.52–2.01). Similarly, renal AEs were more commonly reported in ICIs polytherapy other than monotherapy group (ROR: 1.18, 95% CI: 1.10–1.27). Notably, ICIs plus chemotherapy strategies reported more renal toxicities compared to sole ICIs regimens (ROR: 1.30, 95% CI: 1.17–1.45), whereas exhibited lower fatality outcome rates. Importantly, acute kidney injury (1139, 24.88%) and renal failure (464, 10.14%) were the top two most commonly reported ICIs‐associated renal AEs, and also observed with the top two highest level of fatality outcome rates. Conclusions A spectrum of renal AEs was detected in ICIs regimens and could be reinforced by ICIs combination. Compared to sole ICIs regimens, ICIs plus chemotherapy strategy reported more renal toxicities but lower fatality outcome rates. With the increasing popularity of ICIs especially combination strategies, it is vital important for clinicians to guarantee balance between durable clinical effects and potential renal toxicities in latest immunotherapy strategies.

Diffuse reflectance visible and near infrared spectroscopy (Vis/NIR) was applied to screen the heavy metals (As, Cd, Cr, Cu, Hg, Pb and Zn) in suspended solids collected from the Changjiang River Delta. Principal component analysis (PCA) was used to characterized the spectra data of samples. The reflectance of the spectra and variation trends of spectra reflectance were distinguished by the first two principal components. The samples in Jiangsu Province had lower reflectance than those in Zhejiang, with smooth increase of reflectance in 400-800 nm spectra region. Using selected spectra region (410-2408 nm), the Partial-least square (PLS) regression models were applied to screen As, Cd, Cr, Cu, Hg and Pb in sediment, while Hierarchical principal components analysis (HPCA) regression was used only for Zn. The optimal factor and spectra region were obtained for selected models by comparing different pre-processing procedures. Results showed that potential change of hydraulic condition could degrade prediction ability of spectroscopy for heavy metals. Although the correlation coefficients and residual predictive deviation (RPD) displayed relative poor prediction results, the PLS and HPCA models of spectroscopy are useful non-destructive tools to screen heavy metals in sediment in Changjiang River Delta. [ABSTRACT FROM AUTHOR]

Minjiang estuary is located on the Taiwan Channel which receives industrial and agricultural effluents. Samples including sediments (n=30), water (n=10) and marine species (n=10) were collected from this bay. HCHs (hexachlorocyclohexanes) and DDTs (dichloro-diphenyl-trichloroethanes) were tested using GCECD. In sediments, the concentration of HCHs was 0.1-3.59ng/g and the concentration of DDTs was 1.56-81.68ng/g. The concentration ranges of HCHs and DDTs in sea water were 1.31-9.96ng/L and 0.78-6.51ng/L, respectively. And the concentration ranged of HCHs and DDTs in land surface water were 7.04-14.08ng/L and 3.82-9.66ng/L, respectively. The residual level of HCHs and DDTs in marine species samples ranged from 0.1 to 0.6ng/g and from 0.57 to 85.02ng/g, respectively. In this thesis, discussions of DDTs and HCHs in sediment, water and marine species samples were made. The following are the main results and conclusions: When compared with some remote sites, the concentration of HCHs and DDTs in Minjiang estuary is higher. While compared with other industry area, the residual level of them is lower. A general decreasing trend of HCHs and DDTs was found from the inner to outer sectors of the Bay for both sediment and water samples. The distribution of HCH and DDT depends greatly on the different properties pertaining to them. The topography, redox, hydrodynamic condition as well as other factors also play an important role in controlling the distribution and fate of HCHs and DDTs. Bioaccumulation factor of DDTs and HCHs was also calculated and human consumption of this seafood could be a risk because the bioaccumulation factor ranged from 0.50 to 267.6. [ABSTRACT FROM AUTHOR]

Background: Although ibrutinib has been widely used to treat haematological malignancies, many studies have reported associated cardiovascular events. These studies were primarily animal experiments and clinical trials. For more rational clinical drug use, a study based on post-marketing data is necessary. Aim: Based on post-marketing data, we investigated the clinical features, time to onset, and outcomes of potential cardiovascular toxicities of ibrutinib. Methods: This disproportionality study utilised data from the 2014–2021 United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. We used two disproportionality methods information component (IC) and reporting odds ratio (ROR)) to detect the potential cardiovascular toxicities of ibrutinib. Positive signals were defined as IC025 > 0 and ROR025 > 1. Results: A total of 10 cardiovascular events showed positive signals: supraventricular tachyarrhythmias, haemorrhagic central nervous system vascular conditions, ventricular tachyarrhythmias, cardiac failure, ischaemic central nervous system vascular conditions, cardiomyopathy, conduction defects, myocardial infarction, myocardial infarction disorders of sinus node function, and torsade de pointes/QT prolongation. Cardiomyopathy and supraventricular tachyarrhythmias were the two most common signals. Disorders of sinus node function were observed for the first time, which may be a new adverse effect of ibrutinib. Conclusions: This pharmacovigilance study systematically explored the adverse cardiovascular events of ibrutinib and provided new safety signals based on past safety information. Attention should be paid to some high-risk signals.

A numerical method is formulated and analyzed for solving the miscible displacement problem under low regularity assumptions. The scheme employs discontinuous Galerkin time stepping with mixed and interior penalty discontinuous Galerkin finite elements in space. The numerical approximations of the pressure, velocity, and concentration converge to the weak solution as the mesh size and time step tend to zero. To pass to the limit a compactness theorem is developed which generalizes the Aubin-Lions theorem to accommodate discontinuous functions both in space and in time. [ABSTRACT FROM AUTHOR]

This study was to scientifically and systematically explore the association between cardiotoxicity and immune checkpoint inhibitors (ICIs) and also to characterize the spectrum of ICI-related cardiac complications. From the first quarter of 2014 to the fourth quarter of 2019, data from the FDA Adverse Event Reporting System database were selected to conduct the disproportionality analysis. Reporting odds ratios and information components were used to evaluate the signal after statistical shrinkage transformation. In total, 7,443,137 cases and 36,326,611 drug-adverse event pairs were collected, among which 9,271 cases were identified to be related to ICI-induced cardiotoxicities. The number of male patients was much higher than that of females (5,579 vs. 3,031) and males presented a slightly higher reporting frequency than females in general, which was statistically significant (ROR = 1.04, 95%CI: 0.99–1.09, p < 0.001). Simultaneously, the proportion of serious or life-threatening outcomes in males was significantly higher than in females (ROR = 1.05, 95%CI: 0.96–1.15, p < 0.001). Importantly, ICIs were associated with over-reporting frequencies of cardiotoxicities in general (ROR025 = 1.06, IC025 = 0.08). PD-1 and PD-L1 were found to be related to cardiac adverse events, corresponding to ROR025 = 1.06, IC025 = 0.08, and ROR025 = 1.06, IC025 = 0.08, respectively, while anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) was significantly associated with some specific adverse events rather than common adverse events. The spectrum of cardiotoxicities induced by ICIs mostly differed among individual agents, but also demonstrated some common features. Dyspnea (N = 2,527, 21.25%), myocarditis (N = 614, 5.16%), atrial fibrillation (N = 576, 4.84%), cardiac failure (N = 476, 4.00%), and pericardial effusion (N = 423, 3.56%) were the top five cardiac adverse events reported in the database. Among them, myocarditis was the only one caused by all ICIs with strong signal value and high risk, warranting further attention. Overall, this investigation mainly showed the profile of cardiotoxicities caused by ICIs, which varied between different ICI therapies, but also shared some similarities in specific symptoms such as myocarditis. Therefore, it is vital and urgent to recognize and manage ICI-related cardiotoxicities, known to frequently occur in clinical practice, at the earliest point.

Background: Ectopic TSH-secreting pituitary adenoma (TSH-oma) is a very unusual disorder. To date, there are only four cases reported. It is difficult to distinguish ectopic cases from both regular TSH-omas and resistance to thyroid hormone (RTH). Case presentation: A newly identified case of ectopic TSH-oma arising from the nasal pharynx was described, and reports of four prior cases were reviewed. The patient was a 41-year-old male who developed what appeared to be typical hyperthyroidism and atrial fibrillation in 2009. Thyroid function tests showed elevated basal levels of free T3 (FT3, 24.08 pmol/L), free T4 (FT4, 75.73 pmol/L), and serum TSH (7.26 μIU/ml). Both TSH-oma and resistance to thyroid hormone syndrome were considered. TRH stimulating test was negative, whereas octreotide inhibition test showed a reduction in TSH by 30.8%. Furthermore, a large space-occupying lesion located at the nasopharynx was found by computed tomography and magnetic resonance imaging (MRI). A normal pituitary was visualized. Ectopic TSH-oma was preliminarily established. Using an endoscopic endonasal approach, the tumor was resected. Histological features and immunophenotypes were consistent with those of TSH-secreting tumor. The levels of both free thyroxine and TSH returned to normal ranges the day after surgery and remained within normal range for 48 months. Conclusions: Although exceedingly rare, ectopic TSH-oma should be considered for patients with inappropriate secretion of TSH with hyperthyroidism and pituitary tumor undetectable by computed tomography and MRI. To our knowledge, this is the first case followed up more than 4 years. The characteristics and successful interventions summarized in this report provide a guideline for clinicians. [ABSTRACT FROM AUTHOR]

The magnitudes of the terms in periodic orbit semiclassical trace formulas are determined by the orbits' stability exponents. In this paper, we demonstrate a simple asymptotic relationship between those stability exponents and the phase-space positions of particular homoclinic points. [ABSTRACT FROM AUTHOR]