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Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

Background: To investigate the feasibility of the simultaneous multi-slice (SMS) accelerated acquisition technique in 2 dimension-RARE/turbo spin echo (TSE) sequence with special purpose coils in head and neck imaging. Methods: Thirty-six healthy volunteers and eight patients with head and neck squamous cell carcinoma were recruited in this prospective study. The MR protocols included 2D-T1/T2-weighted TSE sequences, both with the SMS (T1/T2w-SMS-TSE) technique and without it (T1/T2w-TSE). A pair of special purpose coils was additionally used in sub-group of participants. Subjective image quality scores, quantitative values of images, including signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs), were evaluated. Results: The acquisition time was 1:15 min and 1:09 min for T1w and T2w-SMS-TSE, with a respective 39% and 47% reduction compared to conventional sequences. The image quality of all the images were scored equivalent. Although the SMS technique seemed to slightly reduce the SNRs of T1/T2w images and CNRs of T1w images, the additional use of special purpose coils further increased the SNRs and CNRs in most cases. Focal lesions of eight HNSCC patients were finely delineated in all the protocols with similar and good diagnostic value. Conclusions: Combining SMS–TSE imaging with special purpose coils is a feasible and effective approach to reduce the total acquisition time, and obtain equivalent image quality and better SNRs and CNRs in most cases, as compared to the conventional T1/T2w-TSE sequence in head and neck imaging.

Undersea cables play a crucial role in enabling global communication and data transfer, significantly affecting Internet speeds. Without them, global communication would be severely limited. As technology advances and network demands increase, the number and variety of optical fibers within cables are constantly increasing. This growth results in more costly cable networks with the ability to transmit more data and enhances the speed and reliability of data transmission. The construction of an undersea cable system requires careful consideration of the appropriate bandwidth of the cable to meet network bandwidth requirements while minimizing costs. In this article, we formulate the undersea cable network optimization problem taking account of the bandwidth capacity of each cable edge on the cable network as a weighted edges Steiner minimum tree problem and describe a new algorithm called the weighted edges Steiner minimum tree (WE-SMT) algorithm. For the given locations of the terminal nodes and the bandwidth capacity requirement, the WE-SMT algorithm optimizes the position of Steiner nodes, the bandwidth capacity of each cable edge, and the cable path. We implement our algorithm in a real-world setting, evaluating the benefit gained against the outcomes obtained without accounting for bandwidth optimization, as well as studying the effect of data resolution on the quality of the path planning results. In addition, we assess the performance of our new algorithm in comparison with that of an operational real-world cable system.

N4-acetylcytidine (ac4C), a conserved but recently rediscovered RNA modification on tRNAs, rRNAs and mRNAs, is catalyzed by N-acetyltransferase 10 (NAT10). Lysine acylation is a ubiquitous protein modification that controls protein functions. Our latest study demonstrates a NAT10-dependent ac4C modification, which occurs on the polyadenylated nuclear RNA (PAN) encoded by oncogenic DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV), can induce KSHV reactivation from latency and activate inflammasome. However, it remains unclear whether a novel lysine acylation occurs in NAT10 during KSHV reactivation and how this acylation of NAT10 regulates tRNAs ac4C modification. Here, we showed that NAT10 was lactylated by α-tubulin acetyltransferase 1 (ATAT1), as a writer at the critical domain, to exert RNA acetyltransferase function and thus increase the ac4C level of tRNASer-CGA-1-1. Mutagenesis at the ac4C site in tRNASer-CGA-1-1inhibited its ac4C modifications, translation efficiency of viral lytic genes, and virion production. Mechanistically, KSHV PAN orchestrated NAT10 and ATAT1 to enhance NAT10 lactylation, resulting in tRNASer-CGA-1-1ac4C modification, eventually boosting KSHV reactivation. Our findings reveal a novel post-translational modification in NAT10, as well as expand the understanding about tRNA-related ac4C modification during KSHV replication, which may be exploited to design therapeutic strategies for KSHV-related diseases.

The assessment of bone marrow iron stores is typically performed on an aspirate smear slide that has been manually stained by a technologist using a commercially available kit. This approach can contribute to inconsistent results and limit the broad use of iron staining in bone marrow specimens, particularly when laboratories have low staffing and/or high specimen volumes. Here, we describe the adaptation and validation of the Ventana Benchmark automated stainer and iron stain kit for routine clinical use of staining iron in bone marrow aspirate smear slides. We assessed accuracy and precision of the Ventana automated iron staining protocol compared to the Perls Prussian blue manual iron staining index method. Hematopathologists assigned Gale scores and enumerated the percentages of erythroid sideroblasts on paired patient bone marrow aspirate smear slides stained by the automated method and the manual iron staining method. We found a similar level of performance of the Ventana automated iron stain relative to the index manual method (as assessed by Pearson correlation and Bland–Altman analyses). In addition, there was low imprecision between replicates performed via the automated iron stain protocol. We also report superior qualitative findings of the automated method in ease of localization of iron storage, visualization of sideroblasts, and counterstain consistency. Automated iron staining of bone marrow aspirate smear slides performed similarly to the manual method and may allow for accurate routine evaluation of bone marrow iron stores as part of bone marrow analysis.

(Abstracted from Prenatal Diagnosis2023;43:1416–1424Reproductive carrier screening is designed to identify couples who are at a high risk of passing genetic disorders to their children. Advances in genetic screening technology have recently allowed for the commercial development and availability of genetic tests that can screen for autosomal recessive and X-linked genes for many disorders simultaneously.

There is no currently approved adoptive cellular therapy for solid tumors. Pre-clinical and clinical studies have demonstrated that low-dose radiotherapy (LDRT) can enhance intratumoral T cell infiltration and efficacy. This case report describes a 71-year-old female patient with rectal mucosal melanoma that had developed metastases to liver, lung, mediastinum, axillary nodes, and brain. After systemic therapies had failed, she enrolled in the radiation sub-study of our phase-I clinical trial exploring the safety and efficacy of afamitresgene autoleucel (afami-cel), genetically engineered T cells with a T cell receptor (TCR) targeting the MAGE-A4 tumor antigen in patients with advanced malignancies (NCT03132922). Prior to the infusion of afami-cel, she received concurrent lymphodepleting chemotherapy and LDRT at 5.6 Gy/4 fractions to the liver. Time to partial response was 10 weeks, and duration of overall response was 18.4 weeks. Although the patient progressed at 28 weeks, the disease was well controlled after high-dose radiotherapy to liver metastases and checkpoint inhibitors. As of the last follow-up, she remains alive over two years after LDRT and afami-cel therapy. This report suggests that afami-cel in combination with LDRT safely enhanced clinical benefit. This provides evidence for further exploring the benefit of LDRT in TCR-T cell therapy.

Hardware disaggregation decouples resources (e.g., processors and memory) from monolithic servers, potentially improving service reliability. However, from another perspective, directly exposing resource modules to a shared network may adversely affect service reliability. In this article, we study a reliable resource allocation problem in disaggregated data centers, considering network impact and different disaggregation scales. We provide a mixed-integer linear programming formulation and a resource allocation framework named Radar for this problem. The numerical results demonstrate that the benefits of hardware disaggregation may be adversely affected by an imperfect network. It also shows that both the hardware backup and a proposed migration-based restoration can be applied to overcome this potential adverse effect.

Sika deerare known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement by explaining the genome of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGTand CYPgene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of the UGTfamily 2 subfamily B of UGTgenes. The first chromosome-level assembly and genetic characterization of the tolerance to a highly toxic diet suggest that the sika deer genome may serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with sufficient sequencing depth (>500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53 variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development.

Submarine communications cables are essential infrastructure in modern society, but they are also vulnerable to unpredictable disasters, and their breakage may have dire social and economic consequences. Motivated by the lessons from the Tonga volcano eruption in 2022, we incorporate the volcano risk factor with the other considerations (including earthquakes, fishing, anchoring, terrain slope, and marine protected areas) that have been considered in previous publications, and explain the Fast Marching Method-based path planning of submarine cables. To consider the effect of volcanos, we also introduce constraints based on keeping safety distances (zero, short or long) from each volcano, by setting infinite risk value in areas to be avoided. We then provide the approximate Pareto front of the cost and risk of submarine cable paths for different stakeholders' reference. We demonstrate that significant cost savings and reduced cable faults could have been achieved for the Tonga-Fiji cable system using our method, keeping in mind that our conclusions are based only on publicly available data.

This paper optimizes path planning for a trunk-and-branch topology network in an irregular 2-dimensional manifold embedded in 3-dimensional Euclidean space with application to submarine cable network planning. We go beyond our earlier focus on the weighted costs of cables (cable laying cost, resilience, design level and repair rate) to include the cost of branching units (BUs), including material and labor, as well as submarine cable landing stations (CLSs). This optimization also includes choices of locations of BUs and CLSs. These are important issues for the economics of cable laying and significantly change the model and the optimization process. We pose the problem as a variant of the Steiner tree problem, but one in which the Steiner nodes can vary in number, while incurring a penalty. We refer to it as the weighted Steiner node problem. It differs from the Euclidean Steiner tree problem, where Steiner points are forced to have degree three; this is no longer the case, in general, when nodes incur a cost. We are able to prove that our algorithm is applicable to Steiner nodes with degree greater than three, enabling optimization of network costs in this context. The optimal solution is achieved in polynomial-time using dynamic programming.

Well-orchestrated transcriptional programs in intestinal epithelial cells (IECs) are essential for maintenance of optimal mucosal barrier functions, whereas the contribution of elongation-related mechanisms to barrier function remains unknown. Here, a combination of genetic and genomic approaches defined a critical role of IEC-intrinsic negative elongation factor (NELF) complex in maintenance of epithelial homeostasis. By direct occupancy at endogenous gene loci, NELF sustained expression of a subset of genes related to junctional integrity. As a result, epithelial NELF deficiency results in subdued levels of these junction-related genes and excessive IEC necroptosis in vivo secondary to commensal microbial invasion. In a colitis model, NELF-deficient mice exhibited severely impaired barrier integrity characterized by increased intestinal permeability and significantly exacerbated intestinal inflammation with lethal consequences. Our findings reveal the protective function of the NELF complex against intestinal damage and inflammation and suggest that elongation represents a biologically important step in defining IEC transcriptome.

Well-orchestrated transcriptional programs in intestinal epithelial cells (IECs) are essential for maintenance of optimal mucosal barrier functions, whereas the contribution of elongation-related mechanisms to barrier function remains unknown. Here, a combination of genetic and genomic approaches defined a critical role of IEC-intrinsic negative elongation factor (NELF) complex in maintenance of epithelial homeostasis. By direct occupancy at endogenous gene loci, NELF sustained expression of a subset of genes related to junctional integrity. As a result, epithelial NELF deficiency results in subdued levels of these junction-related genes and excessive IEC necroptosis in vivo secondary to commensal microbial invasion. In a colitis model, NELF-deficient mice exhibited severely impaired barrier integrity characterized by increased intestinal permeability and significantly exacerbated intestinal inflammation with lethal consequences. Our findings reveal the protective function of the NELF complex against intestinal damage and inflammation and suggest that elongation represents a biologically important step in defining IEC transcriptome.

The artificial intelligence methods might be applied to see through the education problems, and make effective prediction and decision. The transformation from data to decision are inseparable from the learning analytics. In order to solve the dynamic multi-objective decision problems, a decision learning algorithm is designed to analyze the learning behavior and learning achievement based on the particle swarm optimization mechanism, which ensures the global optimization of data analysis. Compared with the performance indicators of several approximate algorithms, this algorithm has the advantage of association analysis, which improves the accuracy and robustness; Furthermore, three tested problems are constructed by GeoDa tool, and through data training and analysis, the dynamic multi-objective decision rules are obtained. The whole research can provide theoretical and technical support for other related or similar issues.

Droplet impinging on the boundary between hydrophilic and hydrophobic regions of a hybrid-wettability surface is studied both experimentally and numerically in the present paper. The interfacial evolution and dynamic feature and the corresponding underlying mechanisms behind are mainly analyzed. Because of the unbalanced surface energy in the vicinity of a boundary, the droplet undergoes spreading–receding in the hydrophobic region before migration toward the hydrophilic region. This results in an increase first but then a decrease in the spreading factor in the hydrophobic region, while it increases continuously in the hydrophilic region. In addition, increasing Weber number leads to the increase in both the spreading factor and migration displacement of the droplet in the hydrophobic region, but the latter decreases in the hydrophilic region, resulting from different momentums of secondary spreading. The experimental determinations are verified in detail by a series of numerical simulations performed based on the single variable method by fixing contact angles in different regions separately and excluding the impact momentum. It is shown that the highly unsymmetrical pressure field is exactly one important reason for droplet migration on the hybrid-wettability surface. Despite the weak dependence of the spreading factor on the hydrophilic contact angle in the hydrophobic region, it has an appreciably positive effect on droplet migration, which is confirmed by the increased pressure gradient with its action area in the hydrophobic region when decreasing the hydrophilic contact angle. This paper advances the fundamental understanding for droplet migration on the hybrid-/gradient-wettability surface.

The selective electrochemical conversion of glycerol into value-added products is a green and sustainable strategy for the biomass utilization. In this work, Au nanowires (Au-NW) modified with polyethyleneimine (PEI) molecule (Au-NW@PEI) is obtained by an up-bottom post-modification approach. Physical characterization, molecular dynamics simulation and density functional theory demonstrate that the loose-packed PEI monolayer firmly and uniformly distribute on the Au-NW surface due to the strong Au-N interaction. Electrochemical experiments and product analysis display that PEI modification significantly enhance the electro-activity of Au-NW for the glycerol electro-oxidation reaction (GEOR) due to the electronic effect. Meanwhile, the steric hindrance and electrostatic effect of PEI layer make the optimizing adsorption of intermediates possible. Therefore, the selectivity of C3 product glyceric acid over Au-NW@PEI is increased by nearly 20%. The work thus indicates that the rational design of metal-organic interface can effectively elevate the electro-activity and selectivity of Au nanostructures, which may have wide application in biomass development.

Viral protein 35 (VP35), encoded by filoviruses, is a multifunctional dsRNA binding protein that plays important roles in viral replication, innate immune evasion, and pathogenesis. The multifunctional nature of these proteins also presents opportunities to develop countermeasures that target distinct functional regions. However, functional validation and the establishment of therapeutic approaches toward such multifunctional proteins, particularly for nonenzymatic targets, are often challenging. Our previous work on filoviral VP35 proteins defined conserved basic residues located within its C-terminal dsRNA binding interferon (IFN) inhibitory domain (IID) as important for VP35 mediated IFN antagonism and viral polymerase cofactor functions. In the current study, we used a combination of structural and functional data to determine regions of Ebola virus (EBOV) VP35 (eVP35) to target for aptamer selection using SELEX. Select aptamers, representing, two distinct classes, were further characterized based on their interaction properties to eVP35 IID. These results revealed that these aptamers bind to distinct regions of eVP35 IID with high affinity (10–50 nM) and specificity. These aptamers can compete with dsRNA for binding to eVP35 and disrupt the eVP35–nucleoprotein (NP) interaction. Consistent with the ability to antagonize the eVP35–NP interaction, select aptamers can inhibit the function of the EBOV polymerase complex reconstituted by the expression of select viral proteins. Taken together, our results support the identification of two aptamers that bind filoviral VP35 proteins with high affinity and specificity and have the capacity to potentially function as filoviral VP35 protein inhibitors.

Two-dimensional (2D) transition metal dichalcogenide (TMDC) materials have garnered great attention on account of their novel properties and potential to advance modern technology. Recent studies have demonstrated that TMDCs can be utilized to create high-performing heterostructures with combined functionality of the individual layers and new phenomena at these interfaces. Here, we report an ultrafast photoresponse within MoSe2-based heterostructures in which heavily p-doped WSe2and MoS2flakes share an undoped MoSe2channel, allowing us to directly compare the optoelectronic properties of MoSe2-based heterojunctions with different 2D materials. Strong photocurrent signals have been observed in both MoSe2–WSe2and MoSe2–MoS2heterojunctions with a photoresponse time constant of ∼16 μs, surmounting previous MoSe2-based devices by three orders of magnitude. Further studies have shown that the fast response is independent of the integrated 2D materials (WSe2or MoS2) but is likely attributed to the high carrier mobility of 260 cm2V–1s–1in the undoped MoSe2channel as well as the greatly reduced Schottky barriers and near absence of interface states at MoSe2–WSe2/MoS2heterojunctions, which lead to reduced carrier transit time and thus short photocurrent response time. Lastly, a high detectivity on the order of ∼1014Jones has been achieved in MoSe2-based heterojunctions, which supersedes current industry standards. These fundamental studies not only shed light on photocurrent generation mechanisms in MoSe2-based heterojunctions but also open up new avenues for engineering future high-performance 2D optoelectronic devices.

Polyimides with intrinsic microporosity have been well developed and explored in the field of gas adsorption and separation. However, most linear polyimides without rigid and distorted segments do not have porous structure owing to the densely packed polymer chains. Two cross-linked polyimides (PEDA-PI-CL and PEQDA-PI-CL) were synthesized from 3,3′-bis(2,3,5,6-tetrafluoro-4-vinylphenoxy)-4,4′-biphenyldiamine (TFVBPA) with 2,5-bis(3,4-dicarboxyphenoxy)-4′-phenyl dianhydride (PEDA) and 2,5-bis(3,4-dicarboxyphenoxy)-4′-phenylethynyl phenyl dianhydride (PEQDA) through polycondensation and thermal cross-linking reactions. Here, the cross-linked structure is utilized to construct microporous polyimides because it can restrict the movement of polymer segments and prevent the polymer chains from dense packing. The micropore size, microporous structure, and CO2adsorption performance can be finely tuned by increasing the cross-linking density from PEDA-PI-CL to PEQDA-PI-CL. The micropore size reduces from 1.06 to 0.54 nm and CO2adsorption increases from 6.32 to 9.88 wt %. Meanwhile, the CO2/N2and CO2/CH4selectivity values of PEQDA-PI-CL at 273 K/1 bar are 76.62 and 12.40, respectively, which is better than many other common microporous polyimides. These results reveal that increasing cross-linking density in cross-linked polyimides is favorable for preparing microporous polyimide networks with smaller pores and higher CO2adsorption selectivity.

Porphyrin units are a kind of ideal electron donor units, which have large π conjugation and well-defined planar and electron-rich structures. The inserted alkynyl π bridges between porphyrin units and anhydride moieties can effectively enlarge the π-electron delocalization and molecular dimension effect and thus enhance the electron-donating ability and reduce the dipole moment in the porphyrin-based hyperbranched polyimides (HBPIs). The synergy effect of porphyrin units and alkynyl π bridges can facilitate the charge-transfer formation and dissociation, realize the transformation of memory type, and shorten the retention time of HBPI-TAPEPP-6FDA-based memory devices. The HBPI-TAPEPP-6FDA-based memory devices manifest lower threshold voltages of −2.32 and 2.42 V, a higher ON/OFF current ratio up to 107, and a shorter retention time of ∼20 s.

Interfacial phenomena and heat transfer associated with single droplet impact on a flowing liquid film are studied with three-dimensional simulations. Shear-induced sheet-film contact is detected successfully, governed by both flowing film and droplet velocities. Crown splashing at the downstream position is suppressed significantly, while cooling performance in the downstream crater is poorer than in the upstream crater because of slippage of the impact region along the streamwise direction. Increasing impact velocity and decreasing film thickness result in a very low wall temperature and high heat transfer coefficient because of enhanced convective heat transfer, but the increase in film velocity compromises cooling of the heating surface. Parametric effects of droplet impacting velocity, film thickness, and thermophysical properties on crown upstream and downstream heights in impact on the flowing film are virtually the same as those on the static film, but the unique parameter of film velocity in the former poses a negative effect on crown heights.

Background: This study seeks to assess the utility of T1 and T2 mapping in distinguishing metastatic lymph nodes from reactive lymphadenopathy in patients with head and neck squamous cell carcinoma (HNSCC), using diffusion-weighted imaging (DWI) as a comparison. Methods: Between July 2017 and November 2019, 46 HNSCC patients underwent neck MRI inclusive of T1 and T2 mapping and DWI. Quantitative measurements derived from preoperative T1 and T2 mapping and DWI of metastatic and non-metastatic lymph nodes were compared using independent samples t-test or Mann–Whitney U test. Receiver operating characteristic curves and the DeLong test were employed to determine the most effective diagnostic methodology. Results: We examined a total of 122 lymph nodes, 45 (36.9%) of which were metastatic proven by pathology. Mean T2 values for metastatic lymph nodes were significantly lower than those for benign lymph nodes (p< 0.001). Conversely, metastatic lymph nodes exhibited significantly higher apparent diffusion coefficient (ADC) and standard deviation of T1 values (T1SD) (p< 0.001). T2 generated a significantly higher area under the curve (AUC) of 0.890 (0.826–0.954) compared to T1SD(0.711 [0.613–0.809]) and ADC (0.660 [0.562–0.758]) (p= 0.007 and p< 0.001). Combining T2, T1SD, ADC, and lymph node size achieved an AUC of 0.929 (0.875–0.983), which did not significantly enhance diagnostic performance over using T2 alone (p= 0.089). Conclusions: The application of T1 and T2 mapping is feasible in differentiating metastatic from non-metastatic lymph nodes in HNSCC and can improve diagnostic efficacy compared to DWI.

Presents corrections to the article “Optimal Tree Topology for a Submarine Cable Network With Constrained Internodal Latency”.

We report a carbon nanotube (CNT) force sensor that combines a suspended CNT transistor with dual-trap optical tweezers to explore the interactions between two individual molecules in the near-equilibrium regime with sub-piconewton resolution. The directly measured equilibrium force (1.2 ± 0.5 pN) is likely related to the binding force between a CNT and a single DNA base, where two aromatic rings spontaneously attract to each other due to the noncovalent forces between them. On the basis of our force measurements, the binding free energy per base is calculated (∼0.34 eV), which is in good agreement with theoretical simulations. Moreover, three-dimensional scanning photocurrent microscopy enables us to simultaneously monitor the morphology changes of the CNT, leading to a comprehensive reconstruction of the CNT-DNA binding dynamics. These experimental results shed light on the fundamental understanding of the mechanical coupling between CNTs and DNA molecules and, more importantly, provide a new platform for direct observation of intermolecular interfaces at the single-molecule level.

Selective hydrogen peroxide (H2O2) electrogeneration by oxygen reduction reaction (ORR) is an efficient and promising synthetic method for H2O2production. Herein, we build a particular inorganic–organic interface to enhance the electrocatalytic selectivity of reduced graphene oxide (rGO) aerogels for H2O2electrogeneration by modifying rGO aerogels with polyethyleneimine (PEI). The three-dimensional porous structure of aerogels and the steric hindrance effect of PEI on rGO endow PEI-functionalized rGO (rGO/PEI) aerogels with enhanced selectivity (90.7%), production rate (106.4 mmol gcat–1h–1), and durability for H2O2electrogeneration by the two-electron pathway of ORR.

Sika deerare known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement by explaining the genome of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGTand CYPgene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of the UGTfamily 2 subfamily B of UGTgenes. The first chromosome-level assembly and genetic characterization of the tolerance to a highly toxic diet suggest that the sika deer genome may serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.

Droplet boiling on the heating surface is a representative phenomenon in two-phase spray cooling under low volumetric fluxes. In particular, droplet boiling in the transition boiling regime holds the advantages of avoiding heat transfer deterioration in a film boiling regime and achieving comparable high heat transfer capacity in a nucleate boiling regime. While it is known to consist of intermittent liquid contact with the surface and surface dryout, quantifying the ensuing transient heat transfer performance and droplet behavior is very illusive. In this study, droplet boiling in the transition boiling regime on a micropillar array surface is investigated systematically, using the lattice Boltzmann model built up in the lab. The major contents discussed include the transient behaviors of the droplet, motion of the liquid bridge, and pinning/depinning of the three-phase contact line (TPCL), as well as the corresponding heat transfer performance. The evolution of a vapor film pierced by micropillars is analyzed from the views of morphological change and pressure distribution. The thickness of the vapor film is determined by the vapor generation rate dominated by the contact area and effective thermal conductivity, and the vapor escape rate by the permeability. The low permeability under a large pillar side length is responsible for the pressure buildup below the droplet, thus facilitating droplet rebound. The competition between capillary pressure and vapor film pressure dominates the trigger mode of the droplet rebound, i.e., fracture of the liquid bridge or filament and depinning of TPCL. The micropillar array surface is optimized to pursue the best cooling performance by assessing the impact from micropillar geometric dimensions on droplet contact time and area.

The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.

The cell of origin and the tumor microenvironment’s role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment’s pathogenic role in these aggressive lymphomas.

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53variant detected. Three MM samples with sufficient sequencing depth (>500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53mutation. The recurrent variants in TP53in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development.

Goldsmith: Wugen Inc.: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Multiple myeloma (MM) is a hematological cancer of the antibody-secreting plasma cells. Despite therapeutic advancements, MM remains incurable due to high incidence of drug-resistant relapse. In recent years, targeted immunotherapies, which take advantage of the immune system's cytotoxic defenses to specifically eliminate tumor cells expressing certain cell surface and intracellular proteins have shown promise in combating this and other B cell hematologic malignancies. A major limitation in the development of these therapies lies in the discovery of optimal candidate targets, which require both high expression in tumor cells as well as stringent tissue specificity.

Molecular imaging has greatly advanced basic biology and translational medicine through visualization and quantification of single/multiple molecular events temporally and spatially in a cellular context and in living organisms. Aptamers, short single-stranded nucleic acids selected in vitroto bind a broad range of target molecules avidly and specifically, are ideal molecular recognition elements for probe development in molecular imaging. This review summarizes the current state of aptamer-based biosensor development (probe design and imaging modalities) and their application in imaging small molecules, nucleic acids and proteins mostly in a cellular context with some animal studies. The article is concluded with a brief discussion on the perspective of aptamer-based molecular imaging.

Kumar: Roche-Genentech: Consultancy, Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Carsgen: Research Funding; Bluebird Bio: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy.

Inkjet printing (IJP) has demonstrated its capabilities to produce high-quality and high-resolution parts, such as sensors, bio-chips, etc., with outstanding functionality. However, the quality of the printed parts can be endangered by the abnormal droplet jetting behaviors, which are substantially governed by the process dynamics and ambient conditions. Additionally, the droplet behaviors extensively define the final drop deposition quality in IJP. Timely capturing and identifying abrupt anomalies that the ejected droplets may suffer from are primordial for the quality assurance of the printed parts. Machine vision systems are able to record the droplet videos during IJP. Nevertheless, it is challenging to timely detect the anomalies from the collected droplet videos. The objective of this work is to build an analytical framework that allows for online droplet anomaly detection from droplet videos. There are several challenges that have not been addressed before: (1) the features of the droplet videos need to be extracted in an online fashion; and (2) there is no well-defined baseline to support the droplet anomalies detection, due to the complex process dynamics. Here, we propose a novel online framework to efficiently detect the anomalies from process streaming videos. In particular, we extend the multivariate Bayesian online change detection (BOCD) framework to high-dimensional data (i.e., tensor data of droplet videos) by leveraging online tensor factorization (OTF). OTF decomposes the streaming data into non-temporal and temporal low-dimensional factorization matrices. The non-temporal factorization matrices are deployed to extract the frame-specific temporal factorization matrix within a user-defined sliding window. Subsequently, the temporal factorization matrix for each frame is monitored with BOCD, which accurately detects anomalies in the streaming data. The proposed framework is demonstrated by detecting droplet anomalies from streaming data in IJP, showing excellent accuracy and efficiency.

Droplet jetting behavior largely determines the final drop deposition quality in the inkjet printing process. Forming such behavior is governed by the fluid flow pattern. Therefore, a measurement of the flow pattern is of great importance for improving the printing quality of the inkjet printing process. Most of the current works use static images for the study of the drop evolution process. The problem of the static images is that the images cannot recognize the motion information (i.e., temporal transformation) of the droplet. Thus the information of the jetting process in the temporal domain will be lost. Instead of using the images, this paper takes the video data as the study subject to investigate the droplet evolution behavior in the inkjet printing process. Moreover, this paper introduces a deep learning method for the study of such video data. Compared to most of the current learning approaches conducted in a supervised/semi-supervised manner for manufacturing process data, we propose an unsupervised learning method for studying the flow pattern of the droplet, which does not require well-defined ground-truth labels. Regarding the spatial and temporal transformation of the droplet in video data, we apply a deep recurrent neural network (DRNN) to implement the proposed unsupervised learning. To verify the hypothesis that the proposed method can learn a latent representation for reproducing original data, the proposed DRNN is trained and tested on both simulation and experimental datasets. Experimental results demonstrate that the proposed method can learn latent representations of the droplet jetting process video data, which is very useful for the prediction of the droplet behavior. Furthermore, through latent space decoding, the learned representations can infer the droplet forming stimulus parameters such as material properties, which would be very helpful for further understanding of the process dynamics and achieving real-time in-situ droplet deposition quality monitoring and control.

Multiple myeloma (MM) is a disease defined by clonal proliferation of abnormal plasma cells from B-cells. Improved treatments for MM have led to improving overall lifespan, but still remains incurable due to acquired resistance to therapy and tumor heterogeneity. Single-cell RNA sequencing studies (scRNA-seq) of MM patients have highlighted the significant inter-individual heterogeneity and subclonal architecture of the malignant plasma cell populations, emphasizing the importance of developing personalized therapies specific to a patients molecular pathogenesis. In this study, we have integrated scRNA-seq with single-cell proteomics (sc-Prot) for 10 plasma cells and CD4+ T cells to validate and prioritize driver events in malignant cells and evaluate the tumor microenvironment. This effort will be expanded to another 10 cases to further integrate scRNA-seq, snATAC-seq, whole exome sequencing and bulk RNA-sequencing on a fraction of the cells isolated from bone marrow. The remaining cells will be sorted using FACS to select for specific malignant and immune cells including 40 plasma cells, 15 CD4+ T and 15 CD8+ T cells. These sorted cells will be profiled with a scProt technology (BASIL nanoPOTS) to illuminate their cell-to-cell heterogeneity. In our pilot study comparing bulk and single-cell proteomic data of a single patient's plasma cells (CD138+) for 400 representative proteins, while a majority of expression signatures are concurrent between the two methods, some signaling pathways including translation and apoptotic cleavage are discordant. Our findings stress the importance of interrogating subpopulations of immune and malignant cells at the single-cell level to further refine the transcriptomic and proteomic heterogeneity of MM in a cell type specific manner. With the aid of single-cell technology, we have assessed the heterogeneity of malignant and immune cell types to evaluate transcriptomic and proteomic changes contributing to altering the interplay between the immune environment and tumor cells.

O'Neal: Wugen: Patents & Royalties: Patent Pending; WashU: Patents & Royalties: Patent Pending. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. Oh:Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding. DiPersio:Amphivena Therapeutics: Consultancy, Research Funding; Magenta Therapeutics: Equity Ownership; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees.

Fiala: Incyte: Research Funding. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. O'Neal:Wugen: Patents & Royalties: Patent Pending; WashU: Patents & Royalties: Patent Pending. DiPersio:WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Magenta Therapeutics: Equity Ownership; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

Multiple myeloma (MM) is a hematological malignancy, defined by aberrant monoclonal proliferation of plasma cells in the bone marrow, that to date remains an incurable disease despite advances in treatment. Key genetic and epigenetic alterations that drive MM pathogenesis have been identified, but a comprehensive profile of affected cellular pathways has yet to be fully characterized. In this study, we integrate whole-genome and whole-exome sequencing data with single-cell RNA sequencing (scRNA-seq) data from 13 patients across multiple treatment stages to 1) assess differential pathway enrichment between tumor subpopulations, 2) trace the clonal evolution of dominant disease mechanisms, and 3) investigate signaling interactions between surrounding cell types. We also analyzed bulk genomic and transcriptomic data from 662 additional Multiple Myeloma Research Foundation (MMRF) tumor samples as a large reference cohort for highly prevalent pathway disturbances.