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Promising progress has been made in adoptive transfer of allogeneic natural killer (NK) cells to treat relapsed or refractory acute myeloid leukemia (AML). In this regard, chimeric antigen receptor (CAR)-modification of NK cells is considered as a compelling approach to augment the specificity and cytotoxicity of NK cells against AML. Using a non-viral piggyBac transposon technology and human peripheral blood-derived primary NK cells, we generated CAR-NK cells to target NKG2D ligands and demonstrated their in vitro activity in lysing cancer cells expressing the ligands and in vivo efficacy in inhibiting tumor growth in a xenograft KG-1 AML model. We further generated CAR-NK cells co-expressing transgenes for the NKG2D CAR and interleukin-15 (IL-15). The ectopic expression of IL-15 improved the in vitro and in vivo persistence of NKG2D CAR-NK cells, leading to enhanced in vivo tumor control and significant prolongation of mouse survival in the KG-1 AML model. Collectively, our findings demonstrate the ectopic expression of IL-15 as an important means to improve the antileukemic activity of NKG2D CAR-NK cells. Our study further illustrates the feasibility of using the piggyBac non-viral platform as an efficient and cost-effective way for CAR-NK cell manufacturing.

Abstract Background Redirection of natural killer (NK) cells with chimeric antigen receptors (CAR) is attractive in developing off-the-shelf CAR therapeutics for cancer treatment. However, the site-specific integration of a CAR gene into NK cells remains challenging. Methods In the present study, we genetically modified human induced pluripotent stem cells (iPSCs) with a zinc finger nuclease (ZFN) technology to introduce a cDNA encoding an anti-EpCAM CAR into the adeno-associated virus integration site 1, a “safe harbour” for transgene insertion into human genome, and next differentiated the modified iPSCs into CAR-expressing iNK cells. Results We detected the targeted integration in 4 out of 5 selected iPSC clones, 3 of which were biallelically modified. Southern blotting analysis revealed no random integration events. iNK cells were successfully derived from the modified iPSCs with a 47-day protocol, which were morphologically similar to peripheral blood NK cells, displayed NK phenotype (CD56+CD3-), and expressed NK receptors. The CAR expression of the iPSC-derived NK cells was confirmed with RT-PCR and flow cytometry analysis. In vitro cytotoxicity assay further confirmed their lytic activity against NK cell-resistant, EpCAM-positive cancer cells, but not to EpCAM-positive normal cells, demonstrating the retained tolerability of the CAR-iNK cells towards normal cells. Conclusion Looking ahead, the modified iPSCs generated in the current study hold a great potential as a practically unlimited source to generate anti-EpCAM CAR iNK cells.

Mesenchymal stromal cells (MSCs) are viewed as immune-privileged cells and have been broadly applied in allogeneic adoptive cell transfer for regenerative medicine or immune-suppressing purpose. However, the surface expression of human leukocyte antigen (HLA) class I molecules on MSCs could still possibly induce the rejection of allogeneic MSCs from the recipients. Here, we disrupted the β2 microglobulin ( B2M ) gene in human peripheral blood mononuclear cell-derived induced pluripotent stem cells (iPSCs) with two clustered regulatory interspaced short palindromic repeat (CRISPR)-associated Cas9 endonuclease-based methods. The B2M knockout iPSCs did not express HLA class I molecules but maintained their pluripotency and genome stability. Subsequently, MSCs were derived from the HLA-negative iPSCs (iMSCs). We demonstrated that B2M knockout did not affect iMSC phenotype, multipotency, and immune suppressive characteristics and, most importantly, reduced iMSC immunogenicity to allogeneic peripheral blood mononuclear cells. Thus, B2M knockout iPSCs could serve as unlimited off-the-shelf cell resources in adoptive cell transfer, while the derived iMSCs hold great potential as universal grafts in allogeneic MSC transplantation.

Genome manipulation in the mouse via microinjection of CRISPR/Cas9 site-specific nucleases has allowed the production time for genetically modified mouse models to be significantly reduced. Successful genome manipulation in the mouse has already been reported using Cas9 supplied by microinjection of a DNA construct, in vitro transcribed mRNA and recombinant protein. Recently the use of transgenic strains of mice overexpressing Cas9 has been shown to facilitate site-specific mutagenesis via maternal supply to zygotes and this route may provide an alternative to exogenous supply. We have investigated the feasibility of supplying Cas9 genetically in more detail and for this purpose we report the generation of a transgenic mice which overexpress Cas9 ubiquitously, via a CAG-Cas9 transgene targeted to the Gt(ROSA26)Sor locus. We show that zygotes prepared from female mice harbouring this transgene are sufficiently loaded with maternally contributed Cas9 for efficient production of embryos and mice harbouring indel, genomic deletion and knock-in alleles by microinjection of guide RNAs and templates alone. We compare the mutagenesis rates and efficacy of mutagenesis using this genetic supply with exogenous Cas9 supply by either mRNA or protein microinjection. In general, we report increased generation rates of knock-in alleles and show that the levels of mutagenesis at certain genome target sites are significantly higher and more consistent when Cas9 is supplied genetically relative to exogenous supply.

The mechanical properties of the coherently precipitated high-entropy alloys can be further enhanced by enhancing the strain hardening behavior through deformation twins. In this study, a heterogeneously structured Ni45Co21Fe15Cr10Al4·5Ti4.5 (at. %) alloy with micro-meter-sized grains embedded inside a matrix of nanocrystalline or ultrafine grains was obtained through tailored thermomechanical processing steps. The tested alloy exhibited favorable strain hardening behavior, resulting in a remarkable tensile ductility of 32% even under the high yield stress of 1400 MPa. Dense planar defects comprised of deformation twins (DTs) have been activated in the grains composed of γ phase and coherently precipitated γ′ phase during the tensile process at room temperature. The underlying mechanism for the nucleation and growth of DTs in the grains with γ/γ′ duplex phases has been elucidated through transmission electron microscopy observations and density functional theory calculation, emphasizing the importance of the DTs. This research provides new insights into designing high entropy alloys that overcome the trade-off between strength and ductility.

Recent investigations indicate that high entropy alloys (HEAs) may exhibit distinctive thermal characteristics compared to traditional alloys. Through a blend of experiments and atomistic simulations, this study showcases that the lattice thermal conductivity of a highly distorted single-phase B2 alloy with the composition of (CoNi)50(TiZrHf)50 is as low as less than 1 W/(m·K), akin to that of ceramics like alumina, and remains stable across temperatures from 300 to 900 K. This remarkable thermal behavior is attributed to significant lattice distortion and atomic mass variation within this alloy. These findings suggest potential applications for distorted HEAs in thermal insulation technologies tailored for challenging environments.

The advancement of high entropy alloys (HEAs) has stimulated the development of multicomponent L12 γ′ intermetallics, which exhibit both excellent strength and ductility. These intermetallics with long-range order are typically employed as coherent precipitates to enhance the high-temperature performance of HEAs. This study investigates the influence of multicomponent γ′ intermetallics on the irradiation response of the strengthened HEA γ phase, focusing on the role of the multicomponent γ/γ′ interface in defect production and evolution. Our results indicate that the chemical disorder within the multicomponent γ′ phase leads to a broad defect energy spectrum near the interface zone, diminishing its effectiveness as a defect sink. Based on these observations, we propose that, distinct from traditional superalloys, the γ/γ′ interface plays a minor role in the irradiation resilience of multicomponent γ′ intermetallics-strengthened HEAs. Instead, the inherent chemical disorder within the multicomponent γ′ intermetallics emerges as the key factor.

Abstract Background Although low-dose computed tomography (LDCT) screening effectively reduces LC mortality in high-risk individuals with a history of smoking in China, the feasibility and efficacy of lung cancer screening (LCS) in individuals who never smoked versus individuals who smoked remains unclear. Methods We conducted a retrospective analysis of prospective cohort studies at the National Cancer Center (NCC) in China from January 2006 to December 2022. A comprehensive LCS initiative was undertaken, involving 30,468 participants (54.5% male). Participants underwent LCS using LDCT. Potential malignancies were managed through joint consensus between patients and their physicians. Epidemiology, screening eligibility criteria, and LC detection rates and survival outcomes were compared between individuals who smoked and individuals who never smoked. Results Among 30,468 participants, 339 LCs were pathologically confirmed in 289 patients. The LC detection rate was 0.9% (289/30,468) overall, 0.8% in individuals who smoked (71/9,042), and 1.0% in individuals who never smoked (218/21,426). In individuals who smoked, LC detection rates were 0.5% (21/4516) and 1.1% (50/4526) in the

Abstract High-entropy materials have been proposed for applications in nuclear systems recently due to their outstanding properties in extreme environments. Chemical complexity in these materials plays an important role in irradiation tolerance since it significantly affects energy dissipation and defect behaviors under particle bombardment. Indeed, better resistance to irradiation-induced amorphization was observed in the high-entropy MAX (HE-MAX) phase (Ti, M)2SnC (M = V, Nb, Zr, Hf). However, in this work, we report an opposite trend in another series of HE-MAX phases (Ti, M)2AlC (M = Nb, Ta, V, Zr). It is demonstrated that the amorphization resistance is sequentially reduced as the number of components increases from single-component Ti2AlC to (TiNbTa)2AlC and (TiNbTaVZr)2AlC. These phenomena are verified through AIMD simulations and interpreted by analyzing the underlying properties combining lattice distortion and bonding characteristics through the first-principle calculation. By developing a machine-learning (ML) model, we can directly predict lattice distortion to screen HE-MAX phases with excellent resistance to irradiation-induced amorphization. We highlight that the elemental species plays a more crucial role in the irradiation tolerance of these MAX phases than the number of constituent elements. Knowledge gained from this study will enable an improved understanding of the irradiation tolerance in HE-MAX phases and other multi-elemental ceramics.

Abstract Developing high-performance multicomponent ceramics, which are promising in solving challenges posed by emerging technologies, shows grand difficulties because of the immense compositional space and complex local distortions. In this work, an accurate machine learning (ML) model built upon an ab initio database is developed to predict the mechanical properties and structural distortions of multicomponent transition metal carbides (MTMCs). The compositional space of MTMCs is thoroughly explored by the well-trained model. Combined with electronic and geometrical analysis, we show that the elemental adaptability to the rock-salt structure elegantly elucidates the mechanical characteristics of MTMCs, and such adaptability can be quantified by local lattice distortions. We further establish new design principles for high-strength MTMCs, and V–Nb–Ta-based MTMCs are recommended, which are validated by the present experiments. The proposed model and design philosophy pave a broad avenue for the rational design of MTMCs with exceptional properties.

Abstract Background Evidence from observational studies indicates that lung cancer screening (LCS) guidelines with high rates of lung cancer (LC) underdiagnosis, and although current screening guidelines have been updated and eligibility criteria for screening have been expanded, there are no studies comparing the efficiency of LCS guidelines in Chinese population. Methods Between 2005 and 2022, 31,394 asymptomatic individuals were screened using low-dose computed tomography (LDCT) at our institution. Demographic data and relevant LC risk factors were collected. The efficiency of the LCS for each guideline criteria was expressed as the efficiency ratio (ER). The inclusion rates, eligibility rates, LC detection rates, and ER based on the different eligibility criteria of the four guidelines were comparatively analyzed. The four guidelines were as follows: China guideline for the screening and early detection of lung cancer (CGSL), the National Comprehensive Cancer Network (NCCN), the United States Preventive Services Task Force (USPSTF), and International Early Lung Cancer Action Program (I-ELCAP). Results Of 31,394 participants, 298 (155 women, 143 men) were diagnosed with LC. For CGSL, NCCN, USPSTF, and I-ELCAP guidelines, the eligibility rates for guidelines were 13.92%, 6.97%, 6.81%, and 53.46%; ERe for eligibility criteria were 1.46%, 1.64%, 1.51%, and 1.13%, respectively; and for the inclusion rates, they were 19.0%, 9.5%, 9.3%, and 73.0%, respectively. LCs which met the screening criteria of CGSL, NCCN, USPSTF, and I-ELCAP guidelines were 29.2%, 16.4%, 14.8%, and 86.6%, respectively. The age and smoking criteria for CGSL were stricter, hence resulting in lower rates of LC meeting the screening criteria. The CGSL, NCCN, and USPSTF guidelines showed the highest underdiagnosis in the 45–49 age group (17.4%), while the I-ELCAP guideline displayed the highest missed diagnosis rate (3.0%) in the 35–39 age group. Males and females significantly differed in eligibility based on the criteria of the four guidelines (P

Abstract Jamaican fruit bats (Artibeus jamaicensis) naturally harbor a wide range of viruses of human relevance. These infections are typically mild in bats, suggesting unique features of their immune system. To better understand the immune response to viral infections in bats, we infected male Jamaican fruit bats with the bat-derived influenza A virus (IAV) H18N11. Using comparative single-cell RNA sequencing, we generated single-cell atlases of the Jamaican fruit bat intestine and mesentery. Gene expression profiling showed that H18N11 infection resulted in a moderate induction of interferon-stimulated genes and transcriptional activation of immune cells. H18N11 infection was predominant in various leukocytes, including macrophages, B cells, and NK/T cells. Confirming these findings, human leukocytes, particularly macrophages, were also susceptible to H18N11, highlighting the zoonotic potential of this bat-derived IAV. Our study provides insight into a natural virus-host relationship and thus serves as a fundamental resource for future in-depth characterization of bat immunology.

Ordered L12 γ′ Ni3Al intermetallics are essential strengthening components to maintain the high strength of Ni-based superalloys and recently developed high entropy alloys at elevated temperatures. Under service conditions, structural disorder is usually encountered in these intermetallics, resulting in significant loss of their strengthening functionality. Thus, retaining the degree of order of the L12 intermetallics is vital for their long-term reliability and serviceability. In this study, atomistic simulations and rate equation analysis are employed to highlight a notable enhancement in the reordering ability of L12 intermetallics by incorporating multiple principal elements. Specifically, we examine the effects of Co and Ti addition on the irradiation-induced disordering and kinetic reordering process of L12 intermetallics. Our results reveal that the incorporation of Ti in the Al sublattice can maintain comparable disordering resistance as Ni3Al. Better yet, the introduction of Ti or Co fosters vacancy migration, which accelerates the kinetic reordering rate during the defect diffusion stage. A synergistic effect of Ti and Co in promoting kinetic reordering is also observed. Our work thus suggests a promising approach for designing irradiation-resistant multicomponent intermetallics, which can retain a high degree of structural order under irradiation with chemical disorder contributed by desirable compositions.

Abstract Background The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib‐refractory, anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. Methods In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two‐sided 95% confidence intervals (CIs). Next‐generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. Results At the data cut‐off date (August 31, 2022), with a median follow‐up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3‐53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. Conclusion Ensartinib led to a favorable OS in patients with advanced, crizotinib‐resistant, and ALK‐positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

In order to quantitatively analyze the risk caused by each operational step of coal mine blasting and comprehensively and objectively assess its risk, with the help of Monte Carlo method, this paper establishes a risk assessment model of coal mine blasting operation steps, makes cumulative probability distribution of the behavioral risk consequence value of the operation process, and finally determines the risk size and risk level of each operation step based on the mean result of Monte Carlo simulation and the overall risk result of the operation process, and puts forward the measures for the control of the occurrence of such unsafe behaviors. The results of the study show that the order of risk of the blasting operation process is in the following order: clearing the items into the warehouse, loading, linkage, guarding, safety inspection after detonation, receiving and checking the blasting items, detonation, delivery of blasting items, acceptance of the task of blasting, preoperational safety inspection, pre-detonation safety inspection, sealing the holes.

Objective To compare the long-term clinical and radiographic outcomes of transforaminal endoscopic lumbar discectomy (TELD) versus microdiscectomy (MD). Methods The data of 154 patients with lumbar disc herniation (LDH) who underwent TELD (n = 89) or MD (n = 65) were retrospectively analyzed. The patients’ clinical outcomes were evaluated using visual analogue scales for leg and low back pain, the Japanese Orthopaedic Association (JOA) score, and the Oswestry Disability Index (ODI). The evolution of radiographic manifestations was observed during follow-up. Potential risk factors for a poor clinical outcome were investigated. Results During a mean follow-up of 5.5 years (range, 5–7 years), the recurrence rate was 4.49% in the TELD group and 1.54% in the MD group. All scores significantly improved from preoperatively to postoperatively in both groups (p < 0.01). The improvement in the ODI and JOA scores was significantly greater in the TELD than MD group (p < 0.05). Forty-seven patients (52.8%) in the TELD group and 32 (49.2%) in the MD group had Modic changes before surgery, most of which showed no changes at the last follow-up. The degeneration grades of 292 discs (71.0%) were unchanged at the last follow-up, while 86 (20.9%) showed improvement, mostly at the upper adjacent segment. No significant difference was observed in the intervertebral height index or paraspinal muscle-disc ratio. Conclusion Both TELD and MD provide generally satisfactory long-term clinical outcomes for patients with LDH. TELD can be used as a reliable alternative to MD with less surgical trauma. Modic type II changes, decreased preoperative intervertebral height, and a high body mass index are predictors of a poor prognosis.

High-speed segmented annular seals are often subjected to friction and wear, and the groove design on the sealing surface can effectively suppress this loss. For the purpose of improving the sealing performance, the segmented annular seal models of three structures are established, and the accuracy of the calculation model is verified by comparing with the previous results. Through fluid–solid–thermal coupled analysis, the flow field characteristics, opening characteristics, and leakage characteristics of the segmented annular seal under high working condition parameters were studied. The results show that the setting of the shallow groove forms the hydrodynamic effect by squeezing and hindering the flow of fluid in the clearance. The increase in rotational speed and pressure difference can promote the increase in the opening force, while the temperature has no significant effect on the opening of the seal. Seals with ladder-like grooves have the best opening performance, and seals without shallow grooves are already difficult to open under conditions of high pressure difference and large spring forces. Temperature and pressure difference are the main factors affecting the leakage of the seal, while the influence of the rotation speed is small. When the sealed pressure increases from 0.15 MPa to 0.4 MPa, the maximum increase in the leakage of the seal with specific groove design is 4.657 times the original. As the temperature rises from 420 K to 620 K, the maximum decrease in the three structures is up to 22.9%. Among the seals of the three structures, seals with ladder-like grooves have medium leakage. This research will contribute to the improvement of research methods for the sealing performance of segmented annular rings, especially for the evaluation of groove design and opening characteristics.

Summary: Retinoic acid (RA), derived from retinol (ROL), is integral to cell growth, differentiation, and organogenesis. It is known that RA can inhibit herpes simplex virus (HSV) replication, but the interactions between alphaherpesviruses and RA metabolism are unclear. Our present study revealed that alphaherpesvirus (HSV-1 and Pseudorabies virus, PRV) infections suppressed RA synthesis from ROL by activating P53, which increased retinol reductase 3 (DHRS3) expression—an enzyme that converts retinaldehyde back to ROL. This process depended on the virus-triggered DNA damage response, the degradation of class I histone deacetylases, and the subsequent hyperacetylation of histones H3 and H4. Counteracting DHRS3 or P53 enabled higher RA synthesis and reduced viral growth. RA enhanced antiviral defenses by promoting ABCA1- and ABCG1-mediated lipid efflux. Treatment with the retinoic acid receptor (RAR) agonist palovarotene protected mice from HSV-1 infection, thus providing a potential therapeutic strategy against viral infections.

Abstract Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution (SCRaMbLE) is a promising tool to study genomic rearrangements. However, the potential of SCRaMbLE to study genomic rearrangements is currently hindered, because a strain containing all 16 synthetic chromosomes is not yet available. Here, we construct SparLox83R, a yeast strain containing 83 loxPsym sites distributed across all 16 chromosomes. SCRaMbLE of SparLox83R produces versatile genome-wide genomic rearrangements, including inter-chromosomal events. Moreover, when combined with synthetic chromosomes, SCRaMbLE of hetero-diploids with SparLox83R leads to increased diversity of genomic rearrangements and relatively faster evolution of traits compared to hetero-diploids only with wild-type chromosomes. Analysis of the SCRaMbLEd strain with increased tolerance to nocodazole demonstrates that genomic rearrangements can perturb the transcriptome and 3D genome structure and consequently impact phenotypes. In summary, a genome with sparsely distributed loxPsym sites can serve as a powerful tool for studying the consequence of genomic rearrangements and accelerating strain engineering in Saccharomyces cerevisiae.

Abstract The genome of an organism is inherited from its ancestor and continues to evolve over time, however, the extent to which the current version could be altered remains unknown. To probe the genome plasticity of Saccharomyces cerevisiae, here we replace the native left arm of chromosome XII (chrXIIL) with a linear artificial chromosome harboring small sets of reconstructed genes. We find that as few as 12 genes are sufficient for cell viability, whereas 25 genes are required to recover the partial fitness defects observed in the 12-gene strain. Next, we demonstrate that these genes can be reconstructed individually using synthetic regulatory sequences and recoded open-reading frames with a “one-amino-acid-one-codon” strategy to remain functional. Finally, a synthetic neochromsome with the reconstructed genes is assembled which could substitute chrXIIL for viability. Together, our work not only highlights the high plasticity of yeast genome, but also illustrates the possibility of making functional eukaryotic chromosomes from entirely artificial sequences.

Abstract Purpose To investigate the correlations between metabolic parameters (MPs) of 18F‐fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT), serum tumor markers (STMs), and tumor mutational burden (TMB) in patients with non‐small cell lung cancer (NSCLC). Materials and Methods In this retrospective study, we enrolled 129 patients with NSCLC (males, 78; females, 51) who underwent baseline TMB and STM tests and 18F‐FDG PET/CT scans before treatment between March 2018 and September 2022. Patients were categorized into TMB‐high (TMB ≥10 mutations/Mb; n = 27 [20.9%]) and non‐TMB‐high (TMB

The Nishihara creep model is an extremely effective method in the field of sandstone creep model research. However, the Nishihara creep model curve for sandstone under the marine environment (the coupled effect of chemical corrosion and temperature) does not fit the actual creep test data well. Based on the Nishihara creep model, we discovered that, on the one hand, the viscoelastic elements in the Nishihara model are replaced by the viscoelastic elements containing temperature and pH factors, which can accurately describe the influence of temperature and pH on rock creep characteristics; on the other hand, the viscoplastic elements in the Nishihara model are replaced by nonlinear viscoplastic elements, which can accurately describe the accelerated creep stage of the rock mass. After modifying Nishihara’s creep model twice, a new temperature–pH damage nonlinear creep model is established. The creep curve of the temperature–pH damage nonlinear creep model is compared with the creep test data of sandstone. The comparison results indicate that the creep curve of the nonlinear creep model has a high degree of fit with the creep test data of sandstone (accuracy > 92%). This validates the correctness of the newly established temperature–pH damage nonlinear creep model presented in this paper, demonstrating that the new model can effectively reflect the influence of temperature and pH on the creep characteristics of sandstone.

The Department of Medicinal Chemistry, together with the Institute for Structural Biology, Drug Discovery and Development, at Virginia Commonwealth University (VCU) has evolved, organically with quite a bit of bootstrapping, into a unique drug discovery ecosystem in response to the environment and culture of the university and the wider research enterprise. Each faculty member that joined the department and/or institute added a layer of expertise, technology and most importantly, innovation, that fertilized numerous collaborations within the University and with outside partners. Despite moderate institutional support with respect to a typical drug discovery enterprise, the VCU drug discovery ecosystem has built and maintained an impressive array of facilities and instrumentation for drug synthesis, drug characterization, biomolecular structural analysis and biophysical analysis, and pharmacological studies. Altogether, this ecosystem has had major impacts on numerous therapeutic areas, such as neurology, psychiatry, drugs of abuse, cancer, sickle cell disease, coagulopathy, inflammation, aging disorders and others. Novel tools and strategies for drug discovery, design and development have been developed at VCU in the last five decades; e.g., fundamental rational structure-activity relationship (SAR)-based drug design, structure-based drug design, orthosteric and allosteric drug design, design of multi-functional agents towards polypharmacy outcomes, principles on designing glycosaminoglycans as drugs, and computational tools and algorithms for quantitative SAR (QSAR) and understanding the roles of water and the hydrophobic effect.

Literature on integrated coastal zonal management (ICZM) for coastal sustainability from a legal perspective provided significant measures. Recently, sustainable development goals (SDGs) have become a focus in ICZM literature, which establishes coastal goals and connects these goals with other goals. Although integrating coastal goals into ICZM under international law challenges the existing models presented in the literature, the comprehensive literature review (CLR) methodology is appropriate for observing the current literature and provides a way-forward for coastal goals. Therefore, through this research, a CLR on ICZM literature is conducted to observe how far SDGs are integrated for coastal sustainability. The CLR identified that coastal city governance is a pertinent part of ICZM, and the coastal goals are devised in the form of environmental goals of SDG – 14 (life below water). This CLR examines the anthropogenic connections of waste, sanitation, and emissions management and urban planning with coastal ecosystems under the ICZM system. For such purposes, governance tools of science-policy integration under international law and policy for sustainable development are utilized to form an obligatory framework. The CLR further provided coordination, adaptivity, monitoring, and capacity-building tools, which were utilized thoroughly throughout the literature and can be incorporated with the SDGs in a multilevel governance framework of ICZM. Throughout the study, international law formulating SDGs is pivotal to be transplanted successfully into the ICZM governance processes.

Summary: In eukaryotic genomes, rDNA generally resides as a highly repetitive and dynamic structure, making it difficult to study. Here, a synthetic rDNA array on chromosome III in budding yeast was constructed to serve as the sole source of rRNA. Utilizing the loxPsym site within each rDNA repeat and the Cre recombinase, we were able to reduce the copy number to as few as eight copies. Additionally, we constructed strains with two or three rDNA arrays and found that the presence of multiple arrays did not affect the formation of a single nucleolus. Although alteration of the position and number of rDNA arrays did impact the three-dimensional genome structure, the additional rDNA arrays had no deleterious influence on cell growth or transcriptomes. Overall, this study sheds light on the high plasticity of rDNA organization and opens up opportunities for future rDNA engineering.

Abstract Background In China, over 50% of lung cancer cases occur in nonsmokers. Thus, identifying high‐risk individuals for targeted lung cancer screening is crucial. Beyond age and smoking, determining other risk factors for lung cancer in the Asian population has become a focal point of research. Using 30,000 participants in the prospectively enrolled cohort at China's National Cancer Center (NCC) over the past 14 years, we categorized participants by risk, with an emphasis on nonsmoking females. Materials and Methods Between November 2005 and December 2019, 31,431 individuals voluntarily underwent low‐dose computed tomography (LDCT) scans for lung cancer screening at the NCC. We recorded details like smoking history, exposure to hazards, and family history of malignant tumors. Using the 2019 NCCN criteria, participants were categorized into high‐, moderate‐, and low‐risk groups. Additionally, we separated non‐high‐risk groups into female never smokers (aged over 40) exposed to second‐hand smoke (SHS) and others. Any positive results from initial scans were monitored per the I‐ELCAP protocol (2006), and suspected malignancies were addressed through collaborative decisions between patients and physicians. We analyzed and compared the detection rates of positive results, confirmed lung cancers, and cancer stages across risk, age, and gender groups. Results Out of 31,431 participants (55.9% male, 44.1% female), 3695 (11.8%) showed positive baseline LDCT scans with 197 (0.6%; 106 females, 91 males) confirmed as lung cancer cases pathologically. Malignancy rate by age was 0.1% among those aged under 40 years, 0.4% among those aged 40–49 years, 0.8% among those aged 50–59 years, and 1.2% among those aged 60 years and older. From the 25,763 participants (56.9% male, 43.1% female) who completed questionnaires, 1877 (7.3%) were categorized as high risk, 6500 (25.2%) as moderate risk, and 17,386 (67.5%) as low risk. Of the 23,886 in the non‐high‐risk category, 8041 (33.7%) were females over 40 years old exposed to SHS. The high‐risk group showed the highest lung cancer detection rate at 1.4%. However, females exposed to SHS had a notably higher detection rate than the rest of the non‐high‐risk group (1.1% vs. 0.5%; p

Abstract Carbon nanomaterials are unique with excellent functionality and diverse structures. However, agglomerated structures are commonly formed because of small‐size effects and surface effects. Their hierarchical assembly into micro particles enables carbon nanomaterials to break the boundaries of classical Geldart particle classification before stable fluidization under gas‐solid interactions. Currently, there are few systematic reports regarding the structural evolution and fluidization mechanism of carbon nano agglomerations. Based on existing research on carbon nanomaterials, this article reviews the fluidized structure control and fluidization principles of prototypical carbon nanotubes (CNTs) as well as their nanocomposites. The controlled agglomerate fluidization technology leads to the successful mass production of agglomerated and aligned CNTs. In addition, the self‐similar agglomeration of individual ultralong CNTs and nanocomposites with silicon as model systems further exemplify the important role of surface structure and particle‐fluid interactions. These emerging nano agglomerations have endowed classical fluidization technology with more innovations in advanced applications like energy storage, biomedical, and electronics. This review aims to provide insights into the connections between fluidization and carbon nanomaterials by highlighting their hierarchical structural evolution and the principle of agglomerated fluidization, expecting to showcase the vitality and connotation of fluidization science and technology in the new era.

Abstract Background Drug-drug interaction (DDI) information retrieval (IR) is an important natural language process (NLP) task from the PubMed literature. For the first time, active learning (AL) is studied in DDI IR analysis. DDI IR analysis from PubMed abstracts faces the challenges of relatively small positive DDI samples among overwhelmingly large negative samples. Random negative sampling and positive sampling are purposely designed to improve the efficiency of AL analysis. The consistency of random negative sampling and positive sampling is shown in the paper. Results PubMed abstracts are divided into two pools. Screened pool contains all abstracts that pass the DDI keywords query in PubMed, while unscreened pool includes all the other abstracts. At a prespecified recall rate of 0.95, DDI IR analysis precision is evaluated and compared. In screened pool IR analysis using supporting vector machine (SVM), similarity sampling plus uncertainty sampling improves the precision over uncertainty sampling, from 0.89 to 0.92 respectively. In the unscreened pool IR analysis, the integrated random negative sampling, positive sampling, and similarity sampling improve the precision over uncertainty sampling along, from 0.72 to 0.81 respectively. When we change the SVM to a deep learning method, all sampling schemes consistently improve DDI AL analysis in both screened pool and unscreened pool. Deep learning has significant improvement of precision over SVM, 0.96 vs. 0.92 in screened pool, and 0.90 vs. 0.81 in the unscreened pool, respectively. Conclusions By integrating various sampling schemes and deep learning algorithms into AL, the DDI IR analysis from literature is significantly improved. The random negative sampling and positive sampling are highly effective methods in improving AL analysis where the positive and negative samples are extremely imbalanced.

Single-phase concentrated solid-solution alloys (CSAs) have exhibited excellent mechanical and radiation tolerance properties, making them potential candidate materials for nuclear applications. These excellent properties are closely related to dislocation movements, which depend on the stacking fault energies (SFEs). In CSAs, SFEs show large fluctuations due to variations in the local atomic environments in the vicinity of the stacking faults. In this work, first-principle calculations were performed to investigate the origin of the fluctuations in the SFEs of the widely studied CSA, NiCoCr, which show a very wide distribution from about −200 mJ/m2 to 60 mJ/m2. Compared to the common understanding that only atoms in close proximity to the stacking fault influence the SFEs in pure metals and dilute alloys, charge redistribution can be observed in several nearby planes of the stacking fault in NiCoCr, indicating that atoms several atomic layers away from stacking fault also contribute to the SFEs. Our analysis shows that Cr plays a major role in the large fluctuation in the SFEs of NiCoCr based on both electronic and magnetic responses. The flexible electronic structure of Cr facilitates easier charge transfer with Cr in several nearby atomic planes near the stacking fault, leading to significant changes in the d-electron number, orbital occupation number, and magnetic moments of Cr.

Introduction The tissue stiffness of donor kidneys in transplantation may increase due to pathological changes such as glomerulosclerosis and interstitial fibrosis, and those changes associate worse outcomes in kidney transplantation recipients. Ultrasound elastography is a noninvasive imaging examination with the ability to quantitatively reflect tissue stiffness. Aim of this study was to evaluate the prognostic value of ultrasound elastography for adverse kidney outcome in kidney transplantation recipients.Methods Shear wave elastography (SWE) examinations were performed by two independent operators in kidney transplantation recipients. The primary outcome was a composite of kidney graft deterioration, all-cause re-hospitalization, and all-cause mortality. Survival analysis was calculated by Kaplan-Meier curves with the log-rank test and Cox regression analysis.Results A total of 161 patients (mean age 46 years, 63.4% men) were followed for a median of 20.1 months. 27 patients (16.77%) reached the primary endpoint. The mean and median tissue stiffness at the medulla (hazard ratio: 1.265 and 1.229, respectively), estimated glomerular filtration rate (eGFR), and serum albumin level were associated with the primary outcome in univariate Cox regression. Adding mean or median medulla SWE to a baseline model containing eGFR and albumin significantly improved its discrimination (C-statistics: 0.736 for the baseline, 0.766 and 0.772 for the model added mean and median medulla SWE, respectively).Conclusion The medullary tissue stiffness of kidney allograft measured by shear wave elastography may provide incremental prognostic value to adverse outcomes in kidney transplantation recipients. Including SWE parameters in kidney transplantation recipients management could be considered to improve risk stratification.

Previous studies revealed that both Helicobacter pylori infection and some cytokine gene polymorphisms are risk factors for gastric diseases. The association between H. pylori and gene polymorphisms is worth exploring. Here we conducted a case–control study and systematically evaluate on association between H. pylori infection and IL4, TNFA, and IL10 polymorphisms in a Chinese Han population in northwestern China, where gastric cancer is the major burden on the health and the leading cause of death in local community. The Sequenom MassArray platform was used to screen the genotypes and 14C-urea breath test was employed to determine H. pylori infection status of 705 participants of the local rural residents. Significant association between H. pylori infection and the IL4 rs34142320 polymorphism was observed in the dominant model (OR = 0.57, 95% CI = 0.40–0.80, P = 0.030). No significant association was found between IL4 rs2243250, TNFA rs1800630, TNFA rs1800629, TNFA rs1799964, IL10 rs1800871, IL10 rs1800896 and H. pylori infection. Haplotype analysis showed that T-DEL and G-C haplotypes of the observed IL4 SNPs were significantly associated with H. pylori infection. Our analysis demonstrated that the IL4 rs34142320 polymorphism has a protective effect on H. pylori infection in Chinese Han population.

BackgroundAdvanced perfusion modalities are increasingly popular for various diseases. However, few studies have focused on contrasting perfusion patterns.ObjectiveThis study aimed to compare the time efficiency and clinical outcomes of patients with acute ischemic stroke (AIS) who underwent endovascular treatment (EVT) before one-stop arterial spin labeling (ASL) and computed tomography perfusion (CTP) protocols.MethodsThis study retrospectively included 326 patients with AIS who had accepted EVT within 24 h of onset from four comprehensive stroke centers between October 2017 and September 2022. After 1:1 matching of the propensity scores, 202 patients were separated into two groups: the ASL group (n = 101) and the CTP group (n = 101).ResultsFunctional independence at 90 days (modified Rankin Scale [mRS] 0–2; p = 0.574), onset-to-puncture time (p = 0.231), door-to-puncture time (p = 0.136), and door-to-perfusion time (p = 0.646) were not significantly different between the two groups. The proportion of EVT complications (31.7% in the ASL group vs. 14.9% in the CTP group, p = 0.005) and symptomatic intracranial hemorrhage (sICH) at 24 h (23.8% in the ASL group vs. 9.9% in the CTP group, p = 0.008) in the CTP group were lower than the ASL group. The ischemic core volume was a common predictor of favorable outcomes in both ASL (p

Insectivorous Old World horseshoe bats (Rhinolophus spp.) are the likely source of the ancestral SARS-CoV-2 prior to its spillover into humans and causing the COVID-19 pandemic. Natural coronavirus infections of bats appear to be principally confined to the intestines, suggesting fecal-oral transmission; however, little is known about the biology of SARS-related coronaviruses in bats. Previous experimental challenges of Egyptian fruit bats (Rousettus aegyptiacus) resulted in limited infection restricted to the respiratory tract, whereas insectivorous North American big brown bats (Eptesicus fuscus) showed no evidence of infection. In the present study, we challenged Jamaican fruit bats (Artibeus jamaicensis) with SARS-CoV-2 to determine their susceptibility. Infection was confined to the intestine for only a few days with prominent viral nucleocapsid antigen in epithelial cells, and mononuclear cells of the lamina propria and Peyer's patches, but with no evidence of infection of other tissues; none of the bats showed visible signs of disease or seroconverted. Expression levels of ACE2 were low in the lungs, which may account for the lack of pulmonary infection. Bats were then intranasally inoculated with a replication-defective adenovirus encoding human ACE2 and 5 days later challenged with SARS-CoV-2. Viral antigen was prominent in lungs for up to 14 days, with loss of pulmonary cellularity during this time; however, the bats did not exhibit weight loss or visible signs of disease. From day 7, bats had low to moderate IgG antibody titers to spike protein by ELISA, and one bat on day 10 had low-titer neutralizing antibodies. CD4+ helper T cells became activated upon ex vivo recall stimulation with SARS-CoV-2 nucleocapsid peptide library and exhibited elevated mRNA expression of the regulatory T cell cytokines interleukin-10 and transforming growth factor-β, which may have limited inflammatory pathology. Collectively, these data show that Jamaican fruit bats are poorly susceptible to SARS-CoV-2 but that expression of human ACE2 in their lungs leads to robust infection and an adaptive immune response with low-titer antibodies and a regulatory T cell-like response that may explain the lack of prominent inflammation in the lungs. This model will allow for insight of how SARS-CoV-2 infects bats and how bat innate and adaptive immune responses engage the virus without overt clinical disease.

Background: Hepatocellular Carcinoma (HCC) is a common lethal digestive system tumor. The oxidative stress mechanism is crucial in the HCC genesis and progression.Methods: Our study analyzed single-cell and bulk sequencing data to compare the microenvironment of non-tumor liver tissues and HCC tissues. Through these analyses, we aimed to investigate the effect of oxidative stress on cells in the HCC microenvironment and identify critical oxidative stress response-related genes that impact the survival of HCC patients.Results: Our results showed increased oxidative stress in HCC tissue compared to non-tumor tissue. Immune cells in the HCC microenvironment exhibited higher oxidative detoxification capacity, and oxidative stress-induced cell death of dendritic cells was attenuated. HCC cells demonstrated enhanced communication with immune cells through the MIF pathway in a highly oxidative hepatoma microenvironment. Meanwhile, using machine learning and Cox regression screening, we identified PRDX1 as a predictor of early occurrence and prognosis in patients with HCC. The expression level of PRDX1 in HCC was related to dysregulated ribosome biogenesis and positively correlated with the expression of immunological checkpoints (PDCD1LG2, CTLA4, TIGIT, LAIR1). High PRDX1 expression in HCC patients correlated with better sensitivity to immunotherapy agents such as sorafenib, IGF-1R inhibitor, and JAK inhibitor.Conclusion: In conclusion, our study unveiled variations in oxidative stress levels between non-tumor liver and HCC tissues. And we identified oxidative stress gene markers associated with hepatocarcinogenesis development, offering novel insights into the oxidative stress response mechanism in HCC.

Orphaned colonies of Cryptotermes domesticus readily produce replacement reproductives and continue propagation. In this study, we aimed to investigate the production and fecundity of neotenic reproductives in 5-year-old colonies of C. domesticus after orphaning. All 15 experimental colonies were successfully re-established by the neotenic reproductive pair. Three types of neotenic reproductives with various wing-bud lengths were observed: type I with micro wing buds, type II with short wing buds, and type III with long wing buds. Four patterns of pairs made up of these neotenics, namely, type I + type II, type I + type III, type II + type II, and type II + type III, exhibited reproductive capacities similar to those of the primary reproductive pair. We speculated that these neotenic reproductives were derived from various nymphal instars. The 5-year-old colonies had three instars of nymphs, with the majority being in the second instar, followed by the first. Thus, the combination of neotenic reproductives with short wing buds and micro wing buds was the dominant differentiation pathway of the orphaned colonies. After the removal of the original primary reproductive pair, the nymphs matured into neotenic reproductives and took over reproduction in the colony in 107.40 ± 15.18 days. This study highlights the importance of quarantine and routine inspection of wood, as well as the significance of early prevention and control of C. domesticus infestation in wood. Moreover, this study confirms the high differentiation and reproductive capacities of C. domesticus.

Helium is the second most abundant element in the universe, and at low temperatures it becomes a quantum crystal with exotic physical properties such as second sound, superfluidity, and giant plasticity. Here authors prepare 2D solid helium at room temperature through diamond lattice confinement.

Abstract Background Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly influences the construction of an immunosuppressive microenvironment. This study aimed to investigate the important interactions between immune cells and their targeting drugs in liver carcinoma, by using single-cell and bulk transcriptomic data. Methods Single-cell and bulk transcriptomic data were retrieved from Gene Expression Omnibus (GSE159977, GSE136103, and GSE125449) and The Cancer Genome Atlas (TGCA-LIHC), respectively. Quality control, dimension reduction, clustering, and annotation were performed according to the Scanpy workflow based on Python. Cell–cell interactions were explored using the CellPhone database and CellChat. Trajectory analysis was executed using a partition-based graph abstraction method. The transcriptomic factors (TFs) were predicted using single-cell regulatory network inference and clustering (SCENIC). The target genes from TFs were used to establish a related score based on the TCGA cohort; this score was subsequently validated by survival, gene set enrichment, and immune cell infiltration analyses. Drug prediction was performed based on the Cancer Therapeutics Response Portal and PRISM Repurposing datasets. Results Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. After dimension reduction and clustering, twenty-two clusters were identified. Cell–cell interaction analyses indicated that macrophage-naive CD4 + T cell interaction significantly affect cancerous state. In brief, macrophages interact with naive CD4 + T cells via different pathways in different states. The results of SCENIC indicated that macrophages present in cancer cells were similar to those present during cirrhosis. A macrophage-naive CD4 + T cell (MNT) score was generated by the SCENIC-derived target genes. Based on the MNT score, five relevant drugs (inhibitor of polo-like kinase 1, inhibitor of kinesin family member 11, dabrafenib, ispinesib, and epothilone-b) were predicted. Conclusions This study reveals the crucial role of macrophage-naive CD4 + T cell interaction in the immunosuppressive microenvironment of liver carcinoma. Tumor-associated macrophages may be derived from cirrhosis and can initiate liver carcinoma. Predictive drugs that target the macrophage-naive CD4 + T cell interaction may help to improve the immunosuppressive microenvironment and prevent immune evasion. The relevant mechanisms need to be further validated in experiments and cohort studies. Graphical Abstract

Nanoparticle strengthening provides a crucial basis for developing high-performance materials, which often fails to work due to poor thermal stability. Here, the authors achieve thermally stable nanoparticles at 800~1000 °C in chemically complex alloys via controllable sluggish lattice diffusion.

We assessed the generalizability of machine learning methods using natural language processing (NLP) techniques to detect adverse drug events (ADEs) from clinical narratives in electronic medical records (EMRs). We constructed a new corpus correlating drugs with adverse drug events using 1,394 clinical notes of 47 randomly selected patients who received immune checkpoint inhibitors (ICIs) from 2011 to 2018 at The Ohio State University James Cancer Hospital, annotating 189 drug-ADE relations in single sentences within the medical records. We also used data from Harvard’s publicly available 2018 National Clinical Challenge (n2c2), which includes 505 discharge summaries with annotations of 1,355 single-sentence drug-ADE relations. We applied classical machine learning (support vector machine (SVM)), deep learning (convolutional neural network (CNN) and bidirectional long short-term memory (BiLSTM)), and state-of-the-art transformer-based (bidirectional encoder representations from transformers (BERT) and ClinicalBERT) methods trained and tested in the two different corpora and compared performance among them to detect drug–ADE relationships. ClinicalBERT detected drug–ADE relationships better than the other methods when trained using our dataset and tested in n2c2 (ClinicalBERT F-score, 0.78; other methods, F-scores, 0.61–0.73) and when trained using the n2c2 dataset and tested in ours (ClinicalBERT F-score, 0.74; other methods, F-scores, 0.55–0.72). Comparison among several machine learning methods demonstrated the superior performance and, therefore, the greatest generalizability of findings of ClinicalBERT for the detection of drug–ADE relations from clinical narratives in electronic medical records.

Abstract Background The ecology and evolution of phoretic mites and termites have not been well studied. In particular, it is unknown whether the specific relationship between mites and termites is commensal or parasitic. High phoretic mite densities have often been found to occur in weak termite colonies, suggesting that the relationship is closer to that of parasitism than commensalism. Results To examine this, Coptotermes formosanus was used as a carrier, and Acarus farris as the phoretic mite. We used video recordings to observe termite social immunity behaviors and bioassay to examine termite fitness. Our results showed that the attachment of the mite on the termite can enhance termite social immunity behaviors like alarm vibration and grooming frequency while decreasing the duration of individual grooming episodes in phoretic mites. Further, A. farris phoresy led to a 22.91% reduction in termite abdomen volume and a 3.31-fold increase in termite mortality. Conclusions When termites groom more frequently, the consequence is short duration of grooming bouts. This may be indicative of a trade-off which provides suggestive evidence that frequent social behaviors may cost termites energy. And this caused phoretic behavior hastened termites’ death, and helped propagate the population of mites feeding on dead termites. So, it provides a case for phoresy being a precursor to parasitism, and the specific relationship between A. farris and C. formosanus is closer to parasitism than to commensalism.

Abstract Objectives Whether curative‐intent radiotherapy could be safely applied to lung cancer patients with interstitial lung diseases (ILD) remains unclear. We aim to evaluate radiation induced lung toxicities (RILTs) and the efficacy of intensity‐modulated radiotherapy (IMRT) in these patients. ILD is characterized by inflammation or fibrosis in the interstitial tissue of the lung. Materials and Methods Stage III non–small cell lung cancer (NSCLC) and ILD patients treated with curative‐intent IMRT between 2010 and 2019 were retrospectively reviewed. Pre‐radiation computed tomography (CT) was scored according to a thin‐section CT scoring system for idiopathic pulmonary fibrosis. Results A total of 85 of 1261 stage III NSCLC patients were found with ILD. Seventeen (20%) of them developed G3+ (greater than or equal to grade 3) RILTs. The incidence abruptly dropped to 11.1%, 3.8%, and 0% for patients with honeycombing score ≤1, V20 1 and V20 ≥20% were independently associated with higher risk of G3+ RILTs. The median overall survival (OS) and progression‐free survival (PFS) were 14.0 months and 7.4 months in the whole group, whereas 26.5 months and 10.6 months in the low‐risk group (patients with honeycombing score 1 and V20 ≥20% were associated with high incidence of RILTs. However, patients with low risk might benefit from IMRT with acceptable toxicities and durable OS.