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Asexual development is the main propagation and transmission mode of Beauveria bassiana and the basis of its pathogenicity. The regulation mechanism of conidiation and the key gene resources for utilization are key links to improving the conidia yield and quality of Beauveria bassiana. Their clarification may promote the industrialization of fungal pesticides. Here, we compared the regulation of morphology, resistance to external stress, virulence, and nutrient utilization capacity between the upstream developmental regulatory gene fluG and the key genes brlA, abaA, and wetA in the central growth and development pathway. The results showed that the ΔbrlA and ΔabaA mutants completely lost the capacity to conidiate and that the ΔwetA mutant had seriously reduced conidiation capacity. Although the deletion of fluG did not reduce the conidiation ability as much as deletions of brlA, abaA, and wetA, it significantly reduced the fungal response to external stress, virulence, and nutrient utilization, while the deletion of the three other genes had little effect. Via transcriptome analysis and screening the yeast nuclear system library, we found that the differentially expressed genes in the ΔfluG mutants were concentrated in the signaling pathways of ABC transporters, propionate metabolism, tryptophan metabolism, DNA replication, mismatch repair, and fatty acid metabolism. FluG directly acted on 40 proteins that were involved in various signaling pathways such as metabolism, oxidative stress, and cell homeostasis. The analysis indicated that the regulatory function of fluG was mainly involved in DNA replication, cell homeostasis, fungal growth and metabolism, and the response to external stress. Our results revealed the biological function of fluG in asexual development and the responses to several environmental stresses as well as its influence on the asexual development regulatory network in B. bassiana. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer. The expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression. The correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells was also examined. A quantitative analysis of protein expression in macrophages and cancer cells revealed that PD-L1-positive cells expressed higher levels of B7-H3 than that of PD-L1-negative cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies. Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163+PD-L1+ macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68+, CD163+, and CK+ cells with PD-L1+ phenotypes had higher B7-H3 expression compared to PD-L1− cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies. [ABSTRACT FROM AUTHOR]

In the cutting process, there are many parameters that affect the cutting effect, and the same parameter has different degrees of influence on different performance indicators, which makes it difficult to select key parameters for parameter optimization and parameter combination evaluation while considering multiple performance indicators at the same time. The process of titanium alloy milling with an integrated end mill is studied herein. The values of cutting tool flank face wear and material removal rates are obtained with experimental and analytical methods. Numerical characteristics and causes of the cutting tool flank face wear at different stages are also analyzed. The dynamic, comprehensive evaluation method based on the double incentives model is used to evaluate the dynamic, comprehensive importance of cutting parameters in view of the problem of considering multiple performance indicators and the characteristics of the dynamic change in performance indicators in the cutting process. According to the result of a dynamic, comprehensive evaluation, the cutting parameters with the highest comprehensive importance are selected. Finally, the radar map is used to plot the comprehensive importance of the cutting parameters. The overall comprehensive importance of each cutting parameter is intuitively displayed as well. As a result of the research, the dynamic, comprehensive evaluation method based on the double incentives model has a good application value in the evaluation of tool performance in the cutting process and can quickly select the best tool performance parameter combination; it is established that the most comprehensive parameter is the cutting speed, and the cutting width is the second most important. In turn, the comprehensive importance of the cutting depth is the lowest. [ABSTRACT FROM AUTHOR]

The collateral system is a compensatory mechanism activated in the acute phase of an ischemic stroke. It increases brain perfusion to the hypoperfused area. Arteries of the Willis' circle supply antegrade blood flow, while pial (leptomeningeal) arteries direct blood via retrograde flow. The aim of our retrospective study was to investigate the relationship between both collateral systems, computed tomography perfusion (CTP) values, and functional outcomes in acute stroke patients. Overall, 158 patients with anterior circulation stroke who underwent mechanical thrombectomy were included in the study. We analyzed the presence of communicating arteries and leptomeningeal arteries on computed tomography angiography. Patients were divided into three groups according to their collateral status. The main outcomes were the rate of functional independence 3 months after stroke (modified Rankin scale score, mRS) and mortality rate. Our study suggests that the collateral status, as indicated by the three groups (unfavorable, intermediate, and favorable), is linked to CT perfusion parameters, potential recuperation ratio, and stroke outcomes. Patients with favorable collateral status exhibited smaller core infarct and penumbra volumes, higher mismatch ratios, better potential for recuperation, and improved functional outcomes compared to patients with unfavorable or intermediate collateral status. [ABSTRACT FROM AUTHOR]

Developing materials with dynamic room-temperature phosphorescence (RTP) properties is crucial for expanding the applications of organic light-emitting materials. In this study, we designed and synthesized two novel RTP molecules by combining functional units, incorporating the folded unit thianthrene into the classic luminescent cores thioxanthone or anthraquinone to construct TASO and TA2O. In this combination, the TA unit contributes to the enhancement of spin–orbit coupling (SOC), while the luminescent core governs the triplet energy level. After the strategic manipulation of SOC using the thianthrene unit, the target molecules exhibited a remarkable enhancement in RTP performance. This strategy led to the successful development of TASO and TA2O molecules with outstanding dynamic RTP properties when exposed to continuous ultraviolet irradiation, a result that can be ascribed to their efficient RTP, improved absorption ability, and oxygen-sensitive RTP properties. Leveraging the oxygen-mediated ultraviolet-radiation-induced RTP enhancement in TASO-doped polymer films, we developed a novel time-resolved detection technique for identifying phase separation in polymers with varying oxygen permeability. This research offers a promising approach for constructing materials with dynamic RTP properties. [ABSTRACT FROM AUTHOR]

The changes in biomass (including yield), copper (Cu) concentration, and the accumulation of wheat (Triticum aestivum. L) in response to soil Cu pollution under nighttime warming had still not been explored. Hence, this study was carried out, and these variations were analyzed from a physiological perspective. Pot trials were performed at two levels of ambient temperatures (no-warming (NT) and average nighttime warming of 0.28 °C (WT)) and two levels of soil Cu concentrations (control check without Cu application (CK) and 100 mg/kg Cu application (Cu)). Soil was collected from the carbonate cinnamon soil region of central China. The warming effects of the passive nighttime warming system were prominent, and the average increment was 0.28 °C. Antioxidant enzyme activities were promoted by warming (p < 0.05) and Cu. The highest yield was achieved in NT-Cu, mainly attributed to relatively strong root activity and photosynthesis caused by supplemental Cu, but the Cu concentration in its grains was close to the threshold (10 mg/kg) for Cu concentration in foodstuff and could present a potential food safety risk. Though nighttime warming did not increase the total biomass and yield of wheat, it decreased the Cu accumulation of wheat grown in Cu-contaminated soil, especially in grains. Moreover, WT-CK and WT-Cu increased the Cu concentration in the roots and glumes and reduced the Cu concentration in grains by 13.09% and 55.84%, respectively, probably because of a lower transpiration rate. Among them, the Cu concentration of grains in WT-Cu was the lowest and significantly lower than other applications. Our findings reveal that nighttime warming has the potential to reduce the Cu risk of grains in wheat grown in the Cu-contaminated carbonate cinnamon soil region of central China and could then provide a theoretical reference for risk assessment of food quality for wheat subjected to dual stress from nighttime warming and Cu pollution. [ABSTRACT FROM AUTHOR]

The ridge–furrow with plastic film mulching (RF) system has been widely adopted in rain-fed crop planting due to its potential to enhance crop yield and water use efficiency. However, the impact of the RF system on maize lodging resistance, particularly when nitrogen fertilizer is applied, remains uncertain. Therefore, a two-year field experiment was carried out with two planting systems (FP: flat planting and RF) and two nitrogen application rates (N180: 180 kg·N ha−1 and N300: 300 kg·N ha−1) to assess the risk of lodging in maize. The results showed that compared to FP, RF resulted in a significant increase of 78.7% in lodging rate. In addition, the lodging rate increased by 22.6% with increasing nitrogen fertilizer application. The lignin content increased by 43.4%, while the stalk bending strength rose by 42.5%, under RF compared to the FP system. These improvements in the mechanical properties of maize stalks contributed to the improved lodging resistance index of RF, which was found to be approximately 21.3% higher than that of FP. In addition, high nitrogen application rates increased the risk of lodging for different planting patterns over two years. In conclusion, fertilization of spring maize with 300 kg·N ha−1 under the RF system led to higher yields but increased lodging rates. The risk of lodging should be considered when planting maize under the RF system. The results of this study can provide scientific basis and technical support for the optimization of rain-fed maize cultivation measures in the Loess Plateau. [ABSTRACT FROM AUTHOR]

Sucrose phosphate synthase (SPS) is an important link in the process of sugar metabolism. In addition, it is also involved in abiotic stresses in plants. In order to study the SPS gene family and its role in abiotic stress, we identified the MdSPS gene family members by bioinformatics methods such as correlation analysis, the HMM method, and the Clustering method, and analyzed the transient expression of MdSPS genes by quantitative real-time fluorescence analysis (qRT-PCR). The MdSPS gene family consists of a total of 19 members divided into three subfamilies distributed on 14 chromosomes in apples. The MdSPS gene family has 12 collinearity gene pairs, indicating significant duplication. Most members of this family contain a large number of plant hormone response elements, light-inducible elements, and abiotic stress response elements 2kb upstream of the promoter. Codon bias analysis shows that there are 28 high-frequency codons and no codons with strong preference in this family. Gene chip results showed that only MdSPS2, MdSPS3, MdSPS11, and MdSPS17 were up-regulated in roots, and they were all members of subfamily C. The qRT-PCR analysis showed that all members of this family responded significantly to drought stress, salt stress, and low temperature stress. Interestingly, the relative expression of MdSPS12 was significantly down-regulated under salt stress and low temperature stress. In addition, the expression of MdSPS3, MdSPS8, MdSPS11, and MdSPS17 was more than 20 fold higher than that of the control under drought stress, salt stress, and low temperature stress. These four genes could be candidates for molecular breeding in the MdSPS family. [ABSTRACT FROM AUTHOR]

Beauveria bassiana is an entomopathognic fungus, which is widely employed in the biological control of pests. Gene disruption is a common method for studying the functions of genes involved in fungal development or its interactions with hosts. However, generating gene deletion mutants was a time‐consuming work. The transcriptional factor OpS3 has been identified as a positive regulator of a red secondary metabolite oosporein in B. bassiana. In this study, we have designed a new screening system by integrating a constitutive OpS3 expression cassette outside one of the homologous arms of target gene. Ectopic transformants predominantly exhibit a red colour with oosporein production, while knockout mutants appear as white colonies due to the loss of the OpS3 expression cassette caused by recombinant events. This screening strategy was used to obtain the deletion mutants of both tenS and NRPS genes. Correct mutants were obtained by screening fewer than 10 mutants with a positive efficiency ranging from 50% to 75%. This system significantly reduces the workload associated with DNA extraction and PCR amplification, thereby enhancing the efficiency of obtaining correct transformants in B. bassiana. [ABSTRACT FROM AUTHOR]

Polyploid plants often exhibit enhanced stress tolerance. Switchgrass is a perennial rhizomatous bunchgrass that is considered ideal for cultivation in marginal lands, including sites with saline soil. In this study, we investigated the physiological responses and transcriptome changes in the octoploid and tetraploid of switchgrass (Panicum virgatum L. 'Alamo') under salt stress. We found that autoploid 8× switchgrass had enhanced salt tolerance compared with the amphidiploid 4× precursor, as indicated by physiological and phenotypic traits. Octoploids had increased salt tolerance by significant changes to the osmoregulatory and antioxidant systems. The salt-treated 8× Alamo plants showed greater potassium (K+) accumulation and an increase in the K+/Na+ ratio. Root transcriptome analysis for octoploid and tetraploid plants with or without salt stress revealed that 302 upregulated and 546 downregulated differentially expressed genes were enriched in genes involved in plant hormone signal transduction pathways and were specifically associated with the auxin, cytokinin, abscisic acid, and ethylene pathways. Weighted gene co-expression network analysis (WGCNA) detected four significant salt stress-related modules. This study explored the changes in the osmoregulatory system, inorganic ions, antioxidant enzyme system, and the root transcriptome in response to salt stress in 8× and 4× Alamo switchgrass. The results enhance knowledge of the salt tolerance of artificially induced homologous polyploid plants and provide experimental and sequencing data to aid research on the short-term adaptability and breeding of salt-tolerant biofuel plants. [ABSTRACT FROM AUTHOR]

It is well known that application of exogenous trehalose can enhance the heat resistance of plants. To investigate the underlying molecular mechanisms by which exogenous trehalose induces heat resistance in C. sinensis, a combination of physiological and transcriptome analyses was conducted. The findings revealed a significant increase in the activity of superoxide dismutase (SOD) and peroxidase (POD) upon treatment with 5.0 mM trehalose at different time points. Moreover, the contents of proline (PRO), endogenous trehalose, and soluble sugar exhibited a significant increase, while malondialdehyde (MDA) content decreased following treatment with 5.0 mM trehalose under 24 h high-temperature stress (38 °C/29 °C, 12 h/12 h). RNA-seq analysis demonstrated that the differentially expressed genes (DEGs) were significantly enriched in the MAPK pathway, plant hormone signal transduction, phenylpropanoid biosynthesis, flavone and flavonol biosynthesis, flavonoid biosynthesis, and the galactose metabolism pathway. The capability to scavenge free radicals was enhanced, and the expression of a heat shock factor gene (HSFB2B) and two heat shock protein genes (HSP18.1 and HSP26.5) were upregulated in the tea plant. Consequently, it was concluded that exogenous trehalose contributes to alleviating heat stress in C. sinensis. Furthermore, it regulates the expression of genes involved in diverse pathways crucial for C. sinensis under heat-stress conditions. These findings provide novel insights into the molecular mechanisms underlying the alleviation of heat stress in C. sinensis with trehalose. [ABSTRACT FROM AUTHOR]

Adolescent idiopathic scoliosis (AIS) is a three-dimensional structural deformity of the spine that affects 2–3% of adolescents under the age of 16. AIS etiopathogenesis is not completely understood; however, the disease phenotype is correlated to multiple genetic loci and results from genetic–environmental interactions. One of the primary, still unresolved issues is the implementation of reliable diagnostic and prognostic markers. For clinical management improvement, predictors of curve progression are particularly needed. Recently, an epigenetic contribution to AIS development and progression was proposed; nevertheless, validation of data obtained in peripheral tissues and identification of the specific mechanisms and genes under epigenetic control remain limited. In this study, we propose a methodological approach for the identification of epigenetic markers of AIS progression through an original workflow based on the preliminary characterization of local expression of candidate genes in tissues directly involved in the pathology. The feasibility of the proposed methodological protocol has been originally tested here in terms of identification of the putative epigenetic markers of AIS progression, collection of the different tissues, retrieval of an appropriate amount and quality of RNA and DNA, and identification of suitable reference genes. [ABSTRACT FROM AUTHOR]

The lung is prone to infections from respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A challenge in combating these infections is the difficulty in targeting antiviral activity directly at the lung mucosal tract. Boosting the capability of the respiratory mucosa to trigger a potent immune response at the onset of infection could serve as a potential strategy for managing respiratory infections. This study focused on screening immunomodulators to enhance innate immune response in lung epithelial and immune cell models. Through testing various subfamilies and pathways of pattern recognition receptors (PRRs), the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family was found to selectively activate innate immunity in lung epithelial cells. Activation of NOD1 and dual NOD1/2 by the agonists TriDAP and M-TriDAP, respectively, increased the number of IL-8+ cells by engaging the NF-κB and interferon response pathways. Lung epithelial cells showed a stronger response to NOD1 and dual NOD1/2 agonists compared to control. Interestingly, a less-pronounced response to NOD1 agonists was noted in PBMCs, indicating a tissue-specific effect of NOD1 in lung epithelial cells without inducing widespread systemic activation. The specificity of the NOD agonist pathway was confirmed through gene silencing of NOD1 (siRNA) and selective NOD1 and dual NOD1/2 inhibitors in lung epithelial cells. Ultimately, activation induced by NOD1 and dual NOD1/2 agonists created an antiviral environment that hindered SARS-CoV-2 replication in vitro in lung epithelial cells. [ABSTRACT FROM AUTHOR]

The CCT gene family is present in plants and is involved in biological processes such as flowering, circadian rhythm regulation, plant growth and development, and stress resistance. We identified 87, 62, 46, and 40 CCTs at the whole-genome level in B. napus, B. rapa, B. oleracea, and A. thaliana, respectively. The CCTs can be classified into five groups based on evolutionary relationships, and each of these groups can be further subdivided into three subfamilies (COL, CMF, and PRR) based on function. Our analysis of chromosome localization, gene structure, collinearity, cis-acting elements, and expression patterns in B. napus revealed that the distribution of the 87 BnaCCTs on the chromosomes of B. napus was uneven. Analysis of gene structure and conserved motifs revealed that, with the exception of a few genes that may have lost structural domains, the majority of genes within the same group exhibited similar structures and conserved domains. The gene collinearity analysis identified 72 orthologous genes, indicating gene duplication and expansion during the evolution of BnaCCTs. Analysis of cis-acting elements identified several elements related to abiotic and biotic stress, plant hormone response, and plant growth and development in the promoter regions of BnaCCTs. Expression pattern and protein interaction network analysis showed that BnaCCTs are differentially expressed in various tissues and under stress conditions. The PRR subfamily genes have the highest number of interacting proteins, indicating their significant role in the growth, development, and response to abiotic stress of B. napus. [ABSTRACT FROM AUTHOR]

Simple Summary: Guidelines from oncologic societies recommend high-dose systemic corticosteroids as the primary therapy with or without biologics for moderate to severe colitis secondary to immune checkpoint inhibitors; budesonide is a gut selective steroid that undergoes first past metabolism with less systemic adverse events in comparison to systemic steroids, although its use has not been studied or established for colitis secondary to immune checkpoint inhibitors. Budesonide employed for other gastrointestinal diseases, such as inflammatory bowel disease, is associated with decreased infections and metabolic side effects. In our analysis, we observed that budesonide may be an effective strategy to treat and prevent the recurrence of colitis with similar results as systemic corticosteroids in this immunocompromised cancer patient population. Background: Current treatment guidelines for moderate to severe colitis (IMC) secondary to immune checkpoint inhibitors (ICI) recommend systemic corticosteroids as the primary therapy in conjunction with biologics, namely infliximab and/or vedolizumab. We aimed to explore the efficacy and safety of oral budesonide in the treatment of IMC. Methods: We performed a retrospective analysis at MD Anderson Cancer Center of adult cancer patients with a confirmed (based on clinical, radiographic and laboratory assessment) diagnosis of IMC between 1 January 2015 and 31 November 2022, treated with budesonide. Data collection included demographics, oncologic history, IMC-related information and outcomes up to 6 months after the last dose of ICI. Results: Our sample (n = 69) comprised primarily of Caucasian (76.8%) females (55.1%). The majority of patients received combination therapy with anti-PD-1/L1 and anti-CTLA-4 (49.3%), and the most common malignancy treated was melanoma (37.6%). The median grade of diarrhea was 3 and of colitis was 2. Of the 50 patients who underwent endoscopic evaluation, a majority had non-ulcerative inflammation (64%) and active colitis on histology (78%). Budesonide was used as primary treatment at onset of IMC in 56.5% patients, as well as a bridging therapy from systemic corticosteroids in 33.3%. Less than half of the patients (44.9%) required additional therapies such as biologics or fecal microbiota transplant. Additionally, 75.3% of patients achieved full remission of IMC and 24.6% had a recurrence of IMC. ICI was resumed in 31.9% of patients and 17.4% received other forms of cancer therapies. Conclusions: Budesonide may be an effective strategy to treat and prevent the recurrence of IMC. The remission rates observed in our analysis with budesonide alone are comparable to systemic corticosteroids. Patients that require an extended duration of steroid exposure and those with moderate to severe colitis may benefit from budesonide given its lower risk of infection and complications. Furthermore, we observe that budesonide may serve as a successful bridge from systemic corticosteroids with subsequent biologic treatment. Larger prospective studies are necessary to determine the role of budesonide as well as its safety profile. [ABSTRACT FROM AUTHOR]

Oral cancer (OC) is among the most common malignancies in the world. Despite advances in therapy, the worst-case scenario for OC remains metastasis, with a 50% survival rate. Therefore, it is critical to comprehend the pathophysiology of the condition and to create diagnostic and treatment plans for OC. The development of high-throughput genome sequencing has revealed that over 90% of the human genome encodes non-coding transcripts, or transcripts that do not code for any proteins. This paper describes the function of these different kinds of non-coding RNAs (ncRNAs) in OC as well as their intriguing therapeutic potential. The onset and development of OC, as well as treatment resistance, are linked to dysregulated ncRNA expression. These ncRNAs' potentially significant roles in diagnosis and prognosis have been suggested by their differing expression in blood or saliva. We have outlined every promising feature of ncRNAs in the treatment of OC in this study. [ABSTRACT FROM AUTHOR]

Considering the characteristics of both quality and quantity losses in fresh produce as well as the existence of spot markets, optimal retailer ordering, pricing, and freshness-keeping decisions through the single ordering policy (firm ordering only or option ordering only) and the mixed ordering policy (firm ordering and option ordering simultaneously) are constructed based on option contracts and analyzed for the retailer under different ordering policies. The results show that there is a unique optimal pricing, ordering, and freshness-keeping decision under all three ordering policies, but there is no joint decision. The optimal freshness-keeping and retail price under the mixed ordering policy are lower than those under the option ordering only but higher than those under the firm ordering only. When only a single order can be placed, the retailer's optimal ordering policy is determined by demand risk. When all three ordering policies are available, the optimal ordering policy for the retailer is the mixed ordering policy. A spot market will weaken the role of option contracts in mitigating supply chain risks, and the larger the risk, the more significant the role of the spot market. [ABSTRACT FROM AUTHOR]

Tomato (Solanum lycopersicum) is the most important vegetable and fruit crop in the family Solanaceae worldwide. Numerous pests and pathogens, especially viruses, severely affect tomato production, causing immeasurable market losses. In Taiwan, the cultivation of tomato crops is mainly threatened by insect-borne viruses, among which pepper veinal mottle virus (PVMV) is one of the most prevalent. PVMV is a member of the genus Potyvirus of the family Potyviridae and is non-persistently transmitted by aphids. Its infection significantly reduces tomato fruit yield and quality. So far, no PVMV-resistant tomato lines are available. In this study, we performed nitrite-induced mutagenesis of the PVMV tomato isolate Tn to generate attenuated PVMV mutants. PVMV Tn causes necrotic lesions in Chenopodium quinoa leaves and severe mosaic and wilting in Nicotiana benthamiana plants. After nitrite treatment, three attenuated PVMV mutants, m4-8, m10-1, and m10-11, were selected while inducing milder responses to C. quinoa and N. benthamiana with lower accumulation in tomato plants. In greenhouse tests, the three mutants showed different degrees of cross-protection against wild-type PVMV Tn. m4-8 showed the highest protective efficacy against PVMV Tn in N. benthamiana and tomato plants, 100% and 97.9%, respectively. A whole-genome sequence comparison of PVMV Tn and m4-8 revealed that 20 nucleotide substitutions occurred in the m4-8 genome, resulting in 18 amino acid changes. Our results suggest that m4-8 has excellent potential to protect tomato crops from PVMV. The application of m4-8 in protecting other Solanaceae crops, such as peppers, will be studied in the future. [ABSTRACT FROM AUTHOR]

Evaluating prospective graduates' health literacy profiles before they enter the job market is crucial. Our research aimed to explore the health literacy levels of medical and health students by assessing their ability to obtain health-related information, understand healthcare systems, use e-health, and be informed about vaccination as well as to explore the factors associated with health literacy. Short versions of the HLS19-Q12 were used for a cross-sectional survey that was carried out among 1042 students enrolled in various medical and health educational programs at three medical universities in Kazakhstan between September and November of 2023. Additionally, instruments such as Digital Health Literacy (HLS19-DIGI), Navigational Health Literacy (HLS19-NAV), and Vaccination Health Literacy (HLS19-VAC) were employed. The score of General Health Literacy was 88.26 ± 17.5. One in eight students encountered difficulties in Vaccination Health Literacy. Despite overall high health literacy, Navigational Health Literacy posed challenges for all students. The Public Health students exhibited the highest General Health Literacy (91.53 ± 13.22), followed by students in Nursing, General Medicine, other educational programs (Dentistry and Biomedicine) and Pharmacy. Financial constraints for medication and medical examinations significantly influenced health literacy across all types of individuals. Since comprehensive health literacy instruction or interventions are still uncommon in the curricula, it seems reasonable to develop and incorporate appropriate courses for medical and health educational programs. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer mortality. Treatment of HCC remains challenging, especially for those with advanced stages or those with postoperative recurrence. Molecular research of signaling pathways to afford new options of treatments is urgent. Moreover, among the various signaling pathways, the Sonic hedgehog (SHH) signaling pathway is implicated in multiple aspects of HCC, including cancer development, growth, invasiveness, recurrence, metastasis, the tumor microenvironment, and the maintenance of its cancer stem cells. The SHH signaling pathway also contributes to the resistance of HCC to chemotherapy, target therapy, and radiation therapy. This narrative review of the update studies reappraises the roles of SHH signaling in HCC. A deeper understanding of the SHH signaling pathway is crucial. It may provide more insights into the regulatory processes to establish novel treatments for HCC. HCC remains one of the leading causes of cancer-related death globally. The main challenges in treatments of hepatocellular carcinoma (HCC) primarily arise from high rates of postoperative recurrence and the limited efficacy in treating advanced-stage patients. Various signaling pathways involved in HCC have been reported. Among them, the Sonic hedgehog (SHH) signaling pathway is crucial. The presence of SHH ligands is identified in approximately 60% of HCC tumor tissues, including tumor nests. PTCH-1 and GLI-1 are detected in more than half of HCC tissues, while GLI-2 is found in over 84% of HCC tissues. The SHH signaling pathway (including canonical and non-canonical) is involved in different aspects of HCC, including hepatocarcinogenesis, tumor growth, tumor invasiveness, progression, and migration. The SHH signaling pathway also contributes to recurrence, metastasis, modulation of the cancer microenvironment, and sustaining cancer stem cells. It also affects the resistance of HCC cells to chemotherapy, target therapy, and radiotherapy. Reappraisal of the roles of the SHH signaling pathway in HCC may trigger some novel therapies for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Survival for many pediatric cancers has improved over recent decades. However, for pediatric patients with solid tumors that fail to respond to standard therapies, or relapse after initial response, outcomes generally remain poor, indicating a need for novel and improved treatments. Many cancers have an impaired ability to repair DNA damage, which in excess can become toxic to cells. As such, one potential approach for these challenging cancers is to target the DNA damage repair pathways of cancer cells, with the goal of inducing a lethal amount of DNA damage. This article reviews the current research efforts into targeting DNA damage repair pathways in pediatric extracranial solid tumors. It reviews the biology of DNA damage repair pathways, the biology of several extracranial pediatric cancers, the preclinical research investigating targeting the DNA damage repair in pediatric cancers, and the clinical trials using these agents in patients. This article also reviews the ability to harness a patient's immune system to kill cancer cells, and the research that has been done investigating ways in which DNA damage can activate the anti-tumor immune response. DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR. [ABSTRACT FROM AUTHOR]

Background: Immunomodulating therapies, which are commonly used in patients with Crohn's disease (CD) and ulcerative colitis (UC), have been linked to an increased risk of contracting opportunistic infectious diseases, the majority of which are preventable through vaccination. Nonetheless, vaccination rates in these patients are suboptimal, and frequently lower than in the general population. The COVID-19 immunization schedule provided a new scenario for investigating vaccine acceptance in patients with inflammatory bowel disease (IBD), with uncertainty and concerns emerging and the number of subjects receiving the third and fourth doses of the vaccine gradually decreasing. This study investigated IBD patients' attitudes towards previous COVID-19 vaccine programs and identified the factors that influence their adherence. It considered demographic and disease-related factors as well as the role of gastroenterologists and primary care physicians (PCPs). Methods: Data were collected through a self-completed questionnaire administered to all adult IBD patients (age > 18) who visited the Gastroenterology, Hepatology, and Nutrition division at the University of L'Aquila (Italy) for a regular follow-up between November 2021 and December 2022. Non-IBD gastroenterological outpatients who visited during the same period were included as a control group. Results: A total of 178 patients were included in the analysis. The IBD group consisted of 77 patients, 48.1% with CD and 51.9% with UC; the mean age was 49.5 years and 51.9% were female. Overall, 94.8% of IBD patients had undergone at least one vaccine dose and 79.2% had received two doses, versus 8% of the control group (p < 0.0001). A total of 84.4% of IBD patients reported their propensity towards COVID-19 vaccination, with an average agreement score significantly higher than the controls (p = 0.0044). The trust of IBD patients in the effectiveness of the COVID-19 vaccine (p < 0.0001) and its role in hastening pandemic resolution (p < 0.0001) is strongly related to motivation and propensity. Concerns about the safety of the COVID-19 vaccine in IBD (p = 0.0202) and fear of vaccine-induced flare-ups (p = 0.0192) were reported as the main barriers. No correlation was found between COVID-19 vaccine propensity and clinical features like the type of IBD, years of disease, activity, and ongoing treatment. Regarding the recommendations received from physicians to get vaccinated against COVID-19, IBD patients relied heavily on their gastroenterologists for advice, while the control group relied mainly on their PCPs. Conclusions: The overall positive attitude towards vaccinations reported in our study was better than that observed for other vaccines. The relationship of trust with the gastroenterologist should be used to boost vaccination against other preventable diseases in IBD patients. Our findings add information on the factors influencing vaccine propensity, which can be used to improve current vaccination strategies. [ABSTRACT FROM AUTHOR]

Offshore wind farms on the east offshore of Korea to produce multi-GW power from floating wind platforms are being planned. The objectives of the present study are to develop a new TLP-type floating wind platform with a 15 MW turbine for the planned site and to confirm the feasibility of the TLP design under extreme typhoon environments. The concept design of the 15 MW TLP floating platform was completed for installation at a water depth of 137 m. The platform was vertically moored with highly pretensioned wire rope tendons. The platform and tendons were designed to withstand extreme conditions for up to 50 years. Additionally, a platform with an integrated turbine was designed to be wet-towable from the quayside without dedicated vessels to minimize the pre-service cost and risk. An extreme response analysis was conducted to evaluate the platform motion, acceleration, airgap and tendon tension for wave variation, intact and damaged condition of the tendon, environment heading change, and water level variation. The platform design results were validated using the design criteria from the industry standards and recommendations, and the design was verified to comply with the design requirements for the planned sites. [ABSTRACT FROM AUTHOR]

Medium-carbon, high-strength steels are widely used in the field of hydrogen energy because of their good mechanical properties, and they can be readily tailored by heat treatment processes such as the normalizing–tempering (N&T) and quenching–tempering (Q&T) methods. The hydrogen embrittlement (HE) susceptibility of a medium-carbon, high-strength steel was investigated utilizing microstructural characterization with scanning electron microscopy (SEM), the electron backscatter diffraction (EBSD) technique, and transmission electron microscopy (TEM). A study was also conducted on the steel's hydrogen transport behavior as affected by the N&T and Q&T treatments. The steel contained more hydrogen traps, such as dislocations, grain boundaries, lath boundaries, and carbide interfaces, after the Q&T process, which was associated with a lower HE sensitivity when comparing the two treatments. In comparison, the N&T process produced larger-size and lesser-density carbides distributed along the grain boundaries, and this resulted in a relatively higher HE susceptibility, as revealed by the slow-strain-rate tensile (SSRT) tests of the hydrogen-charged steels and by the fractographic study of the fracture surface. [ABSTRACT FROM AUTHOR]

We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom's syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC. [ABSTRACT FROM AUTHOR]

The effect of hydrogen content on the deformation and fracture behavior of 27Cr−4Mo−2Ni super ferritic stainless steel (SFSS) was investigated in this study. It was shown that the plasticity and yield strength of SFSS were very susceptible to hydrogen content. The introduction of hydrogen led to a significant decrease in elongation and a concurrent increase in yield strength. Nevertheless, a critical threshold was identified in the elongation reduction, after which the elongation remained approximately constant even with more hydrogen introduced, while the yield strength exhibited a monotonic increase with increasing hydrogen content within the experimental range, attributed to the pinning effect of the hydrogen Cottrell atmosphere on dislocations. Furthermore, the hydrogen-charged SFSS shows an apparent drop in flow stress after upper yielding and a reduced work hardening rate during the subsequent plastic deformation. The more hydrogen is charged, the more the flow stress drops, and the lower the work hardening rate becomes. [ABSTRACT FROM AUTHOR]

In recent years, the incidence of fungal infections in humans has increased dramatically, accompanied by an expansion in the number of species implicated as etiological agents, especially environmental fungi never involved before in human infection. Among fungal pathogens, Candida species are the most common opportunistic fungi that can cause local and systemic infections, especially in immunocompromised individuals. Candida albicans (C. albicans) is the most common causative agent of mucosal and healthcare-associated systemic infections. However, during recent decades, there has been a worrying increase in the number of emerging multi-drug-resistant non-albicans Candida (NAC) species, i.e., C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. auris, and C. ciferrii. In particular, Candida ciferrii, also known as Stephanoascus ciferrii or Trichomonascus ciferrii, is a heterothallic ascomycete yeast-like fungus that has received attention in recent decades as a cause of local and systemic fungal diseases. Today, the new definition of the S. ciferrii complex, which consists of S. ciferrii, Candida allociferrii, and Candida mucifera, was proposed after sequencing the 18S rRNA gene. Currently, the S. ciferrii complex is mostly associated with non-severe ear and eye infections, although a few cases of severe candidemia have been reported in immunocompromised individuals. Low susceptibility to currently available antifungal drugs is a rising concern, especially in NAC species. In this regard, a high rate of resistance to azoles and more recently also to echinocandins has emerged in the S. ciferrii complex. This review focuses on epidemiological, biological, and clinical aspects of the S. ciferrii complex, including its pathogenicity and drug resistance. [ABSTRACT FROM AUTHOR]

Cement concrete pavements are crucial to urban infrastructure, significantly influencing road safety and environmental sustainability with their anti-skid and noise reduction properties. However, while texturing techniques like transverse grooving have been widely adopted to enhance skid resistance, they may inadvertently increase road noise. This study addressed the critical need to optimize pavement textures to balance improved skid resistance with noise reduction. Tests were conducted to assess the influence of surface texture on skid resistance and noise, exploring the relationship between texture attributes and their performance in these areas. The investigation examined the effects of texture representation methods, mean profile depth, and the high-speed sideway force coefficient (SFC) on noise intensity and pavement skid resistance. The findings revealed that transverse grooves significantly improved the SFC, enhancing skid resistance. In contrast, longitudinal burlap drag, through its micro- and macro-texture adjustments, effectively reduced vibration frequencies between the tire and pavement, thus mitigating noise. Utilizing the TOPSIS multi-objective optimization framework, an optimization model for pavement textures was developed to augment skid resistance and noise reduction at varying speeds. The results indicated that at 60 km/h, an optimal balance of groove width, depth, and spacing yielded superior skid resistance with a minimal noise increase. At 80 km/h, increased groove spacing and depth were shown to effectively decrease noise while maintaining efficient water evacuation. The optimal pavement texture design must consider the specific context, including traffic volume, vehicle types, and operating speeds. This study provides essential guidance for optimizing urban cement concrete pavement textures, aiming to diminish traffic noise and bolster road safety. [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC), including both non-small (NSCLC) and small (SCLC) subtypes, is currently treated with a combination of chemo- and immunotherapy. However, predictive biomarkers to identify high-risk patients are needed. Here, we explore the role of peripheral blood mononuclear cells (PBMCs) as a tool for novel biomarkers searching. Methods: We analyzed the expression of the cGAS-STING pathway, a key DNA sensor that activates during chemotherapy, in PBMCs from LC patients divided into best responders (BR), responders (R) and non-responders (NR). The PBMCs were whole exome sequenced (WES). Results: PBMCs from BR and R patients of LC cohorts showed the highest levels of STING (p < 0.0001) and CXCL10 (p < 0.0001). From WES, each subject had at least 1 germline/somatic alteration in a DDR gene and the presence of more DDR gene mutations correlated with clinical responses, suggesting novel biomarker implications. Thus, we tested the effect of the pharmacological DDR inhibitor (DDRi) in PBMCs and in three-dimensional spheroid co-culture of PBMCs and LC cell lines; we found that DDRi strongly increased cGAS-STING expression and tumor infiltration ability of immune cells in NR and R patients. Furthermore, we performed FACS analysis of PBMCs derived from LC patients from the BR, R and NR cohorts and we found that cytotoxic T cell subpopulations displayed the highest STING expression. Conclusions: cGAS-STING signaling activation in PBMCs may be a novel potential predictive biomarker for the response to immunotherapy and high levels are correlated with a better response to treatment along with an overall increased antitumor immune injury. [ABSTRACT FROM AUTHOR]

With the increasingly strict limitations on emission standards of vehicles, deep desulfurization in fuel is indispensable for social development worldwide. In this study, a series of hybrid materials based on SiO2-supported polyoxometalate ionic liquid were successfully prepared via a facile ball milling method and employed as catalysts in the aerobic oxidative desulfurization process. The composition and structure of prepared samples were studied by various techniques, including FT-IR, UV-vis DRS, wide-angle XRD, BET, XPS, and SEM images. The experimental results indicated that the synthesized polyoxometalate ionic liquids were successfully loaded on SiO2 with a highly uniform dispersion. The prepared catalyst (C16PMoV/10SiO2) exhibited good desulfurization activity on different sulfur compounds. Moreover, the oxidation product and active species in the ODS process were respectively investigated via GC-MS and ESR analysis, indicating that the catalyst can activate oxygen to superoxide radicals during the reaction to convert DBT to its corresponding sulfone in the fuel. [ABSTRACT FROM AUTHOR]

Developing high−efficiency membrane materials for the rapid removal of organic dyes is crucial but remains a challenge. Polyoxometalates (POMs) clusters with anionic structures are promising candidates for the removal of cationic dyes via electrostatic interactions. However, their shortcomings, such as their solubility and inability to be mass−produced, hinder their application in water pollution treatment. Here, we propose a simple and green strategy utilizing the room temperature stirring method to mass produce nanoscale polyoxometalate−based metal−organic frameworks (POMOFs) with porous rhomboid−shaped dodecahedral and hexagonal prism structures. The products were labeled as POMOF1 (POMOF-PW12) and POMOF2 (POMOF-PMo12). Subsequently, a series of x wt% POMOF1/PAN (x = 0, 3, 5, and 10) nanofiber membranes (NFMs) were prepared using electrospinning technology, where polyacrylonitrile (PAN) acts as a "glue" molecule facilitating the bonding of POMOF1 nanoparticles. The as−prepared samples were comprehensively characterized and exhibited obvious water stability, as well as rapid selective adsorption filtration performance towards cationic dyes. The 5 wt% POMOF1/PAN NFM possessed the highest removal efficiency of 96.7% for RhB, 95.8% for MB, and 86.4% for CV dyes, which realized the selective separation over 95% of positively charged dyes from the mixed solution. The adsorption mechanism was explained using FT−IR, SEM, Zeta potential, and adsorption kinetics model, which proved that separation was determined via electrostatic interaction, hydrogen bonding, and π–π interactions. Moreover, the POMOF1/PAN membrane presented an outstanding recoverable and stable removal rate after four cycles. This study provides a new direction for the systematic design and manufacture of membrane separation materials with outstanding properties for contaminant removal. [ABSTRACT FROM AUTHOR]

Nanobodies have emerged as promising tools in biomedicine due to their single-chain structure and inherent stability. They generally have convex paratopes, which potentially prefer different epitope sites in an antigen compared to traditional antibodies. In this study, a synthetic phage display nanobody library was constructed and used to identify nanobodies targeting a tumor-associated antigen, the human B7-H3 protein. Combining next-generation sequencing and single-clone validation, two nanobodies were identified to specifically bind B7-H3 with medium nanomolar affinities. Further characterization revealed that these two clones targeted a different epitope compared to known B7-H3-specific antibodies, which have been explored in clinical trials. Furthermore, one of the clones, dubbed as A6, exhibited potent antibody-dependent cell-mediated cytotoxicity (ADCC) against a colorectal cancer cell line with an EC50 of 0.67 nM, upon conversion to an Fc-enhanced IgG format. These findings underscore a cost-effective strategy that bypasses the lengthy immunization process, offering potential rapid access to nanobodies targeting unexplored antigenic sites. [ABSTRACT FROM AUTHOR]

The cancer paradigm is generally based on the somatic mutation model, asserting that cancer is a disease of genetic origin. The mitochondrial–stem cell connection (MSCC) proposes that tumorigenesis may result from an alteration of the mitochondria, specifically a chronic oxidative phosphorylation (OxPhos) insufficiency in stem cells, which forms cancer stem cells (CSCs) and leads to malignancy. Reviewed evidence suggests that the MSCC could provide a comprehensive understanding of all the different stages of cancer. The metabolism of cancer cells is altered (OxPhos insufficiency) and must be compensated by using the glycolysis and the glutaminolysis pathways, which are essential to their growth. The altered mitochondria regulate the tumor microenvironment, which is also necessary for cancer evolution. Therefore, the MSCC could help improve our understanding of tumorigenesis, metastases, the efficiency of standard treatments, and relapses. [ABSTRACT FROM AUTHOR]

The study of cold-tolerance mechanisms of wheat as a leading cereal crop is very relevant to science. Primary metabolites play an important role in the formation of increased cold tolerance. The aim of this research is to define changes in the content of primary metabolites (soluble proteins and sugars), growth, and photosynthetic apparatus of freezing-tolerant and cold-sustainable wheat (Triticum aestivum L.) genotypes under optimal conditions and after prolonged (7 days) exposure to low temperature (4 °C). In order to gain a deeper comprehension of the mechanisms behind wheat genotypes' adaptation to cold, we determined the expression levels of photosynthetic genes (RbcS, RbcL) and genes encoding cold-regulated proteins (Wcor726, CBF14). The results indicated different cold-adaptation strategies of freezing-tolerant and cold-sustainable wheat genotypes, with soluble proteins and sugars playing a significant role in this process. In plants of freezing-tolerant genotypes, the strategy of adaptation to low temperature was aimed at increasing the content of soluble proteins and modification of carbohydrate metabolism. The accumulation of sugars was not observed in wheat of cold-sustainable genotypes during chilling, but a high content of soluble proteins was maintained both under optimal conditions and after cold exposure. The adaptation strategies of wheat genotypes differing in cold tolerance were related to the expression of photosynthetic genes and genes encoding cold-regulated proteins. The data improve our knowledge of physiological and biochemical mechanisms of wheat cold adaptation. [ABSTRACT FROM AUTHOR]

Simple Summary: We identified the notch gene in the reproductive system of the Basilepta melanopus beetle, a pest affecting oil tea plants. It was discovered that the Notch signaling pathway is crucial for the early development of insect ovaries. Specifically, suppressing the Notch gene expression by RNAi led to impaired ovarian development, decreased mating rates, and reduced egg production. These findings highlight the potential of RNAi-based, Notch-targeted pest control strategies as a practical approach for managing the forest pest B. melanopus populations. Basilepta melanopus is a pest that severely affects oil tea plants, and the Notch signaling pathway plays a significant role in the early development of insect ovaries. In this study, we explored the function of the notch gene within the Notch signaling pathway in the reproductive system of B. melanopus. The functional domains and expression patterns of Bmnotch were analyzed. Bmnotch contains 45 epidermal growth factor-like (EGF-like) domains, one negative regulatory region, one NODP domain and one repeat-containing domain superfamily. The qPCR reveals heightened expression in early developmental stages and specific tissues like the head and ovaries. The RNA interference (RNAi)-based suppression of notch decreased its expression by 52.1%, exhibiting heightened sensitivity to dsNotch at lower concentrations. Phenotypic and mating experiments have demonstrated that dsNotch significantly impairs ovarian development, leading to reduced mating frequencies and egg production. This decline underscores the Notch pathway's crucial role in fecundity. The findings advocate for RNAi-based, Notch-targeted pest control as an effective and sustainable strategy for managing B. melanopus populations, signifying a significant advancement in forest pest control endeavors. [ABSTRACT FROM AUTHOR]

Viruses provide vital insights into gene expression control. Viral transactivators, with other viral and cellular proteins, regulate expression of self, other viruses, and host genes with profound effects on infected cells, underlying inflammation, control of immune responses, and pathogenesis. The multifunctional Tat proteins of lentiviruses (HIV-1, HIV-2, and SIV) transactivate gene expression by recruiting host proteins and binding to transacting responsive regions (TARs) in viral and host RNAs. SARS-CoV-2 nucleocapsid participates in early viral transcription, recruits similar cellular proteins, and shares intracellular, surface, and extracellular distribution with Tat. SARS-CoV-2 nucleocapsid interacting with the replication–transcription complex might, therefore, transactivate viral and cellular RNAs in the transcription and reactivation of self and other viruses, acute and chronic pathogenesis, immune evasion, and viral evolution. Here, we show, by using primary and secondary structural comparisons, that the leaders of SARS-CoV-2 and other coronaviruses contain TAR-like sequences in stem-loops 2 and 3. The coronaviral nucleocapsid C-terminal domains harbor a region of similarity to TAR-binding regions of lentiviral Tat proteins, and coronaviral nonstructural protein 12 has a cysteine-rich metal binding, dimerization domain, as do lentiviral Tat proteins. Although SARS-CoV-1 nucleocapsid transactivated gene expression in a replicon-based study, further experimental evidence for coronaviral transactivation and its possible implications is warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: The premise that certain checkpoint inhibitors are effective anti-cancer treatments beyond their immune modulatory capabilities influences current cancer research and clinical practice as well as future drug versus therapy development. We propose ways and means to enhance immunotherapy in cancer care by combining anti-PD1/L1 with various therapeutic modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications. [ABSTRACT FROM AUTHOR]

Impact fracture behavior at low temperatures was investigated in medium manganese steel with bcc-fcc duplex microstructures. The impact energy was above 150 J (−80~20 °C) and the fractography showed dimples for inter-critical annealing at 630 °C (QHA) because of the high retained austenite stability and low martensite dislocation density. The impact energy was from 180 J (20 °C) to 60 J (−80 °C) and the fractography was intergranular for inter-critical annealing at 610 °C (QLA) because of the low stability of RA and carbides precipitated at the prior austenite grain boundaries. The impact energy was below 60 J (−80~20 °C) and the fractography showed cleavage for direct quenching (DQ) because of the high dislocation density of martensite. [ABSTRACT FROM AUTHOR]

Programmed death ligand 1 (PD-L1) plays a pivotal role in cancer immune evasion and is a critical target for cancer immunotherapy. This review focuses on the regulation of PD-L1 through the dynamic processes of ubiquitination and deubiquitination, which are crucial for its stability and function. Here, we explored the intricate mechanisms involving various E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) that modulate PD-L1 expression in cancer cells. Specific ligases are discussed in detail, highlighting their roles in tagging PD-L1 for degradation. Furthermore, we discuss the actions of DUBs that stabilize PD-L1 by removing ubiquitin chains. The interplay of these enzymes not only dictates PD-L1 levels but also influences cancer progression and patient response to immunotherapies. Furthermore, we discuss the therapeutic implications of targeting these regulatory pathways and propose novel strategies to enhance the efficacy of PD-L1/PD-1-based therapies. Our review underscores the complexity of PD-L1 regulation and its significant impact on the tumor microenvironment and immunotherapy outcomes. [ABSTRACT FROM AUTHOR]

The genes coding for the tumor suppressors p53 and retinoblastoma (Rb) are inactivated in the vast majority of small cell lung cancer (SCLC) tumors. Data support the notion that these two deleterious genetic events represent the initial steps in the development of SCLC, making them essential for a lung epithelial cell to progress toward the acquisition of a malignant phenotype. With the loss of TP53 and RB1, their broad tumor suppressive functions are eliminated and a normal cell is able to proliferate indefinitely, escape entering into cellular senescence, and evade death, no matter the damage it has experienced. Within this setting, lung epithelial cells accumulate further oncogenic mutations and are well on their way to becoming SCLC cells. Understanding the molecular mechanisms of these genetic lesions and their effects within lung epithelial cells is of paramount importance, in order to tackle this aggressive and deadly lung cancer. The present review summarizes the current knowledge on p53 and Rb aberrations, their biological significance, and their prospective therapeutic potential, highlighting completed and ongoing clinical trials with agents that target downstream pathways. [ABSTRACT FROM AUTHOR]

In recent decades, new nonlinear optical materials have been actively developed to create coherent tunable light sources in the mid-infrared (mid-IR) part of the spectrum used in a variety of scientific fields. In the present review, the main attention is focused on barium chalcogenide crystals, including their linear and nonlinear optical properties, laser-induced damage threshold (LIDT), and frequency down-conversion. [ABSTRACT FROM AUTHOR]

Viruses are obligate, intracellular parasites that co-opt host cell machineries for propagation. Critical among these machineries are those that translate RNA into protein and their mechanisms of control. Most regulatory mechanisms effectuate their activity by targeting sequence or structural features at the RNA termini, i.e., at the 5′ or 3′ ends, including the untranslated regions (UTRs). Translation of most eukaryotic mRNAs is initiated by 5′ cap-dependent scanning. In contrast, many viruses initiate translation at internal RNA regions at internal ribosome entry sites (IRESs). Eukaryotic mRNAs often contain upstream open reading frames (uORFs) that permit condition-dependent control of downstream major ORFs. To offset genome compression and increase coding capacity, some viruses take advantage of out-of-frame overlapping uORFs (oORFs). Lacking the essential machinery of protein synthesis, for example, ribosomes and other translation factors, all viruses utilize the host apparatus to generate virus protein. In addition, some viruses exhibit RNA elements that bind host regulatory factors that are not essential components of the translation machinery. SARS-CoV-2 is a paradigm example of a virus taking advantage of multiple features of eukaryotic host translation control: the virus mimics the established human GAIT regulatory element and co-opts four host aminoacyl tRNA synthetases to form a stimulatory binding complex. Utilizing discontinuous transcription, the elements are present and identical in all SARS-CoV-2 subgenomic RNAs (and the genomic RNA). Thus, the virus exhibits a post-transcriptional regulon that improves upon analogous eukaryotic regulons, in which a family of functionally related mRNA targets contain elements that are structurally similar but lacking sequence identity. This "thrifty" virus strategy can be exploited against the virus since targeting the element can suppress the expression of all subgenomic RNAs as well as the genomic RNA. Other 3′ end viral elements include 3′-cap-independent translation elements (3′-CITEs) and 3′-tRNA-like structures. Elucidation of virus translation control elements, their binding proteins, and their mechanisms can lead to novel therapeutic approaches to reduce virus replication and pathogenicity. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we have explored the impact of a promising new cancer treatment modality called proton therapy (PT) and compared it to traditional X-ray based photon therapy (XRT) for head and neck cancers. Proton therapy is effective because it can be delivered with precision, thus causing fewer side effects. We demonstrate in this study that, when using proton therapy, there was a significant reduction (75%) in the production of small extracellular vesicles, commonly known as exosomes, from cancer cells, which usually suppress the immune system. XRT did not reduce exosome production. Exosomes from both PT and XRT had similar inhibitory effects on immune cells. Our findings suggest that proton therapy might be better at reducing the immune-suppressing effects of cancer exosomes by producing fewer of them. Proton therapy (PT) is emerging as an effective and less toxic alternative to conventional X-ray-based photon therapy (XRT) for patients with advanced head and neck squamous cell carcinomas (HNSCCs) owing to its clustered dose deposition dosimetric characteristics. For optimal efficacy, cancer therapies, including PT, must elicit a robust anti-tumor response by effector and cytotoxic immune cells in the tumor microenvironment (TME). While tumor-derived exosomes contribute to immune cell suppression in the TME, information on the effects of PT on exosomes and anti-tumor immune responses in HNSCC is not known. In this study, we generated primary HNSCC cells from tumors resected from HNSCC patients, irradiated them with 5 Gy PT or XRT, and isolated exosomes from cell culture supernatants. HNSCC cells exposed to PT produced 75% fewer exosomes than XRT- and non-irradiated HNSCC cells. This effect persisted in proton-irradiated cells for up to five days. Furthermore, we observed that exosomes from proton-irradiated cells were identical in morphology and immunosuppressive effects (suppression of IFN-γ release by peripheral blood mononuclear cells) to those of photon-irradiated cells. Our results suggest that PT limits the suppressive effect of exosomes on cancer immune surveillance by reducing the production of exosomes that can inhibit immune cell function. [ABSTRACT FROM AUTHOR]

Simple Summary: The heterogeneous expression of signaling molecules within the tumor, including kinases, is the major contributor to the acquisition of drug resistance and poor survival observed in small-cell lung cancer (SCLC). The addition of immunotherapy to chemotherapy has only marginally prolonged survival in patients with extensive-stage SCLC (ES-SCLC). Recent clinical trials have combined immunotherapy with the pharmacological inhibitors of kinases often dysregulated in SCLC. However, the regime has not been effective in the long term. Here, we review studies and clinical trials exploring dysregulated kinases in SCLC progression and resistance to chemotherapies and immunotherapies. We also discuss the possibility of repurposing kinase inhibitors against SCLC that have already demonstrated promising results for other types of cancers. SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs. [ABSTRACT FROM AUTHOR]

Simple Summary: Large amounts of conventional insecticides are used to control insect pests in agricultural production worldwide. New sustainable strategies, more specific and environmentally friendly, are urgently needed to combat insect pests. RNA interference (RNAi) is a natural mechanism of gene expression regulation that has been repurposed for biotechnological applications. Double-stranded RNAs homologous to endogenous genes, which could be produced in the crop plant or exogenously synthesized and applied onto crops, efficiently trigger gene silencing in insects, reducing pest damage. Consequently, these molecules are envisioned as the new generation of insecticidal compounds. Insect pests rank among the major limiting factors in agricultural production worldwide. In addition to direct effect on crops, some phytophagous insects are efficient vectors for plant disease transmission. Large amounts of conventional insecticides are required to secure food production worldwide, with a high impact on the economy and environment, particularly when beneficial insects are also affected by chemicals that frequently lack the desired specificity. RNA interference (RNAi) is a natural mechanism gene expression regulation and protection against exogenous and endogenous genetic elements present in most eukaryotes, including insects. Molecules of double-stranded RNA (dsRNA) or highly structured RNA are the substrates of cellular enzymes to produce several types of small RNAs (sRNAs), which play a crucial role in targeting sequences for transcriptional or post-transcriptional gene silencing. The relatively simple rules that underlie RNAi regulation, mainly based in Watson–Crick complementarity, have facilitated biotechnological applications based on these cellular mechanisms. This includes the promise of using engineered dsRNA molecules, either endogenously produced in crop plants or exogenously synthesized and applied onto crops, as a new generation of highly specific, sustainable, and environmentally friendly insecticides. Fueled on this expectation, this article reviews current knowledge about the RNAi pathways in insects, and some other applied questions such as production and delivery of recombinant RNA, which are critical to establish RNAi as a reliable technology for insect control in crop plants. [ABSTRACT FROM AUTHOR]

Strength assessment for thermal barrier coatings (TBCs) is vital in the safety design of hot-section components in engines. However, several crucial factors, including thermally grown oxide (TGO) growth and creep–plasticity interaction, have been less considered in thermo-mechanical analyses for TBCs near air holes. In this study, a unified viscoplastic constitutive model incorporating TGO growth is developed and integrated into a finite element framework. The model considers multiple factors, including TGO growth, creep–plasticity interaction, interface undulation, and temperature gradient. Additionally, an analytical solution for the non-uniform temperature field of a TBC is derived. The model is then applied to calculate interfacial stresses and accumulated strain energies in the TBC near an air hole, which promote interface debonding. The obtained results can be utilized to investigate the mechanisms of hole edge delamination in TBCs, considering the combined effects of multiple complex factors. A competition for the potential failure initiation location is revealed between the first oxide layer and the evolving TGO/bond coat interface. The developed viscoplasticity model demonstrates effective capability in modelling a range of dynamic behaviors that collectively contribute to hole edge delamination failure. [ABSTRACT FROM AUTHOR]

Because large oil-immersed transformers are enclosed by a metal shell, the on-site localization means it is difficult to achieve the accurate location of the patrol micro-robot inside a given transformer. To address this issue, a spatial ultrasonic localization method based on wavelet decomposition and PHAT-β-γ generalized cross correlation is proposed in this paper. The method is carried out with a five-element stereo ultrasonic array for the location of a transformer patrol robot. Firstly, the localization signal is decomposed into wavelet coefficients of different scales, which would realize the adaptive decomposition of the frequency of the localization signal from low frequencies to high frequencies. Then, the wavelet coefficients are denoised and reconstructed by using the semi-soft threshold function. Second, a modified phase transform-beta-gamma (PHAT-β-γ) method is used to calculate the exact time delay between different sensors by increasing the weights of the PHAT weighting function and introducing a correlation function. Finally, by using the proposed method, the accurate localization of the transformer patrol micro-robot is achieved with a five-element stereo ultrasonic array. The simulation and test results show that inside a transformer experimental oil tank (120 cm × 100 cm × 100 cm, L × W × H), the relative error of transformer patrol micro-robot spatial localization is within 4.1%, and the maximum localization error is less than 3 cm, which meets the requirement of engineering localization. [ABSTRACT FROM AUTHOR]

Cu-Be alloys exhibit excellent comprehensive performance in electrics, thermotics, and mechanics, and hence, they attract much attention. Among them, low-Be copper alloys are more environmentally friendly and promising. This study explores the effects of different Ni contents and heat treatment parameters on the properties, microstructures, and precipitates of Cu-0.2 wt% Be-x wt% Ni (0 < x < 2.0) alloys. The experimental results demonstrate that the fast cooling rate of cast alloys during solidification contributes to retention of the solute atoms in the copper matrix, which is beneficial for subsequent solid solution treatment. Furthermore, solid solution treatment slightly reduces the electrical conductivities, microhardness values, and compressive yield strengths of Cu-0.2 wt% Be-1.0/1.6 wt% Ni alloys. The optimal solution temperature and time are about 925 ℃ and 60 min, respectively. Aging treatment significantly increases the electrical conductivities, microhardness values, and compressive yield strengths of Cu-0.2 wt% Be-1.0/1.6 wt% Ni alloys. The best aging temperature is around 450 ℃. However, the properties of Cu-0.2 wt%Be-0.4 wt%Ni alloys remain unaffected by solution and aging treatments. Around x = 1.0, Cu-0.2 wt% Be-x wt% Ni alloys possess the best comprehensive properties, which are about 72%IACS of electrical conductivity, 241 HV of microhardness, and 281MPa of compressive yield strength, respectively. TEM and EDS analyses reveal that the precipitate evolution of Cu-0.2 wt% Be-1.0 wt% Ni alloys with aging time is GP zones → γ″ → γ′. Notably, a distinct double-peak age strengthening phenomenon emerges with Cu-0.2 wt% Be-1.0/1.6 wt% Ni alloys. The precipitation of plenty of GP zones at the early stage of aging should account for the first strengthening peak, and the strengthening mechanism transformation of the γ″ or γ′ phase from shear to Orowan should induce the second strengthening peak. This work may help to design new low-Be copper alloys and their preparation processes. [ABSTRACT FROM AUTHOR]

Electric buses have been vigorously promoted and implemented in major countries worldwide and have generated a huge demand for charging stations. Optimizing the daily charging experience of electric buses, adapting the daily operation scheduling, improving the utilization rate of charging stations, reducing the load on the power grid, and improving the operation efficiency of electric bus line networks require the reasonable layout of the charging stations. In this study, public transportation charging station layout and siting is the research object. We summarize the progress of analysis methods from the charging station and vehicle sides; introduce related research on the planning and layout of charging stations based on optimization models, including cost analysis and siting and layout for electric bus systems; summarize the data-driven station planning and siting research; and provide an overview of the current charging demand estimation, accuracy, and charging efficiency. Finally, we address the problems of the charging demand estimation accuracy, the mismatch between the charging station layouts for electric buses, and the charging demand on a long time scale. We suggest that research be conducted on data fusion for the temporal and spatial refinement of charging demand prediction in the context of the electrification of public transportation systems and the big data of telematics. [ABSTRACT FROM AUTHOR]