Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood–brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition. Full article

Microalgae have considerable potential as a renewable feedstock for biochemical and bioethanol production that can be employed in processes associated with carbon capture. Large-scale microalgae cultivations are often non-axenic and are often cohabited by bacteria. A better understanding of the influence of cohabiting bacteria on microalgae productivity is required to develop sustainable synthetic co-culture processes at scale. Nutrient limitation is a frequently employed strategy in algal cultivations to accumulate energy reserves, such as lipids and carbohydrates. Here, a non-axenic culture of an estuarine green microalga, Chlorella vulgaris CCAP 211/21A, was studied under nutrient replete and deplete conditions to assess how changes in nutrient supply influenced the cohabiting bacterial population and its association with intracellular carbohydrate accumulations in the alga. Nutrient limitation resulted in a maximum carbohydrate yield of 47%, which was 74% higher than that in nutrient replete conditions. However, the latter condition elicited a 2-fold higher carbohydrate productivity. Three cohabiting bacterial isolates were cultivable from the three culture conditions tested. These isolates were identified using the 16S rRNA gene sequence to belong to Halomonas sp. and Muricauda sp. The composition of the bacterial population varied significantly between the growth conditions and time points. In all cases and at all time points, the dominant species was Halomonas isolates. Nutrient depletion resulted in an apparent loss of Muricauda sp. This finding demonstrates that nutrient supply can be used to control cohabiting bacterial populations in algal cultures, which will enable the development of synthetic co-culture strategies for improving algae productivity. Full article

We develop a framework for creating distortion functions that are used to construct new bivariate copulas. It is achieved by transforming non-negative random variables with Lomax-related distributions. In this paper, we apply the distortions to the base copulas of independence, Clayton, Frank, and Gumbel copulas. The properties of the tail dependence coefficient, tail order, and concordance ordering are explored for the new families of distorted copulas. We conducted an empirical study using the daily net returns of Amazon and Google stocks from January 2014 to December 2023. We compared the popular Clayton, Gumbel, Frank, and Gaussian copula models to their corresponding distorted copula models induced by the unit-Lomax and unit-inverse Pareto distortions. The new families of distortion copulas are equipped with additional parameters inherent in the distortion function, providing more flexibility, and are demonstrated to perform better than the base copulas. After analyzing the data, we have found that the joint extremes of Amazon and Google stocks are more likely for high daily net returns than for low daily net returns. Full article

Automatic detection of tire defects has become an important issue for tire production companies since these defects cause road accidents and loss of human lives. Defects in the inner structure of the tire cannot be detected with the naked eye; thus, a radiographic image of the tire is gathered using X-ray cameras. This image is then examined by a quality control operator, and a decision is made on whether it is a defective tire or not. Among all defect types, the foreign object type is the most common and may occur anywhere in the tire. This study proposes an explainable deep learning model based on Xception and Grad-CAM approaches. This model was fine-tuned and trained on a novel real tire dataset consisting of 2303 defective tires and 49,198 non-defective. The defective tire class was augmented using a custom augmentation technique to solve the imbalance problem of the dataset. Experimental results show that the proposed model detects foreign objects with an accuracy of 99.19%, recall of 98.75%, precision of 99.34%, and f-score of 99.05%. This study provided a clear advantage over similar literature studies. Full article

The development of strong and ductile alloys for application in cryogenic temperatures has long been sought after. In this work, we have developed a face-centered cubic Ni₁₀Co_56.5V_33.5 multi-principal element alloy (MPEA) that exhibits a balanced combination of high strength and good ductility at 77 K, based on the considerations of large local lattice distortion (LLD) and low stacking fault energy. The small-grained Ni₁₀Co_56.5V_33.5 MPEA exhibits a yield strength of 1400 MPa and an ultimate tensile strength of 1890 MPa, while preserving a good ductility of 23%. Moreover, precession electron diffraction and transmission electron microscopy revealed multiple deformation mechanisms, including wavy dislocations, atypically severely twisted dislocation bands, hierarchical stacking faults, and deformation twins, which are implicated in the alloy’s outstanding mechanical performance. These insights offer a strategic guide for the design of strong and ductile alloys, particularly for utilization in extreme environments. Full article

Nitrogen is an essential element for maize growth, but excessive application can lead to various environmental and ecological issues, including water pollution, air pollution, greenhouse gas emissions, and biodiversity loss. Hence, developing maize hybrids resilient to low-N conditions is vital for sustainable agriculture, particularly in nitrogen-deficient soils. Combining ability and genetic relationships among parental lines is crucial for breeding superior hybrids under diverse nitrogen levels. This study aimed to assess the genetic diversity of maize inbred lines using simple sequence repeat (SSR) markers and evaluate their combining ability to identify superior hybrids under low-N and recommended conditions. Local and exotic inbred lines were genotyped using SSR markers, revealing substantial genetic variation with high gene diversity (He = 0.60), moderate polymorphism information content (PIC = 0.54), and an average of 3.64 alleles per locus. Twenty-one F1 hybrids were generated through a diallel mating design using these diverse lines. These hybrids and a high yielding commercial check (SC-131) were field-tested under low-N and recommended N conditions. Significant variations (p < 0.01) were observed among nitrogen levels, hybrids, and their interaction for all recorded traits. Additive genetic variances predominated over non-additive genetic variances for grain yield and most traits. Inbred IL3 emerged as an effective combiner for developing early maturing genotypes with lower ear placement. Additionally, inbreds IL1, IL2, and IL3 showed promise as superior combiners for enhancing grain yield and related traits under both low-N and recommended conditions. Notably, hybrids IL1×IL4, IL2×IL5, IL2×IL6, and IL5×IL7 exhibited specific combining abilities for increasing grain yield and associated traits under low-N stress conditions. Furthermore, strong positive associations were identified between grain yield and specific traits like plant height, ear length, number of rows per ear, and number of kernels per row. Due to their straightforward measurability, these relationships underscore the potential of using these traits as proxies for indirect selection in early breeding generations, particularly under low-N stress. This research contributes to breeding nitrogen-efficient maize hybrids and advances our understanding of the genetic foundations for tolerance to nitrogen limitations. Full article

As a result of the uneven growth of rice, unbalanced vibration of threshing drum caused by stalk entanglement in combine harvester is more and more severe. In order to reveal the influence of unbalanced excitation on the roller axis locus during rice threshing, the stability of threshing drum was studied. The dynamic signal test and analysis system are used to test the axial trajectory of threshing drum. At the same time, the influence of the unbalanced excitation caused by the axis winding on the axis trajectory is analyzed by the experimental results. Axis locus rules under no-load and threshing conditions are obtained. In order to simulate the axial and radial distribution of unbalanced excitation along the threshing drum, the counterweight was distributed on the threshing drum instead of the entangled stalk. Then, the definite effect of unbalanced excitation on the rotating stability of threshing drum is analyzed. Results show that the amplitude of stem winding along the grain drum is larger in the vertical direction and smaller in the horizontal direction when compared with the unloaded state under 200 g weight. It was found that the amplitude in both horizontal and vertical directions decreased after 400 g and 600 g counterweights were added, respectively, to simulate the radial distribution of stalk winding along the grain barrel. Finally, it can be seen that with the increase in the weight of the counterweight, the characteristics of the trajectory misalignment of the threshing cylinder axis become more and more obvious. This study can provide reference for reducing the unbalanced excitation signal of threshing drum and improving driving comfort. Full article

François’ langur is an Endangered colobine inhabiting limestone habitats in southern China and northern Vietnam. Its global population has been estimated to be just more than 2000 mature individuals. Populations in Vietnam are highly fragmented with reportedly fewer than 200 adults in total and 50 in a single location. Although the François’ langur in Vietnam is highly imperiled as remnant populations persist in only three to four sites, little research has been carried out to provide a reliable estimate of its remaining population. In this study, we conducted field surveys in Lam Binh District, Tuyen Quang Province, northeastern Vietnam. In total, we recorded at least 16 groups of François’ langurs, with 156 individuals, raising the total number of individuals by approximately 10% compared to a previous study. The group structure, group size, activity budget, and density of the Lam Binh population resemble those reported in François’ langurs in China and other limestone langur species. The results show that the behavior ecology of limestone langurs significantly differs from that of forest langurs probably because they occupy separate habitats with distinctly different environmental variables. During our surveys, we detected a number of direct threats to this population, namely illegal logging, hunting, firewood collecting, hydropower development, grazing, and mining. It is recommended that the protection forest be elevated to the nature reserve status to better protect the most important population of the François’ langur in Vietnam. Full article

Our paper deals with gas-geochemical measurements of CH₄ and CO₂, as well as the first measurements of dissolved H₂ and He in the waters of the eastern shelf of Sakhalin Island, obtained during cruise 68 on the R/V Akademik Oparin (OP68) on 12–18 August 2023. The shallow eastern shelf has high concentrations of dissolved methane and helium in the water. The combined anomalies of methane and helium indicate the presence of an ascending deep fluid. The sources of methane in the studied area are the underlying oil- and gas-bearing rocks extending to the coast of the island. The deep faults of the region and the minor discontinuities that accompany them along the eastern coast of Sakhalin Island create a fluid-permeable geological environment both on the shallow shelf and on the coastal part of the island. East Sakhalin current and counter-current influence gases that migrate from lithospheric sources; these currents form a special hydrological regime that ensures high solubility of the gases released and their transfer under the lower boundary of the seasonal pycnocline to the east, where they are involved in the general circulation of the Sea of Okhotsk. Full article

Drainage water management (DWM), also known as controlled drainage (CD), is one of the edge-of-field strategies mainly designed to reduce the nitrate load from subsurface drainage systems. By limiting runoff, we also increase local retention, contributing to the sustainable management of water resources. For that purpose, CD involves using different kinds of controlled drainage devices. They are usually based on simple flashboard risers or stoplogs that regulate the drainage intensity by raising and lowering the drainage outlet. The problem with this type of device is the need for manual control, which can cause the CD system to be more demanding in terms of maintenance. A new approach to water management by CD allows the possibility of individual disassembly of each board without necessarily removing all of them. Thanks to the use of sideling runners, the water management process is much quicker. This is especially important when a farmer needs to manage water in a few controlled drainage devices in the field. The different variants of the design are shown here, as well as the way of stop-log assembly and control and the costs of maintaining similar devices. The advantages and disadvantages are described, and the usefulness of the new patented solution is assessed. Full article

The aim of this study was to test the inactivation of viruses on germ carriers of different types of wood using a disinfectant in order to assess the biosafety of wood as a building material in animal husbandry. The laboratory disinfectant efficacy tests were based on German testing guidelines and current European standards. Five different types of wood germ carriers, i.e., spruce (Picea abies), pine (Pinus sylvestris), poplar (Populus sp.), beech (Fagus sylvatica) and Douglas fir (Pseudotsuga menziesii), were inoculated with enveloped or non-enveloped viruses and then treated with one of three different disinfectants. The results revealed that intact, fine-sawn timber with a low roughness depth can be effectively inactivated. Peracetic acid proved to be the most effective disinfectant across all tests. Regardless of the pathogen and the type of wood, a concentration of 0.1% of the pure substance at a temperature of 10 °C and an exposure time of one hour can be recommended. At a temperature of −10 °C, a concentration of 0.75% is recommended. The basic chemicals formic acid and glutaraldehyde demonstrated only limited effectiveness overall. The synergistic effects of various wood components on the inactivation of viruses offer potential for further investigation. Disinfectant tests should also be conclusively verified in field trials to ensure that the results from standardised laboratory tests can be transferred to real stable conditions. Full article

Human fungal diseases are infections caused by any fungus that invades human tissues, causing superficial, subcutaneous, or systemic diseases. Fungal infections that enter various human tissues and organs pose a significant threat to millions of individuals with weakened immune systems globally. Over recent decades, the reported cases of invasive fungal infections have increased substantially and research progress in this field has also been rapidly boosted. This review provides a comprehensive list of human fungal pathogens extracted from over 850 recent case reports, and a summary of the relevant disease conditions and their origins. Details of 281 human fungal pathogens belonging to 12 classes and 104 genera in the divisions ascomycota, basidiomycota, entomophthoromycota, and mucoromycota are listed. Among these, Aspergillus stands out as the genus with the greatest potential of infecting humans, comprising 16 species known to infect humans. Additionally, three other genera, Curvularia, Exophiala, and Trichophyton, are recognized as significant genera, each comprising 10 or more known human pathogenic species. A phylogenetic analysis based on partial sequences of the 28S nrRNA gene (LSU) of human fungal pathogens was performed to show their phylogenetic relationships and clarify their taxonomies. In addition, this review summarizes the recent advancements in fungal disease diagnosis and therapeutics. Full article

Steel structures are prone to corrosion, a chemical reaction between steel and the atmosphere that gradually weakens the material. Over time, this reaction can significantly reduce the structural integrity and lifespan of steel elements. Without intervention, corrosion can cause structures to fail, leading to financial, environmental, and potential human losses. Enhancing steel’s corrosion resistance is crucial, and one method involves adding niobium (Nb). Niobium microalloyed steels are known for their increased strength, and some research indicates that Nb may also improve corrosion resistance by making the grain structure of the steel finer. However, the complete potential of Nb in corrosion prevention remains underexplored, with significant research gaps across various scales, from microstructural impacts on durability to macroscopic effects on mechanical properties. The research community has utilized numerous experimental approaches to test corrosion resistance under different conditions, but there is a lack of comprehensive studies that aggregate and analyze these findings. This paper seeks to fill that void by reviewing the impact of Nb on the strength and corrosion resistance of structural steels, examining how steel beams’ ultimate capacity degrades over time and identifying key areas where further research is needed to understand Nb’s role in mitigating corrosion. Full article

Microplastics (MPs) and antibiotics (ATs) have been detected in various aquatic environments and characterized as novel contaminants that have attracted worldwide attention. This review summarizes the characteristics of MPs and ATs, analyzes the sources of MPs and ATs in aquatic environments, reviews the concentration distribution of the two pollutants in China, and introduces the environmental effects of mixing MPs and ATs. Studies on single pollutants of MPs or ATs are well established, but the interactions between the two in aquatic environments are rarely mentioned. The physicochemical characteristics of MPs make them carriers of ATs, which greatly increase their risk of being potential hazards to the environment. Therefore, in this article, the interaction mechanisms between MPs and ATs are systematically sorted out, mainly including hydrophobic, electrostatic, intermolecular interactions, microporous filling, charge-assisted hydrogen bonding, cation-bonding, halogen bonding, and CH/π interactions. Also, factors affecting the interaction between ATs and MPs, such as the physicochemical properties of MPs and ATs and environmental factors, are also considered. Finally, this review identifies some new research topics and challenges for MPs and ATs, in order to gain deeper insight into their behavioral fate and toxic mechanisms. Full article

Intracellular delivery, the process of transporting substances into cells, is crucial for various applications, such as drug delivery, gene therapy, cell imaging, and regenerative medicine. Among the different approaches of intracellular delivery, mechanoporation stands out by utilizing mechanical forces to create temporary pores on cell membranes, enabling the entry of substances into cells. This method is promising due to its minimal contamination and is especially vital for stem cells intended for clinical therapy. In this review, we explore various mechanoporation technologies, including microinjection, micro–nano needle arrays, cell squeezing through physical confinement, and cell squeezing using hydrodynamic forces. Additionally, we highlight recent research efforts utilizing mechanoporation for stem cell studies. Furthermore, we discuss the integration of mechanoporation techniques into microfluidic platforms for high-throughput intracellular delivery with enhanced transfection efficiency. This advancement holds potential in addressing the challenge of low transfection efficiency, benefiting both basic research and clinical applications of stem cells. Ultimately, the combination of microfluidics and mechanoporation presents new opportunities for creating comprehensive systems for stem cell processing. Full article

Forage yield estimates provide relevant information to manage and quantify ecosystem services in grasslands. We fitted and validated prediction models of forage yield for several prominent grasses used in restoration projects in semiarid areas. We used field forage harvests from three different sites in Northern Utah and Southern California, USA, in conjunction with multispectral, high-resolution UAV imagery. Different model structures were tested with simple models using a unique predictor, the forage volumetric 3D space, and more complex models, where RGB, red edge, and near-infrared spectral bands and associated vegetation indices were used as predictors. We found that for most dense canopy grasses, using a simple linear model structure could explain most (R² 0.7) of the variability of the response variable. This was not the case for sparse canopy grasses, where a full multispectral dataset and a non-parametric model approach (random forest) were required to obtain a maximum R² of 0.53. We developed transparent protocols to model forage yield where, in most circumstances, acceptable results could be obtained with affordable RGB sensors and UAV platforms. This is important as users can obtain rapid estimates with inexpensive sensors for most of the grasses included in this study. Full article

Human papilloma virus (HPV) infection and its progression still represent a great medical challenge worldwide. Clinical evidence has demonstrated the beneficial effects of polyhexamethylene biguanide (PHMB) on HPV clinical manifestations; however, evidence of the effect of this molecule on HPV viral load is still lacking. In this in vitro study, 13 ThinPrep Papanicolaou (Pap) tests were treated with a PHMB solution (0.10 g/100 mL) for 2 h. We observed no cytological changes but a significant reduction in the viral load of high-risk (HR) HPV after PHMB treatment, also revealing a dose-dependent antiviral effect. In addition, by stratifying the obtained results according to HR-HPV genotype, we observed a significant reduction in the viral load of HPV 16, P2 (56, 59, 66), 31, and P3 (35, 39, 68) and a strong decrease in the viral load of HPV 45, 52, and P1 (33, 58). Overall, 85% of the analyzed cervical cell samples exhibited an improvement in HPV viral load after PHMB exposure, while only 15% remain unchanged. For the first time, the data from this pilot study support the activity of PHMB on a specific phase of the HPV viral lifecycle, the one regarding the newly generated virions, reducing viral load and thus blocking the infection of other cervical cells. Full article

(1) Background: The interplay between coronavirus disease 2019 (COVID-19) and laryngeal cancer represents a substantial challenge for both patients and healthcare. To garner information on recent mortality data for laryngeal cancer, including during the COVID-19 pandemic, we analyzed real-world data from the US Centers for Disease Control and Prevention (CDC). (2) Methods: We searched the CDC WONDER online database 2018–2022 using the ICD-10 code for laryngeal cancer (C32; malignant neoplasm of the larynx). We also performed a sub-analysis between genders and across ten-year age groups. The data were analyzed with one-way analysis of variance (ANOVA) and Tukey’s post hoc test. (3) Results: The trend of age-adjusted mortality ×100,000 did not change significantly between the years 2018 and 2022 (p = 0.553). Males had higher age-adjusted mortality rates (M/F ratios between 4.6 and 5.0), but no significant variation was found in both genders (males: p = 0.676; females: p = 0.596). Although the mortality rate remained unchanged in people aged 35–84 years, the variation reached statistical significance in those aged 85 or older (p = 0.004), displaying a significant increase in 2021 compared to 2018 (p = 0.006) and 2019 (p = 0.039). (4) Conclusions: The impact of the COVID-19 pandemic on mortality for laryngeal cancer seems to be relatively modest in the general US population. Nevertheless, closer attention must be paid to older people, for whom the unfavorable consequences of misdiagnosis or mistreatment of this and other types of cancers can be exacerbated. Full article

Urinary tract infections are defined as the presence of microorganisms in any part of the urinary system, with the exception of the distal urethra. A majority of them are uncomplicated infections that are resolved on an outpatient basis, with empirical therapy. The objectives of this work were to study the sociodemographic characteristics of patients, analyze associated strains and examine the response of the main microorganisms to antibiotics. A retrospective observational study of all positive urine cultures between 2018 and 2022 was carried out at an institution (8340 samples). Sociodemographic data were also collected. In total, 61.3% were women, with an average age of 63.4 years, and 43.2% were from the Emergency Department. A total of 13.5% were fitted, 56% of whom were women. Also, 95.9% were not taking any antibiotics, and among the individuals who were taking antibiotics, 50% were injected. Escherichia coli (53.5%) and Klebsiella pneumoniae (13.8%) are identified as the most prevalent strains. In the time periods analyzed, Escherichia coli decreased its resistance to 11 antibiotics and increased to 5 antibiotics, while Klebsiella pneumoniae decreased to 7 and increased to 7, with emphasis on the presence of 3 antibiotics with a resistance rate of 100% to all Klebsiella pneumoniae strains identified in 2022. Full article

The gut–brain axis (GBA) represents a complex, bidirectional communication network that intricately connects the gastrointestinal tract with the central nervous system (CNS). Understanding and intervening in this axis opens a pathway for therapeutic advancements for neurological and gastrointestinal diseases where the GBA has been proposed to play a role in the pathophysiology. In light of this, the current review assesses the effectiveness of neuromodulation techniques in treating neurological and gastrointestinal disorders by modulating the GBA, involving key elements such as gut microbiota, neurotrophic factors, and proinflammatory cytokines. Through a comprehensive literature review encompassing PubMed, Google Scholar, Web of Science, and the Cochrane Library, this research highlights the role played by the GBA in neurological and gastrointestinal diseases, in addition to the impact of neuromodulation on the management of these conditions which include both gastrointestinal (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and gastroesophageal reflux disease (GERD)) and neurological disorders (Parkinson’s disease (PD), Alzheimer’s disease (AD), autism spectrum disorder (ASD), and neuropsychiatric disorders). Despite existing challenges, the ability of neuromodulation to adjust disrupted neural pathways, alleviate pain, and mitigate inflammation is significant in improving the quality of life for patients, thereby offering exciting prospects for future advancements in patient care. Full article

In recent years, the rapid growth of air traffic has intensified pressure on the air transport system, leading to congestion problems in airports and airspace. The projected increase in demand exacerbates these issues, necessitating immediate attention. Additionally, there is a growing concern regarding the environmental impact of the aviation sector. To tackle these challenges, the adoption of advanced methods and technologies shows promise in expanding current airspace capacity and improving its management. This paper presents an overview of sustainable aviation, drawing on publications from academia and industry. The emphasis is on optimizing both flight and ground operations. Specifically, the review delves into recent advancements in airline operations, airport operations, flight operations, and disruption management, analyzing their respective research objectives, problem formulations, methodologies, and computational experiments. Furthermore, the review identifies emerging trends, prevailing obstacles, and potential directions for future research. Full article

In this review article, we summarize the most common clinical manifestations of Primary biliary cholangitis (PBC): pruritus, fatigue, osteoporosis, and dyslipoproteinemia and discuss their impact of the patients’ quality of life. More than half of PBC patients suffer from pruritus or fatigue at the time of diagnosis. We discuss the pathophysiological aspects of the PBC clinical manifestations and treatment options. The pathophysiology of pruritus and fatigue is not adequately elucidated, but IL-31 is associated with the severity of pruritus and could be used to objectify the subjective reporting by questionnaires. Although PBC patients suffer from atherogenic dyslipidemia, they do not seem to have a higher cardiovascular risk; however, this observation needs to be clarified by further clinical studies. The second-line of PBC treatment affects pruritus severity: Obeticholic acid (OCA) worsens pruritus while fibrates improve it. Itching can be alleviated by both non-pharmacological and pharmacological approach, however the are multiple barriers to pharmacological treatment. There is no adequate treatment for fatigue today. Treatment of osteoporosis and dyslipidemia is similar for non-PBC patients; stage of liver disease should be considered in treatment. Further research to clarify the pathophysiology and to eventually discover an effective treatment to improve survival and quality of life (especially pruritus and fatigue) in PBC patients is needed. Full article