Preventing trogocytosis by cathepsin B inhibition augments CAR T cell function.

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of treatment. CAR-mediated trogocytosis (CMT) is a potential tumor escape mechanism in which cell surface proteins transfer from tumor cells to CAR T cells. CMT results in the emergence of antigen-negative tumor cells, which can evade future CAR detection, and antigen-positive CAR T cells, which is hypothesized to lead to CAR T cell fratricide and dysfunction. Using a system to selectively degrade trogocytosed antigen in CAR T cells, we show that the presence of trogocytosed antigen in CAR T cells directly causes CAR T cell fratricide and exhaustion. By performing a small molecule screening using a custom high throughput CMT-screening assay, we identified the cysteine protease cathepsin B (CTSB) as a key driver of CMT. We show that overexpression of cystatin A (CSTA), an endogenous human inhibitor of CTSB, reduces trogocytosis resulting in prolonged antitumor activity and increased CAR T cell expansion/persistence. Overall, we show that targeting CMT is an effective approach to enhance CAR T cell function, which may improve their clinical efficacy.

Chirality-Induced Spin Selectivity: Analysis of Density Functional Theory Calculations.

Chirality-induced spin selectivity (CISS), which was demonstrated in several molecular and material systems, has drawn much interest recently. The phenomenon, described in electron transport by the difference in the transport rate of electrons of opposite spins through a chiral system, is however not fully understood. Herein, we employed density functional theory in conjunction with spin-orbit coupling to evaluate the percent spin-polarization in a device setup with finite electrodes at zero bias, using an electron transport program developed in-house. To study the interface effects and the level of theory considered, we investigated a helical oligopeptide chain, an intrinsically chiral gold cluster, and a helicene model system that was previously studied (Zöllner et al. J. Chem. Theory Comput. 2020, 16, 7357-7371). We find that the magnitude of the spin-polarization depends on the chiral system-electrode interface that is modeled by varying the interface boundary between the system's regions, on the method of calculating spin-orbit coupling, and on the exchange-correlation functional, e.g., the amount of exact exchange in the hybrid functionals. In addition, to assess the effects of bias, we employ the nonequilibrium Green's function formalism in the Quantum Atomistix Toolkit program, showing that the spin-flip terms could be important in calculating the CISS effect. Although understanding CISS in comparison to experiment is still not resolved, our study provides intrinsic responses from first-principles calculations.

Academic performance warning system based on data driven for higher education.

Academic probation at universities has become a matter of pressing concern in recent years, as many students face severe consequences of academic probation. We carried out research to find solutions to decrease the situation mentioned above. Our research used the power of massive data sources from the education sector and the modernity of machine learning techniques to build an academic warning system. Our system is based on academic performance that directly reflects students' academic probation status at the university. Through the research process, we provided a dataset that has been extracted and developed from raw data sources, including a wealth of information about students, subjects, and scores. We build a dataset with many features that are extremely useful in predicting students' academic warning status via feature generation techniques and feature selection strategies. Remarkably, the dataset contributed is flexible and scalable because we provided detailed calculation formulas that its materials are found in any university or college in Vietnam. That allows any university to reuse or reconstruct another similar dataset based on their raw academic database. Moreover, we variously combined data, unbalanced data handling techniques, model selection techniques, and research to propose suitable machine learning algorithms to build the best possible warning system. As a result, a two-stage academic performance warning system for higher education was proposed, with the F2-score measure of more than 74% at the beginning of the semester using the algorithm Support Vector Machine and more than 92% before the final examination using the algorithm LightGBM.

Theoretical Investigation of the Electronic Spectra of Cadmium Chalcogenide 2D Nanoplatelets.

Although colloidal cadmium chalcogenide 2D nanoplatelets (NPLs) have recently demonstrated strongly enhanced one- and two-photon absorption (OPA, TPA) spectra, an understanding of the effects of quantum confinement in the lateral and vertical (thickness) dimensions is mostly lacking. In this work, we investigate theoretically CdS and CdSe NPLs passivated with formate and acetate ligands with thicknesses of two and three monolayers (MLs) and different lateral dimensions. Initial structures for CdS nanoplatelets were obtained using our recently developed deep neural network potential, and the low-energy geometries were subsequently optimized using density functional theory (DFT). Linear- and nonlinear-response calculations using time-dependent DFT (TDDFT) and the simplified Tamm-Dancoff approximation (sTDA) demonstrated good agreement between measured spectra and calculated TDDFT and sTDA spectra for 2 and 3 ML NPLs. The OPA red-shifts from 2 to 3 ML NPLs can be attributed to the electron delocalization in the lateral and vertical directions. TPA responses for CdS and CdSe NPLs were found to be dominated by weakly absorbing and forbidden OPA states.

Calculated linear and nonlinear optical absorption spectra of phosphine-ligated gold clusters.

Although prediction of optical excitations of ligated gold clusters by time-dependent density functional theory (TDDFT) is relatively well-established, limitations still exist, for example in the choice of the exchange-correlation functional. In aiming to improve on the accuracy of the calculated linear absorption, we report a theoretical study on phosphine-ligated gold clusters, specifically Au9(PR3)83+ and Au8(PR3)72+ characterized by highly resolved UV/Vis spectra, using mass-selective electronic absorption photofragmentation spectroscopy (A. Cirri, H. M. Hernández and C. J. Johnson, J. Phys. Chem. A, 2020, 124, 1467-1479, and references therein). The optical absorption spectra of the Au9(PR3)83+ and Au8(PR3)72+ clusters were calculated using TDDFT and the many-body GW (G-Green's function, and W-screened Coulomb interaction)-BSE (Bethe Salpeter Equation) method, and compared to the experimental measurements. The evGW-BSE results demonstrated fair agreement with the experimental data, comparable to the TDDFT results, but with less dependence on the reference exchange-correlation functional. Experimentally observed ligand-effects in these materials were reproduced in our calculations as well. Finally, to assess the utility of the materials for nonlinear optical absorption, a theoretical evaluation of two-photon absorption cross-sections is included.

Hepatitis B Screening, Vaccination, and Linkage to Care: Lessons Learned from a Mississippi Vietnamese Community.

BACKGROUND: Asian-Americans and Pacific Islanders are disproportionately impacted by chronic hepatitis B infection (CHBI). The long-term effects of untreated CHBI include cirrhosis of the liver, hepatocellular carcinoma, and liver failure. Approximately two-thirds of those living with CHBI are unaware of their HBV status. OBJECTIVES: Plan, implement, and evaluate a culturally and linguistically appropriate screening, vaccination, and linkage-to-care initiative that used Vietnamese-speaking community health workers for care navigation among Vietnamese-Americans residing in the Mississippi coastal counties of Hancock, Harrison, and Jackson. METHODS: The initiative employed a community-based participatory framework to plan and implement the program. An active community advisory board was established and was representative of all the partners that worked together to make the initiative a success.Results and Lessons Learned: Before program implantation, results from focus groups indicated that the Vietnamese community had low knowledge about the risk of CHBI. Additionally, there were no Vietnamese-speaking health care providers, nor primary care providers treating CHBI in the prioritized counties. A total of 505 Vietnamese individuals were screened. One-half were immune by infection (n = 235 [46.5%]), 83 (16.4%) were immune by vaccination, 46 (9.1%) had CHBI, 130 (25.7%) were vaccine naïve, and 40 (7.9%) were undetermined, (n = 130), 101 (77.7%) received the complete three-injection vaccine series. Five new primary care providers now provide treatment for those with CHBI. Cultural competency and community/medical interpreter training were also provided to reduce language barriers during medical encounters. CONCLUSIONS: To ensure success, it is paramount that community input is not only solicited but that partnerships provide a space where the input informs all aspects of the program.

Detection and Establishment of Aedes notoscriptus (Diptera: Culicidae) Mosquitoes in Southern California, United States.

Aedes notoscriptus (Skuse), the Australian backyard mosquito, is a pestiferous daytime-biting species native to Australia and the surrounding southwestern Pacific region. It is suspected to play a role in the transmission of several arboviruses and is considered a competent vector of dog heartworm, Dirofilaria immitis (Leidy). This highly adaptable mosquito thrives in natural and artificial water-holding containers in both forested and urbanized areas, from tropical to temperate climates, and has benefitted from a close association with humans, increasing in abundance within its native range. It invaded and successfully established in New Zealand as well as in previously unoccupied temperate and arid regions of Australia. Ae. notoscriptus was discovered in Los Angeles County, CA, in 2014, marking the first time this species had been found outside the southwestern Pacific region. By the end of 2019, immature and adult mosquitoes had been collected from 364 unique locations within 44 cities spanning three southern California counties. The discovery, establishment, and rapid spread of this species in urban areas may signal the global movement and advent of a new invasive container-inhabiting species. The biting nuisance, public health, and veterinary health implications associated with the invasion of southern California by this mosquito are discussed.

Development of a paddy-based biorefinery approach toward improvement of biomass utilization for more bioproducts.

Improvement of biomass utilization productivity following cascading strategy is a priority for the biorefinery-based circular bioeconomy. In recent years, the field of energy research has seen an increasing interest in bio-products from paddy-based biorefinery, but the utilization of the entire value of paddy biomass to guide the commercial viability of its products has not been got feasible outcomes. Here we propose a potential pathway for a conceptual paddy biorefinery framework by addressing wastes for producing more products. The feasibility of the integrated biorefinery was demonstrated by the conversion of wastes into value-added products such as nano-silica and lignin. In particular, this is the first time that silica recovered from bioethanol system was continued to be reused to produce ZSM-5 and Ni/ZSM-5 as catalysts of rice straw lignin depolymerization achieving high conversion of lignin up to 95% and fair yield of phenolic products up to 41%. Material flow of an integrated biorefinery model was reported to give a future outlook for making most of the processing routes of rice residues. We also established a life cycle that follows the circular bioeconomy concept and discussed the relationship between each of potential bioproducts and their market opportunities.

Theoretical analysis of structures and electronic spectra of molecular colloidal cadmium sulfide clusters and nanoplatelets.

In the present study, we systematically examine structures and absorption spectra for CdS nanoplatelets (NPLs) with thicknesses of two and three monolayers (2 MLs and 3 MLs) and extended lateral dimensions. These nanoplatelet model systems, passivated with formate and acetate ligands, are used to analyze the effects of quantum confinement in the lateral dimension within an extended monolayer and the effects of thickness when changing from two to three monolayers. Based on the computed cubic structures using density functional theory (DFT), we found good agreement between observed and time-dependent DFT-calculated spectra, revealing little ligand participation to influence the color and intensity of low-energy absorption bands as the structures are laterally extended to eight and seven monolayers for 2-ML and 3-ML systems, respectively. The spectral redshift for 3-ML CdS NPLs is attributed to the electron delocalization due to expansion of the nanoplatelet in the lateral and vertical directions.

Impact of underground storm drain systems on larval ecology of Culex and Aedes species in urban environments of Southern California.

An extensive network of storm water conveyance systems in urban areas, often referred to as the "underground storm drain system" (USDS), serves as significant production habitats for mosquitoes. Knowledge of whether USDS habitats are suitable for newly introduced dengue vectors Aedes aegypti and Ae. albopictus will help guide surveillance and control efforts. To determine whether the USDS functions as a suitable larval habitat for Culex, Ae. aegypti and Ae. albopictus in southern California, we examined mosquito habitat utilization and larval survivorship using laboratory microcosm studies. The data showed that USDS constituted 4.1% of sampled larval habitats for Ae. aegypti and Ae. albopictus, and 22.0% for Cx. quinquefasciatus. Furthermore, USDS water collected in the summer completely inhibited Aedes larval development, but yielded a 15.0% pupation rate for Cx. quinquefasciatus. Food supplementation in the microcosms suggests that nutrient deficiency, toxins and other factors in the USDS water led to low success or complete failure of larval development. These results suggest that USDS habitats are currently not major productive larval habitats for Aedes mosquitoes in southern California. Our findings prompt inclusion of assessments of pupal productivity in USDS habitats and adult mosquito resting sites in the mosquito surveillance program.

Metabolic Intersection of Cancer and Cardiovascular Diseases: Opportunities for Cancer Therapy.

According to data from the World Health Organization, cardiovascular diseases and cancer are the two leading causes of mortality in the world [1]. Despite the immense effort to study these diseases and the constant innovation in treatment modalities, the number of deaths associated with cardiovascular diseases and cancer is predicted to increase in the coming decades [1]. From 2008 to 2030, due to population growth and population aging in many parts of the world, the number of deaths caused by cancer globally is projected to increase by 45%, corresponding to an annual increase of around four million people [1]. For cardiovascular diseases, this number is six million people [1]. In the United States, treatments for these two diseases are among the most costly and result in a disproportionate impact on low- and middleincome people. As the fight against these fatal diseases continues, it is crucial that we continue our investigation and broaden our understanding of cancer and cardiovascular diseases to innovate our prognostic and treatment approaches. Even though cardiovascular diseases and cancer are usually studied independently [2-12], there are some striking overlaps between their metabolic behaviors and therapeutic targets, suggesting the potential application of cardiovascular disease treatments for cancer therapy. More specifically, both cancer and many cardiovascular diseases have an upregulated glutaminolysis pathway, resulting in low glutamine and high glutamate circulating levels. Similar treatment modalities, such as glutaminase (GLS) inhibition and glutamine supplementation, have been identified to target glutamine metabolism in both cancer and some cardiovascular diseases. Studies have also found similarities in lipid metabolism, specifically fatty acid oxidation (FAO) and synthesis. Pharmacological inhibition of FAO and fatty acid synthesis have proven effective against many cancer types as well as specific cardiovascular conditions. Many of these treatments have been tested in clinical trials, and some have been medically prescribed to patients to treat certain diseases, such as angina pectoris [13, 14]. Other metabolic pathways, such as tryptophan catabolism and pyruvate metabolism, were also dysregulated in both diseases, making them promising treatment targets. Understanding the overlapping traits exhibited by both cancer metabolism and cardiovascular disease metabolism can give us a more holistic view of how important metabolic dysregulation is in the progression of diseases. Using established links between these illnesses, researchers can take advantage of the discoveries from one field and potentially apply them to the other. In this chapter, we highlight some promising therapeutic discoveries that can support our fight against cancer, based on common metabolic traits displayed in both cancer and cardiovascular diseases.

Systematic Study of the Properties of CdS Clusters with Carboxylate Ligands Using a Deep Neural Network Potential Developed with Data from Density Functional Theory Calculations.

Although structures of the inorganic core of CdS atomically precise quantum dots were reported, characterizing the nature of the metal-carboxylate coordination in these materials remains a challenge due to the large number of possible isomers. The computational cost imposed by first-principles methods is prohibitive for such a configurational search, and empirical potentials are not available. In this work, we applied deep neural network algorithms to train a potential for CdS clusters with carboxylate ligands using a database of energies and gradients obtained from density functional theory calculations. The derived potential provided energies and gradients based on a set of reference structures. Our trained potential was then used to accelerate genetic algorithm and molecular dynamics simulations searches of low-energy structures, which in turn, were used to compute the X-ray diffraction and electronic absorption spectra. Our results for CdS clusters with carboxylate ligands, analyzed and compared with experimental findings, demonstrated that the structure of a cluster whose properties agree better with experiment may deviate from the one previously assumed.

Theoretical Prediction of Optical Absorption and Emission in Thiolated Gold Clusters.

Although the photoluminescence of gold clusters has been extensively studied so far, there are still questions on the origin of the emission in these materials. In this work, we report time-dependent density functional theory calculations on the absorption and emission spectra of the well-studied Au25(SR)18- cluster, the lowest energy isomer of the Au38(SR)24 cluster, and five isomers of the Au22(SR)18 cluster. Good agreement between the calculated and measured absorption spectra, as well as with the lowest-energy emission values for these clusters, was demonstrated, verifying the accuracy of the theoretical methods employed. Our results for Au25(SR)18- explain a newly observed feature in the absorption peak, also rationalizing the optical response in terms of the superatom model. The analysis of the absorption and emission characteristics of the Au25(SR)18- and Au38(SR)24 clusters provides an estimate of the spectral regions, where fluorescence or phosphorescence is predicted to occur. Interestingly, we find that for Au22(SR)18, one of the five proposed structures could be present at a significant concentration in the sample, even though it is not the lowest in energy structure, which can be explained, in part, by solvent effects.

Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer.

The targeting of glutamine metabolism specifically via pharmacological inhibition of glutaminase 1 (GLS1) has been translated into clinical trials as a novel therapy for several cancers. The results, though encouraging, show room for improvement in terms of tumor reduction. In this study, the glutaminase II pathway is found to be upregulated for glutamate production upon GLS1 inhibition in pancreatic tumors. Moreover, genetic suppression of glutamine transaminase K (GTK), a key enzyme of the glutaminase II pathway, leads to the complete inhibition of pancreatic tumorigenesis in vivo unveiling GTK as a new metabolic target for cancer therapy. These results suggest that current trials using GLS1 inhibition as a therapeutic approach targeting glutamine metabolism in cancer should take into account the upregulation of other metabolic pathways that can lead to glutamate production; one such pathway is the glutaminase II pathway via GTK.

Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer.

N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.

Systematic Study of Structure, Stability, and Electronic Absorption of Tetrahedral CdSe Clusters with Carboxylate and Amine Ligands.

In this work, we carried out a systematic investigation to assess the effects of ligands on the structure, stability, and absorption spectra of ultrasmall CdSe tetrahedral quantum dots, where the cores of small tetrahedral quantum dots have been postulated to be stabilized by amine and carboxylate ligands. We found that amine and carboxylate ligands form extensive hydrogen bonding networks, which provide thermodynamic stability to the clusters. On the basis of the optimized structures, good agreement between observed and computed spectra was obtained. The ligands were also found to have a large influence on the color and intensity of the electronic absorption spectra, particularly for the small clusters, which were previously monitored with in situ UV-visible absorbance spectroscopy. Our work provides an understanding of the effect of ligands that influence thermodynamic stability and electronic absorption of ultrasmall quantum dots, thus potentially motivating further experimental exploration.

Theoretical Analysis of Optical Absorption and Emission in Mixed Noble Metal Nanoclusters.

In this work, we studied theoretically two hybrid gold-silver clusters, which were reported to have dual-band emission, using density functional theory (DFT) and linear and quadratic response time-dependent DFT (TDDFT). Hybrid functionals were found to successfully predict absorption and emission, although explanation of the NIR emission from the larger cluster (cluster 1) requires significant vibrational excitation in the final state. For the smaller cluster (cluster 2), the Δ H(0-0) value calculated for the T1 → S0 transition, using the PBE0 functional, is in good agreement with the measured NIR emission, and the calculated T2 → S0 value is in fair agreement with the measured visible emission. The calculated T1 → S0 phosphorescence Δ H(0-0) for cluster 1 is close to the measured visible emission energy. In order for the calculated phosphorescence for cluster 1 to agree with the intense NIR emission reported experimentally, the vibrational energy of the final state (S0) is required to be about 0.7 eV greater than the zero-point vibrational energy.

Assessment of Workers' Exposure to Grain Dust and Bioaerosols During the Loading of Vessels' Hold: An Example at a Port in the Province of Québec.

Longshoremen are exposed to large amounts of grain dust while loading of grain into the holds of vessels. Grain dust inhalation has been linked to respiratory diseases such as chronic bronchitis, hypersensitivity, pneumonitis, and toxic pneumonitis. Our objective was to characterize the exposure of longshoremen to inhalable and total dust, endotoxins, and cultivable bacteria and fungi during the loading of grain in a vessel's hold at the Port of Montreal in order to assess the potential health risks. Sampling campaigns were conducted during the loading of two different types of grain (wheat and corn). Environmental samples of microorganisms (bacteria, fungus, and actinomycetes) were taken near the top opening of the ship's holds while personal breathing zone measurements of dust and endotoxins were sampled during the worker's 5-hour shifts. Our study show that all measurements are above the recommendations with concentration going up to 390 mg m-3 of total dust, 89 mg m-3 of inhalable fraction, 550 000 EU m-3 of endotoxins, 20 000 CFU m-3 of bacteria, 61 000 CFU m-3 of fungus and 2500 CFU m-3 of actinomycetes. In conclusion, longshoremen are exposed to very high levels of dust and of microorganisms and their components during grain loading work. Protective equipment needs to be enforced for all workers during such tasks in order to reduce their exposure.

Calculations of One- and Two-Photon Absorption Spectra for Molecular Metal Chalcogenide Clusters with Electron-Acceptor Ligands.

We present calculated one- and two-photon absorption (OPA, TPA) spectra for molecular neutral, cation, and anion cadmium chalcogenide nonstoichiometric clusters [CdnE'm'(ER)m, E = S and Se, R = hydrogen, methyl, phenyl, para-nitrophenyl, para-cyanophenyl], ranging from less than 1 nm to more than 2 nm in size with well-defined structures. A systematic treatment of the clusters is carried out to assess the effects of size and ligand on their linear and nonlinear optical properties. Ligands and cluster size were found to have a large influence on the color and intensity of the electronic absorption spectra. TPA cross sections were found to increase linearly with cluster size. Electron-accepting ligands were also found to induce linear enhancement in TPA cross sections. Blue shifts of TPA maxima were observed for the first band with reduced molecular size. The effects of phenyl, para-nitrophenyl, and para-cyanophenyl substitutions, as well as changes in the chalcogenide atom, have been analyzed in detail.

A Theoretical Investigation of the Structure and Optical Properties of a Silver Cluster in Solid Form and in Solution.

Using density functional theory (DFT) and linear and quadratic response time-dependent DFT, we investigated the structure and optical properties of a silver sulfide cluster with the interesting property of dual emission that was observed when in crystal form but not in solution. Since the dual fluorescence is observed only in the crystal, a supposition of stabilization of a higher-energy excited state by an excimer-like complex was analyzed by calculations for a cluster dimer, formed through π-stacking of aromatic groups bonded to the sulfur atoms. However, because of the complexity of the system, a simple one-dimensional method for dimer optimization, which works moderately well in predicting the red-shifted fluorescence compared to its absorption in a naphthalene dimer, predicts only partially the red shift for the emission energy. Interestingly, calculations of the two-photon absorption (TPA) cross-section on the optimized isolated cluster as well as the crystal structure geometry indicate significant off-resonance TPA. While some materials have significantly larger TPA cross-sections, such a TPA cross-section off-resonance could be useful. The high density of states in the dimer system results in a higher probability for significant resonance enhancement and thus much larger TPA cross-sections.