An evaluation of intelligent and immersive digital applications in eliciting cognitive states in humans through the utilization of Emotiv Insight.

The amalgamation of Virtual Reality (VR) and Artificial Intelligence (AI) results in the development of many promising applications that are helpful for society in many aspects. This research was done to study the effect of immersive and non-immersive applications on user's psychological parameters. In this paper, an intelligent, interactive, and immersive digital application was designed, and the various psychological parameters of users while using the application were analyzed through the brain computer interactive device, Emotiv. The impact of these robust and immersive applications on the emotions of human beings was analyzed. According to the observations, the stress and relaxation levels are getting minimally affected, whereas the engagement levels are high for an immersive application rather than a non-immersive application. Hence, it can be concluded that immersive applications put users "in" the application environment and provide a near-realistic experience by blurring the line between the real and virtual worlds. Deeper immersion results from the increased sensation of presence, which in turn is helpful in increasing motivation and emotional investment.•This paper demonstrates the implementation of the A* algorithm within the Unity 3D Game Engine to develop an intelligent digital application, fostering interactivity and depth.•This paper explores the integration of VR technology to transform the digital application into an immersive and interactive experience, enhancing user engagement and realism.•This paper investigates the utilization of the Emotiv Insight device to analyze cognitive parameters within both non-immersive AI-based and immersive AI & VR-based applications, providing insights into user experiences.

A maize semidwarf mutant reveals a GRAS transcription factor involved in brassinosteroid signaling.

Brassinosteroids (BR) and gibberellins (GA) regulate plant height and leaf angle in maize (Zea mays). Mutants with defects in BR or GA biosynthesis or signaling identify components of these pathways and enhance our knowledge about plant growth and development. In this study, we characterized three recessive mutant alleles of GRAS transcription factor 42 (gras42) in maize, a GRAS transcription factor gene orthologous to the DWARF AND LOW TILLERING (DLT) gene of rice (Oryza sativa). These maize mutants exhibited semi-dwarf stature, shorter and wider leaves, and more upright leaf angle. Transcriptome analysis revealed a role for GRAS42 as a determinant of BR signaling. Analysis of the expression consequences from loss of GRAS42 in the gras42-mu1021149 mutant indicated a weak loss of BR signaling in the mutant, consistent with its previously demonstrated role in BR signaling in rice. Loss of BR signaling was also evident by the enhancement of weak BR biosynthetic mutant alleles in double mutants of nana plant1-1 and gras42-mu1021149. The gras42-mu1021149 mutant had little effect on GA-regulated gene expression, suggesting that GRAS42 is not a regulator of core GA signaling genes in maize. Single cell expression data identified gras42 expressed among cells in the G2/M phase of the cell cycle consistent with its previously demonstrated role in cell cycle gene expression in Arabidopsis (Arabidopsis thaliana). Cis-acting natural variation controlling GRAS42 transcript accumulation was identified by expression genome-wide association study (eGWAS) in maize. Our results demonstrate a conserved role for GRAS42/SCARECROW-LIKE 28 (SCL28)/DLT in BR signaling, clarify the role of this gene in GA signaling, and suggest mechanisms of tillering and leaf angle control by BR.

Detecting androgen receptor (AR), AR variant 7 (AR-V7), prostate-specific membrane antigen (PSMA), and prostate-specific antigen (PSA) gene expression in CTCs and plasma exosome-derived cfRNA in patients with metastatic castration-resistant prostate cancer (mCRPC) by integrating the VTX-1 CTC isolation system with the QIAGEN AdnaTest.

BACKGROUND: Therapies for metastatic castration-resistant prostate cancer (mCRPC) include targeting the androgen receptor (AR) with androgen receptor inhibitors (ARIs) and prostate-specific membrane antigen (PSMA). Having the ability to detect AR, AR splice variant 7 (AR-V7), or PSMA in circulating tumor cells (CTCs) or circulating exosomal cell-free RNA (cfRNA) could be helpful to guide selection of the appropriate therapy for each individual patient. The Vortex Biosciences VTX-1 system is a label-free CTC isolation system that enables the detection of the expression of multiple genes in both CTCs and exosomal cfRNA from the same blood sample in patients with mCRPC. Detection of both AR-V7 and PSMA gene expression in both CTCs and cfRNA simultaneously has not yet been reported. METHODS: To characterize the combined VTX-1-AdnaDetect workflow, 22Rv1 cancer cells were spiked into blood from healthy donors and processed with the VTX-1 to mimic patient samples and assess performances (capture efficiency, purity, AR and AR-V7 expression). Then, we collected 19 blood samples from 16 patients with mCRPC and therapeutic resistance to androgen receptor inhibitors (ARIs). Plasma was separated and the plasma-depleted blood was processed further with the VTX-1 to collect CTCs. Both plasma exosomal cfRNA and CTCs were subsequently analyzed for AR, AR-V7, PSMA, and prostate-specific antigen (PSA) mRNA expression using the AdnaTest ProstateCancerPanel AR-V7 assay. RESULTS: AR-V7 expression could be detected in 22Rv1 cells spiked into blood from healthy volunteers as well as in CTCs and plasma-derived exosomal cfRNA from patients with mCRPC by processing blood with the VTX-1 CTC isolation system followed by the AdnaTest ProstateCancerPanel AR-V7 assay. 94.7% of patient blood samples (18/19) had detectable AR expression in either CTCs or exosomal cfRNA (16 in CTCs, 12 in cfRNA). 15.8% of the 19 patient blood samples (3/19) were found to have AR-V7-positive (AR-V7+) CTCs, one of which was also AR-V7+ in the exosomal cfRNA analysis. 42.1% of patient blood samples (8/19) were found to be PSMA positive (PSMA+): 26.3% (5/19) were PSMA+ in the CTC analysis and 31.6% (6/19) were PSMA+ in the exosomal cfRNA analysis. Of those 8 PSMA+ samples, 2 had detectable PSMA only in CTCs, and 3 had detectable PSMA only in exosomal cfRNA. CONCLUSION: VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood.

Lysosomal Degradation Targets Mutant Calreticulin and the Thrombopoietin Receptor in Myeloproliferative Neoplasms.

Somatic mutants of calreticulin (CRT) drive myeloproliferative neoplasms (MPNs) via binding to the thrombopoietin receptor (MPL) and aberrant activation of the JAK/STAT pathway. Compared with healthy donors, platelets from MPN patients with CRT mutations display low cell surface MPL. Additionally, co-expression of MPL with an MPN-linked CRT mutant (CRTDel52) reduces cell surface MPL, suggesting that CRTDel52 may induce MPL degradation. We show that lysosomal degradation is relevant to the turnover of CRTDel52 and MPL. Furthermore, CRTDel52 increases the lysosomal localization and degradation of MPL. Mammalian target of rapamycin (mTOR) inhibitors reduce cellular CRTDel52, MPL and secreted CRTDel52 levels, and impair CRTDel52-mediated cell proliferation. mTOR inhibition also reduces colony formation and differentiation of CD34+ cells from MPN patients but not healthy donors. Together, these findings indicate low surface MPL as a biomarker of mutant CRT-mediated MPN and induced degradation of CRTDel52 and MPL as an avenue for therapeutic intervention.

Genome-wide association identifies a BAHD acyltransferase activity that assembles an ester of glucuronosylglycerol and phenylacetic acid.

Genome-wide association studies (GWAS) are an effective approach to identify new specialized metabolites and the genes involved in their biosynthesis and regulation. In this study, GWAS of Arabidopsis thaliana soluble leaf and stem metabolites identified alleles of an uncharacterized BAHD-family acyltransferase (AT5G57840) associated with natural variation in three structurally related metabolites. These metabolites were esters of glucuronosylglycerol, with one metabolite containing phenylacetic acid as the acyl component of the ester. Knockout and overexpression of AT5G57840 in Arabidopsis and heterologous overexpression in Nicotiana benthamiana and Escherichia coli demonstrated that it is capable of utilizing phenylacetyl-CoA as an acyl donor and glucuronosylglycerol as an acyl acceptor. We, thus, named the protein Glucuronosylglycerol Ester Synthase (GGES). Additionally, phenylacetyl glucuronosylglycerol increased in Arabidopsis CYP79A2 mutants that overproduce phenylacetic acid and was lost in knockout mutants of UDP-sulfoquinovosyl: diacylglycerol sulfoquinovosyl transferase, an enzyme required for glucuronosylglycerol biosynthesis and associated with glycerolipid metabolism under phosphate-starvation stress. GGES is a member of a well-supported clade of BAHD family acyltransferases that arose by duplication and neofunctionalized during the evolution of the Brassicales within a larger clade that includes HCT as well as enzymes that synthesize other plant-specialized metabolites. Together, this work extends our understanding of the catalytic diversity of BAHD acyltransferases and uncovers a pathway that involves contributions from both phenylalanine and lipid metabolism.

Age-dependent loss of HAPLN1 erodes vascular integrity via indirect upregulation of endothelial ICAM1 in melanoma.

Melanoma, the most lethal form of skin cancer, often has worse outcomes in older patients. We previously demonstrated that an age-related decrease in the secreted extracellular matrix (ECM) protein HAPLN1 has a role in slowing melanoma progression. Here we show that HAPLN1 in the dermal ECM is sufficient to maintain the integrity of melanoma-associated blood vessels, as indicated by increased collagen and VE-cadherin expression. Specifically, we show that HAPLN1 in the ECM increases hyaluronic acid and decreases endothelial cell expression of ICAM1. ICAM1 phosphorylates and internalizes VE-cadherin, a critical determinant of vascular integrity, resulting in permeable blood vessels. We found that blocking ICAM1 reduces tumor size and metastasis in older mice. These results suggest that HAPLN1 alters endothelial ICAM1expression in an indirect, matrix-dependent manner. Targeting ICAM1 could be a potential treatment strategy for older patients with melanoma, emphasizing the role of aging in tumorigenesis.

Unraveling endophytic diversity in dioecious Siraitia grosvenorii: implications for mogroside production.

Host and tissue-specificity of endophytes are important attributes that limit the endophyte application on multiple crops. Therefore, understanding the endophytic composition of the targeted crop is essential, especially for the dioecious plants where the male and female plants are different. Here, efforts were made to understand the endophytic bacterial composition of the dioecious Siraitia grosvenorii plant using 16S rRNA amplicon sequencing. The present study revealed the association of distinct endophytic bacterial communities with different parts of male and female plants. Roots of male and female plants had a higher bacterial diversity than other parts of plants, and the roots of male plants had more bacterial diversity than the roots of female plants. Endophytes belonging to the phylum Proteobacteria were abundant in all parts of male and female plants except male stems and fruit pulp, where the Firmicutes were most abundant. Class Gammaproteobacteria predominated in both male and female plants, with the genus Acinetobacter as the most dominant and part of the core microbiome of the plant (present in all parts of both, male and female plants). The presence of distinct taxa specific to male and female plants was also identified. Macrococcus, Facklamia, and Propionibacterium were the distinct genera found only in fruit pulp, the edible part of S. grosvenorii. Predictive functional analysis revealed the abundance of enzymes of secondary metabolite (especially mogroside) biosynthesis in the associated endophytic community with predominance in roots. The present study revealed bacterial endophytic communities of male and female S. grosvenorii plants that can be further explored for monk fruit cultivation, mogroside production, and early-stage identification of male and female plants. KEY POINTS: • Male and female Siraitia grosvenorii plants had distinct endophytic communities • The diversity of endophytic communities was specific to different parts of plants • S. grosvenorii-associated endophytes may be valuable for mogroside biosynthesis and monk fruit cultivation.

An Insight into the Repurposing of Phytoconstituents obtained from Delhi's Aravalli Biodiversity Park as Antifungal Agents.

The global prevalence of fungal infections is alarming in both the pre- and postCOVID period. Due to a limited number of antifungal drugs, there are hurdles in treatment strategies for fungal infections due to toxic potential, drug interactions, and the development of fungal resistance. All the antifungal targets (existing and newer) and pipeline molecules showing promise against these targets are reviewed. The objective was to predict or repurpose phyto-based antifungal compounds based on a dual target inhibition approach (Sterol-14-αdemethylase and HSP-90) using a case study. In pursuit of repurposing the phytochemicals as antifungal agents, a team of researchers visited Aravalli Biodiversity Park (ABP), Delhi, India, to collect information on available medicinal plants. From 45 plants, a total of 1149 ligands were collected, and virtual screening was performed using Schrodinger Suite 2016 software to get 83 hits against both the target proteins: Sterol-14-α-demethylase and HSP-90. After analysis of docking results, ligands were selected based on their interaction against both the target proteins and comparison with respective standard ligands (fluconazole and ganetespib). We have selected Isocarthamidin, Quercetin and Boeravinone B based on their docking score and binding interaction against the HSP-90 (Docking Score -9.65, -9.22 and -9.21, respectively) and 14-α-demethylase (Docking Score -9.19, -10.76 and -9.74 respectively). The docking protocol was validated and MM/GBSA studies depicted better stability of selected three ligands (Isocarthamidin, Quercetin, Boeravinone B) complex as compared to standard complex. Further, MD simulation studies were performed using the Desmond (67) software package version 2018-4. All the findings are presented as a case study for the prediction of dual targets for the repurposing of certain phytochemicals as antifungal agents.

Development of metasurface based hyperthermia lens applicator for heating of cancerous tissues.

Numerous designs and methods have been examined to improve penetration depth (PD), but there is a need for research to explore the potential increase in PD through uniform heating, a compact applicator, and low input power. This paper presents metasurface based hyperthermia lens applicator with water bolus for uniform heating of cancerous tissues. The proposed applicator consists of a stacked spiral antenna and a spiral-shaped frequency selective surface as a superstrate. The spiral antenna and superstrate are optimized on a low cost FR4 substrate having a size of 32 × 32 × 3.27mm3 and 10 × 10 × 1.6mm3 (size of the unit cell), respectively. The proposed applicator is simulated with heterogeneous phantom (skin, fat, and muscle layers) and with the Gustav voxel model with and without a water bolus layer. The number of unit cells in the superstrate is optimized to direct the maximum energy toward the tumor location. The performance study of the applicator is carried out in terms of specific absorption rate, PD, and effective field size. Further, thermal analysis is carried out with 1.9 W of input power at the antenna port, and the highest 44.7 °C temperature rise is obtained. The cancerous tissue's (tumor) surrounding temperature is between 41 and 45 °C, which is adequate for efficient hyperthermia treatment. Finally, the proposed metasurface hyperthermia lens applicator is fabricated and experimentally validated in a mimicked phantom's presence. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-023-00300-z.

Sex Differences in the Association of Age at Hypertension Diagnosis With Brain Structure.

BACKGROUND: Sex differences exist in the likelihood of cognitive decline. The age at hypertension diagnosis is a unique contributor to brain structural changes associated with cerebral small vessel disease. However, whether this relationship differs between sexes remains unclear. Therefore, our objective was to evaluate sex differences in the association between the age at hypertension diagnosis and cerebral small vessel disease-related brain structural changes. METHODS: We used data from the UK Biobank to select participants with a known age at hypertension diagnosis and brain magnetic resonance imaging (n=9430) and stratified them by sex and age at hypertension diagnosis. Control participants with magnetic resonance imaging scans but no hypertension were chosen at random matched by using propensity score matching. For morphological brain structural changes, generalized linear models were used while adjusting for other vascular risk factors. For the assessment of white matter microstructure, principal component analysis led to a reduction in the number of fractional anisotropy variables, followed by regression analysis with major principal components as outcomes. RESULTS: Males but not females with a younger age at hypertension diagnosis exhibited lower brain gray and white matter volume compared with normotensive controls. The volume of white matter hyperintensities was greater in both males and females with hypertension than normotensive controls, significantly higher in older females with hypertension. Compared with normotensive controls, white matter microstructural integrity was lower in individuals with hypertension, which became more prominent with increasing age. CONCLUSIONS: Our study demonstrates that the effect of hypertension on cerebral small vessel disease-related brain structure differs by sex and by age at hypertension diagnosis.

Metamaterial based AMC backed archimedean spiral antenna for in-vitro microwave hyperthermia of skin cancer.

This research article presents a study that uses microwave frequencies (ISM band) for treatment of skin cancer by heating the malignant cells on skin with a Microwave Hyperthermia (MWHT) applicator. The proposed MWHT applicator has been designed as an Archimedean Spiral Microstrip Patch Antenna (AMSPA) of dimensions 38 × 38 × 1.64 mm3 backed with a Meshed-shaped AMC (48 × 48 × 3.27mm3) reflector, placed at an optimized distance of 12 mm from AMSPA. The proposed AMSPA is designed as a single spiral resonator and fabricated on FR-4 substrate, excited using a feed network. The proposed AMSPA shows a resonance at 2.5 GHz with an impedance BW of 260 MHz (2.37-2.63 GHz) and peak gain of 3.20 dB with a bidirectional radiation pattern. An AMC is placed at its backside that can be exploited as a phase-compensation surface to attain an in-phase profile for directive emission and improve the BW upto 470 MHz, peak gain to 6.8 dB and also enhance the front-to-back ratio of the radiating antenna with radiation efficiency of 80%. The simulated environment for hyperthermia analysis is set up using penne's Bio-Heat equations to deliver microwave energy to the bio-mimic, that leads to a rise in temperature over the designed bio-mimic in CST MWS in the range of 41-45°C. The validation of MWHT radiation properties and temperature rise inside the malignancy of phantom is carried out by fabricating the bio-mimic using gelatine, vegetable oils and glycerol. This set up enhances the penetration-depth of EM waves inside the tri-layered phantom up-to 29.5 mm with Effective Field Surface of 36 × 36 mm2 and SAR of 8 W/Kg.

This article discusses the design and development of a device designed to treat skin cancer, specifically melanoma. This device is called a Microwave Hyperthermia (MWHT) applicator. The applicator sends out focused waves of microwave energy but at a specific frequency of ISM band. These waves heat up a model of human skin, simulating what would happen if this is used on a real person with cancer. The goal is to heat the cancer to around 45°C, which can help treat it. The special thing about this applicator is that it's designed to be very compact and have good gain. It heats up the cancer without causing harm to the healthy tissues nearby. The researchers tested it extensively and found that it works well. It has a wide range of effectiveness for different tumor sizes and depths within the skin. To make sure it is safe and accurate, a model of a human forearm using materials like gelatin and water has been prepared. Then used the applicator on this model and measured the temperature increase. After about 40 minutes of exposure, there is a temperature rise of about 45 degrees Celsius. Thus this article is about a device that uses special waves to heat up and treat skin cancer. It's designed to be safe and effective, and the tests show it works on a model of human skin. This could be a useful tool for treating skin cancer in the future.

Corrigendum: Unravelling the genetic framework associated with grain quality and yield-related traits in maize (Zea mays L.).

[This corrects the article DOI: 10.3389/fgene.2023.1248697.].

SMRT-AgRenSeq-d in potato (Solanum tuberosum) as a method to identify candidates for the nematode resistance Gpa5.

Potato is the third most important food crop in the world. Diverse pathogens threaten sustainable crop production but can be controlled, in many cases, through the deployment of disease resistance genes belonging to the family of nucleotide-binding, leucine-rich-repeat (NLR) genes. To identify effective disease resistance genes in established varieties, we have successfully established SMRT-AgRenSeq in tetraploid potatoes and have further enhanced the methodology by including dRenSeq in an approach that we term SMR-AgRenSeq-d. The inclusion of dRenSeq enables the filtering of candidates after the association analysis by establishing a presence/absence matrix across resistant and susceptible varieties that is translated into an F1 score. Using a SMRT-RenSeq-based sequence representation of the NLRome from the cultivar Innovator, SMRT-AgRenSeq-d analyses reliably identified the late blight resistance benchmark genes Rpi-R1, Rpi-R2-like, Rpi-R3a, and Rpi-R3b in a panel of 117 varieties with variable phenotype penetrations. All benchmark genes were identified with an F1 score of 1, which indicates absolute linkage in the panel. This method also identified nine strong candidates for Gpa5 that controls the potato cyst nematode (PCN) species Globodera pallida (pathotypes Pa2/3). Assuming that NLRs are involved in controlling many types of resistances, SMRT-AgRenSeq-d can readily be applied to diverse crops and pathogen systems.

A mixed-methods approach to understanding barriers and facilitators to healthy eating and exercise from five European countries: highlighting the roles of enjoyment, emotion and social engagement.

Healthy adults are consistently falling below national and international recommendations for physical activity and dietary intake across Europe. This study took a co-creative approach with adult samples from five European countries to qualitatively and quantitatively establish motivators, barriers and sustaining factors for positive health behaviour change. Stage 1 delivered a newly-designed online programme, creating a community who identified challenges, motivators and solutions to sustaining positive healthy eating and physical activity behaviours. Stage 2 administered an online survey (developed from Stage 1 findings) to a larger sample to quantify the relative importance of these motivators and barriers. Results from both stages indicated enjoyment, positive emotions, and reward as key motivators for both behaviours across all five countries. Barriers included habit-breaking difficulties, temptation and negative affective states. Those with a high BMI placed more importance on social pressure than those with healthy BMI. Participants' reports of motivators and barriers reflected relevant approaches from consumer science, behavioural economics, and psychology. Interventions supporting adults who are not chronically ill but would benefit from improved diet and/or physical activity should not focus exclusively on health as a motivating factor. Emphasis on enjoyable behaviours, social engagement and reward will likely improve engagement and sustained behaviour change.

Computational identification and exploration of novel FGFR tyrosine kinase inhibitors for the treatment of cholangiocarcinoma.

Tyrosine kinase inhibitors are a specific drug class revolutionizing cancer treatment. FGFR (Fibroblast Growth Factor Receptor) is a member of the receptor tyrosine kinase family that has been involved in various alterations which have been increasingly recognized as critical molecular drivers in cholangiocarcinoma, a malignant tumor originating from bile duct epithelial cells. The paper focuses on stepwise computational investigations for the discovery of novel inhibitors of FGFR using pharmacophore modeling, virtual screening, docking, ADMET analysis, molecular dynamics, and knowledge-based structure-activity relationship. To begin with, we have considered a library of 120314868 compounds from the ZINC 15 database through pharmacophore modeling, which was narrowed down to 110 having binding affinity >-8.0 kcal mol-1. The 110 compounds were analyzed using virtual screening and compared with the FDA-approved drug pemigatinib, which provided the 34 hits with binding affinities >-6.5 kcal mol-1. Finally, the top 4 hits were considered for docking, and ADMET property analysis for drug-likeness. MD and MM-GBSA analysis were performed to predict the binding free energy of these chemicals and determine their stability. To gain insight into the structure and binding interactions of these compounds, knowledge-based SAR analyses were performed using their electrostatic potential maps computed with DFT. Several techniques were employed to build improved inhibitors based on these SAR, and they were then analyzed utilizing ADMET, MD studies, and MM-GBSA analyses. Finally, the results suggested that the identified four compounds and developed inhibitors from this current work can be employed effectively as prospective FGFR inhibitors for treating Cholangiocarcinoma.Communicated by Ramaswamy H. Sarma.

The emerging potential of siRNA nanotherapeutics in treatment of arthritis.

RNA interference (RNAi) using small interfering RNA (siRNA) has shown potential as a therapeutic option for the treatment of arthritis by silencing specific genes. However, siRNA delivery faces several challenges, including stability, targeting, off-target effects, endosomal escape, immune response activation, intravascular degradation, and renal clearance. A variety of nanotherapeutics like lipidic nanoparticles, liposomes, polymeric nanoparticles, and solid lipid nanoparticles have been developed to improve siRNA cellular uptake, protect it from degradation, and enhance its therapeutic efficacy. Researchers are also investigating chemical modifications and bioconjugation to reduce its immunogenicity. This review discusses the potential of siRNA nanotherapeutics as a therapeutic option for various immune-mediated diseases, including rheumatoid arthritis, osteoarthritis, etc. siRNA nanotherapeutics have shown an upsurge of interest and the future looks promising for such interdisciplinary approach-based modalities that combine the principles of molecular biology, nanotechnology, and formulation sciences.

Mass Spectrometric Profiling of HLA-B44 Peptidomes Provides Evidence for Tapasin-Mediated Tryptophan Editing.

The extreme polymorphisms of HLA class I proteins result in structural variations in their peptide binding sites to achieve diversity in Ag presentation. External factors could independently constrict or alter HLA class I peptide repertoires. Such effects of the assembly factor tapasin were assessed for HLA-B*44:05 (Y116) and a close variant, HLA-B*44:02 (D116), which have low and high tapasin dependence, respectively, for their cell surface expression. Analyses of the HLA-B*44:05 peptidomes in the presence and absence of tapasin reveal that peptides with C-terminal tryptophans and higher predicted affinities are preferentially selected by tapasin, coincident with reduced frequencies of peptides with other C-terminal amino acids, including leucine. Comparisons of the HLA-B*44:05 and HLA-B*44:02 peptidomes indicate the expected structure-based alterations near the peptide C termini, but also C-terminal amino acid frequency and predicted affinity changes among the unique and shared peptide groups for B*44:02 and B*44:05. Overall, these findings indicate that the presence of tapasin and the tapasin dependence of assembly alter HLA class I peptide-binding preferences at the peptide C terminus. The particular C-terminal amino acid preferences that are altered by tapasin are expected to be determined by the intrinsic peptide-binding specificities of HLA class I allotypes. Additionally, the findings suggest that tapasin deficiency and reduced tapasin dependence expand the permissive affinities of HLA class I-bound peptides, consistent with prior findings that HLA class I allotypes with low tapasin dependence have increased breadth of CD8+ T cell epitope presentation and are more protective in HIV infections.

Unravelling the genetic framework associated with grain quality and yield-related traits in maize (Zea mays L.).

Maize serves as a crucial nutrient reservoir for a significant portion of the global population. However, to effectively address the growing world population's hidden hunger, it is essential to focus on two key aspects: biofortification of maize and improving its yield potential through advanced breeding techniques. Moreover, the coordination of multiple targets within a single breeding program poses a complex challenge. This study compiled mapping studies conducted over the past decade, identifying quantitative trait loci associated with grain quality and yield related traits in maize. Meta-QTL analysis of 2,974 QTLs for 169 component traits (associated with quality and yield related traits) revealed 68 MQTLs across different genetic backgrounds and environments. Most of these MQTLs were further validated using the data from genome-wide association studies (GWAS). Further, ten MQTLs, referred to as breeding-friendly MQTLs (BF-MQTLs), with a significant phenotypic variation explained over 10% and confidence interval less than 2 Mb, were shortlisted. BF-MQTLs were further used to identify potential candidate genes, including 59 genes encoding important proteins/products involved in essential metabolic pathways. Five BF-MQTLs associated with both quality and yield traits were also recommended to be utilized in future breeding programs. Synteny analysis with wheat and rice genomes revealed conserved regions across the genomes, indicating these hotspot regions as validated targets for developing biofortified, high-yielding maize varieties in future breeding programs. After validation, the identified candidate genes can also be utilized to effectively model the plant architecture and enhance desirable quality traits through various approaches such as marker-assisted breeding, genetic engineering, and genome editing.

PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells.

Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting AKT (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogeneous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined AKT and PDK targeting. Biochemically, the combined AKT and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial apoptosis but failed to induce apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154, and DBK-1160. We also provide proof-of-principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain-penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.

Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.

Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.