Distinct Changes Research Articles

Nucleolar dynamics are determined by the ordered assembly of the ribosome.

Ribosome biogenesis occurs in the nucleolus, a nuclear biomolecular condensate that exhibits dynamic biophysical properties thought to be important for function. However, the relationship between ribosome assembly and nucleolar dynamics is incompletely understood. Here, we present a platform for high-throughput fluorescence recovery after photobleaching (HiT-FRAP), which we use to screen hundreds of genes for their impact on dynamics of the nucleolar scaffold nucleophosmin (NPM1). We find that scaffold dynamics and nucleolar morphology respond to disruptions in key stages of ribosome biogenesis. Accumulation of early ribosomal intermediates leads to nucleolar rigidification while late intermediates lead to increased fluidity. We map these biophysical changes to specific ribosomal intermediates and their affinity for NPM1. We also discover that disrupting mRNA processing impacts nucleolar dynamics and ribosome biogenesis. This work mechanistically ties ribosome assembly to the biophysical features of the nucleolus and enables study of how dynamics relate to function across other biomolecular condensates.

Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia.

Inhibition of Bruton's tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib. The large number of available inhibitors for the BTK target creates challenges in choosing the most appropriate BTKi for treatment. Side-by-side comparisons in CLL have shown that different inhibitors may differ in their treatment efficacy. Moreover, the nature of the resistance mutations that arise in patients appears to depend on the specific BTKi administered. We have previously shown that Ibrutinib binding to the kinase active site causes unanticipated long-range effects on the global conformation of BTK (Joseph, R.E., et al., 2020, https://doi.org/10.7554/eLife.60470 ). Here we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W.

Effect of Prebiotic Supplementation on Probiotic Viability and Physicochemical Characteristics of Fermented Coconut Water with Bifidobacterium longum

Background: Probiotics and prebiotics are functional ingredients that provide health benefits to consumers but they are mainly incorporated in dairy products. Designing a non-dairy product in which probiotics and prebiotics would be incorporated would allow more consumers to benefit from their advantages. Objective: This study investigated the effect of supplementation of two different prebiotics, fructooligosaccharide (FOS) and inulin, on the viability of Bifidobacterium longum ATCC BAA-999 in coconut water. Methods: Two concentrations of prebiotics used were 1% and 2%. The physicochemical characteristics of fermented coconut water with B. longum for 9 h at 37oC and during refrigerated storage at 4oC for 2 weeks were analyzed. The viability of B. longum in fermented coconut water was maintained above the recommended therapeutic level (7 log CFU/mL) with or without supplementation with prebiotics. Results: Most distinct changes in colour (∆E > 3) occurred in fermented coconut water compared to unfermented coconut water. An increase in the total soluble solids was also observed in fermented coconut water with the increase in the concentration of prebiotics. There were no significant changes in the clarity, pH, and concentrations of shikimic and malic acids in the fermented coconut water with or without supplementation with prebiotics over the 2 weeks of storage. Acetic acid production was observed in the fermented coconut water with the highest acetic acid production in the fermented coconut water supplemented with 1% FOS after 2 weeks of storage. Conclusion: This study demonstrated the potential use of coconut water as a medium to produce a probiotic drink.

Triangular Greenness Index Analysis for Monitoring Fungal Disease in Pine Trees: A UAV-based Approach

The Triangular Greenness Index (TGI) is a vegetation index derived from high-resolution aerial images acquired using unmanned aerial vehicles (UAVs). It serves as a valuable tool for quantifying vegetation health and dynamics in the visible spectrum. The TGI combines key components, including red reflectance and green reflectance, extracted from UAV-based imagery. The red component represents chlorophyll absorption and photosynthetic activity, while the green component reflects vegetation density and canopy structure. By integrating these components, the TGI offers a comprehensive measure of photosynthetically active vegetation, utilizing UAVs as a data collection platform. This study highlight the importance of the TGI derived from UAV-based imagery in monitoring vegetation changes, assessing ecosystem responses, and tracking variations in land cover and biodiversity. Furthermore, the application of TGI analysis using UAV-based aerial imagery shows promise in accurately identifying and monitoring vegetation affected by fungal diseases. This integrated approach enables the detection of diseased trees based on distinct changes in greenness observed in their foliage. Because fungal diseases dry the plant and cause the green areas to disappear. The integration of UAV technology enhances the accuracy and efficiency of TGI calculation, contributing to effective management and conservation strategies in the context of fungal disease detection in vegetation. In this study, TGI was produced using UAV-based orthophoto and healthy and sick trees were determined. According to the accuracy analysis, producer accuracy for detecting green plants was 99.7% and user accuracy was 98.5%. Fungal disease could be detected with 98.5% producer accuracy and 96.5% user accuracy. The overall accuracy of the study was calculated as 98.6%.

Ultrasensitive Nanofiber Biosensor: Rapid In Situ Chromatic Detection of Bacteria for Healthcare Innovation.

Rapid detection of bacterial presence in skin wounds is crucial to prevent the transition from acute to chronic wounds and the onset of systemic infections. Current methods for detecting infections, particularly at low concentrations (<1.0 × 105 CFU/cm2), often require complex technologies and direct sampling, which can be invasive and time-consuming. Addressing this gap, we introduce a colorimetric nanofibrous biosensor enabling real-time in situ monitoring of bacterial concentrations in wounds. This biosensor employs a colorimetric hemicyanine dye (HCy) probe, which changes color in response to bacterial lipase, a common secretion in infected wounds. To enhance the biosensor's sensitivity, we incorporated two key materials science strategies: aligning the nanofibers to promote efficient bacterial attachment and localization and integrating Tween 80, a surfactant, within the nanofiber matrix. This combination of physical and chemical cues results in a notable increase in lipase activity. The cross-aligned core-shell nanofibers, embedded with Tween 80 and HCy, demonstrate an immediate and distinct color change when exposed to as low as 3.0 × 104 CFU/cm2 of common pathogens such as Pseudomonas aeruginosa and MRSA. Significantly, the presence of Tween 80 amplifies the colorimetric response, making visual detection more straightforward and four times more pronounced. Our nanobiosensor design facilitates the detection of low-concentration bacterial infections in situ without the need to remove wound dressings. This advancement marks a significant step forward in real-time wound monitoring, offering a practical tool for the early detection of clinical bacterial infections.

Neural Network-Based Sum-Frequency Generation Spectra of Pure and Acidified Water Interfaces with Air.

The affinity of hydronium ions (H3O+) for the air-water interface is a crucial question in environmental chemistry. While sum-frequency generation (SFG) spectroscopy has been instrumental in indicating the preference of H3O+ for the interface, key questions persist regarding the molecular origin of the SFG spectral changes in acidified water. Here we combine nanosecond long neural network (NN) reactive simulations of pure and acidified water slabs with NN predictions of molecular dipoles and polarizabilities to calculate SFG spectra of long reactive trajectories including proton transfer events. Our simulations show that H3O+ ions cause two distinct changes in phase-resolved SFG spectra: first, a low-frequency tail due to the vibrations of H3O+ and its first hydration shell, analogous to the bulk proton continuum, and second, an enhanced hydrogen-bonded band due to the ion-induced static field polarizing molecules in deeper layers. Our calculations confirm that changes in the SFG spectra of acidic solutions are caused by hydronium ions preferentially residing at the interface.

Albumin promoter-driven FlpO expression induces efficient genetic recombination in mouse liver.

Tissue-specific gene manipulations are widely used in genetically engineered mouse models. A single recombinase system, such as the one using Alb-Cre, has been commonly used for liver-specific genetic manipulations. However, most diseases are complex, involving multiple genetic changes and various cell types. A dual recombinase system is required for conditionally modifying different genes sequentially in the same cell or inducing genetic changes in different cell types within the same organism. A FlpO cDNA was inserted between the last exon and 3'-UTR of the mouse albumin gene in a bacterial artificial chromosome (BAC-Alb-FlpO). The founders were crossed with various reporter mice to examine the efficiency of recombination. Liver cancer tumorigenesis was investigated by crossing the FlpO mice with FSF-KrasG12D mice and p53frt mice (KPF mice). BAC-Alb-FlpO mice exhibited highly efficient recombination capability in both hepatocytes and intrahepatic cholangiocytes. No recombination was observed in the duodenum and pancreatic cells. BAC-Alb-FlpO-mediated liver-specific expression of mutant KrasG12D and conditional deletion of p53 gene caused the development of liver cancer. Remarkably, liver cancer in these KPF mice manifested a distinctive mixed hepatocellular carcinoma and cholangiocarcinoma phenotype. A highly efficient and liver-specific BAC-Alb-FlpO mouse model was developed. In combination with other Cre lines, different genes can be manipulated sequentially in the same cell, or distinct genetic changes can be induced in different cell types of the same organism.NEW & NOTEWORTHY A liver-specific Alb-FlpO mouse line was generated. By coupling it with other existing CreERT or Cre lines, the dual recombinase approach can enable sequential gene modifications within the same cell or across various cell types in an organism for liver research through temporal and spatial gene manipulations.

Stressing heart cells to study disease

Tension across heart muscle cells in 3D engineered tissues prompts distinct electrical changes in healthy and diseased heart cells.

Genetic variant detection in a South African haemophilia B population.

Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

Quantitative evaluation of gut microbiota composition in pancreatic cancer: A pooled study.

Prior research has demonstrated a positive association between the composition of gut microbiota and the incidence of pancreatic cancer. Nevertheless, a thorough quantitative and systematic evaluation of the distinct properties of gut microbiota in individuals diagnosed with pancreatic cancer has yet to be conducted. The objective of this study is to examine alterations in the diversity of intestinal microbiota in individuals diagnosed with pancreatic cancer. Search for relevant literature published before July 2023 in 4 databases: PubMed, Embase, Web of Science, and Cochrane Library, without any language restrictions. A total of 12 studies were included, including 535 patients with pancreatic cancer and 677 healthy controls. Analysis was conducted on 6 phyla, 16 genera, and 6 species. The study found significant and distinctive changes in the α-diversity of gut microbiota, as well as in the relative abundance of multiple gut bacterial groups at the phylum, genus, and species levels in pancreatic cancer patients. Overall, there are certain characteristic changes in the gut microbiota of pancreatic cancer patients. However, further research is warranted to elucidate the specific mechanism of action and the potential for treatment.

Ratiometric Fluorescence and Chromogenic Probe for Trace Detection of Selected Transition Metals.

The design and development of a fluorescence sensor aimed at detecting and quantifying trace amounts of toxic transition metal ions within environmental, biological, and aquatic samples has garnered significant attention from diagnostic and testing laboratories, driven by the imperative to mitigate the health risks associated with these contaminants. In this context, we present the utilization of a heterocyclic symmetrical Schiff Base derivative for the purpose of fluorogenic and chromogenic detection of Co2+, Cu2+ and Hg2+ ions. The characterization of the ligand involved a comprehensive array of techniques, including physical assessments, optical analyses, NMR, FT-IR, and mass spectrometric examinations. The mechanism of ligand-metal complexation was elucidated through the utilization of photophysical parameters and FT-IR spectroscopic analysis, both before and after the interaction between the ligand and the metal salt solution. The pronounced alterations observed in absorption and fluorescence spectra, along with the distinctive chromogenic changes, following treatment with Co2+, Cu2+ and Hg2+, affirm the successful formation of complexes between the ligands and the treated metal ions. Notably, the receptor's complexation response exhibited selectivity towards Co(II), Cu(II), and Hg(II), with no observed chromogenic changes, spectral variations, or band shifts for the various tested metal ions, including Na+, Ag+, Ni2+, Mn2+, Pd2+, Pb2+, Cd2+, Zn2+, Sn2+, Fe2+, Fe3+, Cr3+ and Al3+. This absence of interaction between these metal ions and the ligand could be attributed to their compact or inadequately conducive conduction bands for complexation with the ligand's structural composition. To quantify the sensor's efficacy, fluorescence titration spectra were employed to determine the detection limits for Co2+, Cu2+ and Hg2+, yielding values of 2.92 × 10-8, 8.91 × 10-8, and 4.39 × 10-3 M, respectively. The Benesi-Hildebrand plots provided association constant values for the ligand-cobalt, ligand-copper, and ligand-mercury complexes as 0.74, 2.52, and 13.89 M-1, respectively.

Effects of inoculation and dry matter content on microbiome dynamics and metabolome profiling of sorghum silage

Sorghum forage was ensiled for 90 days at two dry matter (DM) contents (27 vs. 39%) without or with Lactiplantibacillus plantarum inoculation. On day 90 of fermentation, silages were sampled to assess the microbial community dynamics and metabolome profile. L. plantarum inoculation improved silage quality, as shown by a lower pH and greater acetic acid concentration. Loss of DM remained unaffected by L. plantarum inoculation but was greater in low- vs. high-DM sorghum silages (14.4 vs. 6.62%). The microbiome analysis revealed that Pseudomonas congelans represented the dominant species of the epiphytic microbiota in both low- and high-DM sorghum forage before ensiling. However, L. buchneri represented the dominant species at the end of ensiling. Ensiling fermentation resulted in distinct metabolic changes in silages with varying DM content. In low-DM silages, ensiling fermentation led to the accumulation of 24 metabolites and a reduction in the relative concentration of 13 metabolites. In high-DM silages, ensiling fermentation resulted in an increase in the relative concentration of 26 metabolites but a decrease in the concentration of 8 metabolites. Compared to non-inoculated silages, L. plantarum inoculation resulted in an increased concentration of 3 metabolites and a reduced concentration of 5 metabolites in low-DM silages. Similarly, in high-DM silages, there was an elevation in the relative concentration of 3 metabolites, while a decrease in 7 other metabolites. Ten metabolites with bio-functional activity were identified, including chrysoeriol, isorhamnetin, petunidin 3-glucoside, apigenin, caffeic acid, gallic acid, p-coumaric acid, trans-cinnamic acid, herniarin, and 3,4-dihydroxy-trans-cinnamate. This study presents a comprehensive analysis of microbiome and metabolome profiling of sorghum forage during ensiling as a function of DM content and L. plantarum inoculation, with a particular emphasis on identifying metabolites that may possess bio-functional properties.Key points• DM loss was not different by L. plantarum but higher in low- vs. high-DM silage.• L. buchneri dominated ensiling, regardless of DM level.• 10 metabolites with bio-functional activity were identified.

Unraveling the Nano-Bio Interface Interactions of a Lipase Adsorbed on Gold Nanoparticles under Laser Excitation.

The complex nature and structure of biomolecules and nanoparticles and their interactions make it challenging to achieve a deeper understanding of the dynamics at the nano-bio interface of enzymes and plasmonic nanoparticles subjected to light excitation. In this study, circular dichroism (CD) and Raman spectroscopic experiments and molecular dynamics (MD) simulations were used to investigate the potential changes at the nano-bio interface upon plasmonic excitation. Our data showed that photothermal and thermal heating induced distinct changes in the secondary structure of a model nanobioconjugate composed of lipase fromCandida antarcticafraction B (CALB) and gold nanoparticles (AuNPs). The use of a green laser led to a substantial decrease in the α-helix content of the lipase from 66% to 13% and an increase in the β-sheet content from 5% to 31% compared to the initial conformation of the nanobioconjugate. In contrast, the differences under similar thermal heating conditions were only 55% and 11%, respectively. This study revealed important differences related to the enzyme secondary structure, enzyme-nanoparticle interactions, and the stability of the enzyme catalytic triad (Ser105-Asp187-His224), influenced by the instantaneous local temperature increase generated from photothermal heating compared to the slower rate of thermal heating of the bulk. These results provide valuable insights into the interactions between biomolecules and plasmonic nanoparticles induced by photothermal heating, advancing plasmonic biocatalysis and related fields.

Correlation Of Placental Changes With Fetal And Maternal Outcome In Mothers With Hypertensive Disorders Of Pregnancy

Hypertension represents one of the most prevalent complications encountered during pregnancy, significantly contributing to both maternal and perinatal morbidity and mortality. The placenta, acting as a crucial feto-maternal organ, plays a pivotal role in sustaining pregnancy and fostering the healthy development of the fetus. Notably, the weight of the placenta holds functional importance, as it correlates with the villous surface area and fetal metabolism. Motivated by this context, the present study endeavors to examine the morphological and histological alterations in the placenta associated with hypertensive disorders of pregnancy and to assess their correlation with maternal and fetal outcomes. Methods: A prospective investigation encompassing 120 cases was conducted, comprising 60 normotensive mothers (Group A) and 60 mothers with hypertensive disorders of pregnancy (Group B). Placental specimens obtained from these participants were subjected to morphological and histological analyses, with subsequent correlation with maternal and fetal outcomes. Results: Our findings revealed a notable reduction in placental weight and dimensions within Group B compared to Group A. Histopathological examination unveiled a significant increase in the incidence of syncytial knots, fibrinoid necrosis, hyalinization, and calcification in placentas from the hypertensive group, directly correlating with neonatal complications. Furthermore, the mean neonatal birth weight was significantly higher in Group A compared to Group B. Conclusion: Hypertensive disorders of pregnancy exert a substantial impact on placental morphology, leading to diminished weight and dimensions, indicative of placental insufficiency attributable to compromised utero-placental blood flow. These alterations ultimately influence neonatal weight and overall neonatal outcomes. Our study underscores the presence of distinct morphological changes in the placenta that detrimentally affect fetal growth.

Reduced body-image disturbance by body-image interventions is associated with neural-response changes in visual and social processing regions: a preliminary study.

Body-image disturbance is a major factor in the development of eating disorders, especially among young women. There are two main components: perceptual disturbance, characterized by a discrepancy between perceived and actual body size, and affective disturbance, characterized by a discrepancy between perceived and ideal body size. Interventions targeting body-image disturbance ask individuals to describe their own body without using negative expressions when either viewing it in a mirror or imagining it. Despite the importance of reducing body-image disturbance, its neural mechanisms remain unclear. Here we investigated the changes in neural responses before and after an intervention. We hypothesized that neuralresponses correlated with the degree of body-image disturbance would also be related to its reduction, i.e., a reduction in perceptual and affective disturbances would be related to changes in attentional and socio-cognitive processing, respectively. Twenty-eight young adult women without known psychiatric disorders underwent a single 40-min intervention. Participants completed tasks before and after the intervention, in which they estimated their perceived and ideal body sizes using distorted silhouette images to measure body-image disturbance. We analyzed the behavioral and neural responses of participants during the tasks. The intervention did not significantly reduce body-image disturbance. Analysis of individual differences showed distinct changes in neural responses for each type of disturbance. A decrease in perceptual disturbance was associated with bodily visuospatial processing: increased activation in the left superior parietal lobule, bilateral occipital gyri, and right cuneus. Reduced affective disturbance was associated with socio-cognitive processing; decreased activation in the right temporoparietal junction, and increased functional connectivity between the left extrastriate body area and the right precuneus. We identified distinct neural mechanisms (bodily visuospatial and socio-cognitive processing) associated with the reduction in each component of body-image disturbance. Our results imply that different neural mechanisms are related to reduced perceptual disturbance and the expression thereof, whereas similar neural mechanisms are related to the reduction and expression of affective disturbance. Considering the small sample size of this study, our results should be regarded as preliminary.

Impact of the Eurasian Zonal Circulation on the Interannual Variability of Winter Surface Air Temperature and Subseasonal Temperature Reversal in North China

AbstractThis study focuses on the interannual variability of winter mean surface air temperature (SAT) and subseasonal SAT reversal in North China, which have profound impacts on national life and economic activities. The analysis explores the temporal and spatial distribution characteristics of these variations and their relationship with the Eurasian Zonal Circulation (EZ). The findings reveal distinct interdecadal changes in North China’s winter mean SAT, along with a general subseasonal reversal of cold and warm conditions. In comparison to the North Atlantic oscillation/Arctic Oscillation, the EZ has a more significant influence on the interannual variability of winter and subseasonal reversals. Strong EZ years are associated with the weakening of the Siberian High and the Ural Blocking High, causing the East Asian Trough to move eastward, which leads to the retention of cold air from the north and increased SAT in North China. Conversely, weak EZ years exhibit opposite circulation patterns. The winter mean EZ is influenced by preceding autumn Arctic sea ice concentrations (SIC). Reduced autumn SIC results in decreased heat flux and reduced eddy energy, leading to substantial attenuation of the winter storm track across Scandinavia and Western Asia. This attenuation, mediated through the interaction between eddies and mean flow, triggers a slowdown of Eurasian zonal circulation and intensification of the Siberian High. These conditions favor a positive phase of the winter Scandinavia pattern, facilitating the transport of cold Arctic air into North China. Likewise, subseasonal reversals in SIC influence corresponding alterations in the EZ.

Inlet Guide Vane Stagger Effects on Multistage Compressor Performance and Stall Inception

The effects of variable inlet guide vanes on compressors have been evaluated throughout the turbomachinery industry for decades. These vanes improve both the performance and stability of a machine—the extent to which is highly dependent on the individual machine and the conditions of operation. Evaluating their effects on compressor stall inception via experimental investigations can inform model development and validation since commonly used RANS and URANS tools face limitations in accurately predicting and modeling stall events. The current literature on variable inlet guide vane restaggering, however, is dominated by numerical investigations. This study offers a unique experimental investigation into restaggering effects on compressor stall behavior by evaluating experimental results from different variable inlet guide vane stagger angles in a high-pressure axial compressor. Previous investigations have shown that variable inlet guide vane restaggering may change the stall inception mechanism of axial flow compressors. This investigation found a distinct change in the stage matching of the machine without altering the stall inception mechanism, further demonstrating the need for experimental investigations to inform the specific effects that restaggering inlet guide vanes offers comparable compressors.

Abstract B084: Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer

Abstract Background: Over 20,000 women are diagnosed with ovarian cancer annually, and more than half will die within 5 years. This rate has changed little in the last 30 years, highlighting the need for therapy innovation. Although immunotherapy has revolutionized cancer treatment, efforts to harness endogenous patient immune responses have yielded limited therapeutic activity in ovarian cancer patients. T cells engineered to express a T cell receptor (TCR) targeting proteins uniquely overexpressed in tumors have the potential to control tumor growth without toxicity. Mesothelin (Msln) is over-expressed in ovarian cancer, contributes to the malignant and invasive phenotype, and has limited expression in healthy cells, making it a candidate immunotherapy target in these tumors. Methods: The ID8VEGF mouse cell line was used to evaluate if T cells engineered to express a mouse Msln-specific high-affinity T cell receptor (TCRMsln) can kill ovarian cancer. Tumor-bearing mice were treated with TCRMsln T cells plus anti-PD-1, anti-Tim-3 or anti-Lag-3 checkpoint-blocking antibodies alone or in combination, ultimately targeting up to three inhibitory receptors simultaneously. Single-cell RNA-sequencing (scRNAseq) was used to profile the impact of combination checkpoint blockade on engineered T cells and the tumor microenvironment (TME). Results: In a disseminated ID8 tumor model, adoptively transferred TCRMsln T cells preferentially accumulated in established tumors, delayed ovarian tumor growth, and prolonged mouse survival. However, elements in the TME limited engineered T cell persistence and cytolytic function. Triple checkpoint blockade, but not single- or double-agent treatment, dramatically increased antitumor function by intratumoral TCRMsln T cells. scRNAseq of tumor-infiltrating cells revealed distinct transcriptome changes in engineered and endogenous T cells and myeloid-derived cells. Engineered T cells, when combined with triple checkpoint blockade, increased expression of genes associated with effector and memory gene signatures, including proliferation and metabolic function, and reduced expression of genes associated with exhaustion. Moreover, combining adoptive immunotherapy with triple checkpoint blockade significantly prolonged survival in the cohort of treated tumor-bearing mice, relative to mice that received TCRMsln T cells alone or with anti-PD1 or double-agent treatments. Conclusions: Inhibitory receptor/ligand interactions within the TME can dramatically reduce T cell function, suggesting tumor cells may upregulate the ligands for PD-1, Tim-3 and Lag-3 for protection from tumor-infiltrating lymphocytes. In an advanced ovarian cancer model, triple checkpoint blockade significantly improved engineered T cell function and outcomes in mice in a setting where single checkpoint blockade had no significant activity. These results suggest that disrupting multiple inhibitory pathways simultaneously, which can be more safely pursed in a cell intrinsic form through genetic engineering, may be necessary for improved efficacy in patients. Citation Format: Kristin G. Anderson, Yapeng Su, Madison G. Burnett, Breanna M. Bates, Magdalia L. Rodgers Suarez, Susan L. Ruskin, Valentin Voillet, Raphael Gottardo, Philip D. Greenberg. Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B084.

Deverji's disease after COVID-19: Case report

Deverji's disease is a rare idiopathic skin disease characterized by keratinization disorder and manifested in follicular hyperkeratosis, orange-red peeling plaques, palmar-plantar keratodermia with the possible development of erythroderma. The etiopathogenesis of this dermatosis is still unknown. There are such possible trigger factors as traumatization, ultraviolet radiation, taking certain medications, autoimmune and oncological diseases, bacterial or viral infection, vaccination. The presence of familial cases is due to a mutation in the CARD14 gene. Diagnosis of the disease is based on characteristic clinical symptoms. The histological picture has no pathognomonic features; however, a biopsy is necessary for differential diagnosis with other papulosquamous dermatoses. Treatment of Deverji's disease remains a difficult task, since the disease pathogenesis has not been fully studied.&#x0D; The article describes a clinical case of Deverji's disease manifestation in a 64-year-old woman who had suffered COVID-19 infection twice. She was admitted to the Department of Dermatology and Venerology (Sechenov University) with complaints of skin rashes on her face, trunk, upper and lower extremities, accompanied by severe itching. The absence of any distinctive clinical and histological changes, the torpidity of the skin process and resistance to the therapy made it difficult to make a diagnosis. After the emergence of characteristic clinical symptoms (palmar-plantar keratodermia, salmon-tinged rashes with islands of healthy skin), as well as the results of repeated histological examination (alternating areas of ortho- and parakeratosis; uneven granular layer; vacuolization of basal cells; uneven broad acantholytic strands; loosened dermo-epidermal junction; small perivascular lymph-macrophage infiltrates) Deverji's disease was diagnosed.&#x0D; The use of standard therapies (systemic glucocorticosteroid therapy, methotrexate, topical therapy) did not give any results, and therefore it was decided to initiate the netakimab. After 5 injections, the first positive results were obtained in the form of the color paling and a decrease in the number of rashes, palmar-plantar keratodermia regression and improvement of the patient psychoemotional state. After 11 injections, almost complete remission was achieved, and treatment was continued until all symptoms disappeared completely.&#x0D; The article provides a literature review of the etiopathogenesis, clinical manifestations and treatment methods of Deverji's disease. The described clinical case is the fifth example in the world of the Deverji's disease manifestation after a COVID-19 infection, and is also the first case of the IL-17 inhibitor netakimab successful use for the disease treatment.

Aberrant dynamic properties of whole-brain functional connectivity in acute mild traumatic brain injury revealed by hidden Markov models.

This study aimed to investigate the temporal dynamics of brain activity and characterize the spatiotemporal specificity of transitions and large-scale networks on short timescales in acute mild traumatic brain injury (mTBI) patients and those with cognitive impairment in detail. Resting-state functional magnetic resonance imaging (rs-fMRI) was acquired for 71 acute mTBI patients and 57 age-, sex-, and education-matched healthy controls (HCs). A hidden Markov model (HMM) analysis of rs-fMRI data was conducted to identify brain states that recurred over time and to assess the dynamic patterns of activation states that characterized acute mTBI patients and those with cognitive impairment. The dynamic parameters (fractional occupancy, lifetime, interval time, switching rate, and probability) between groups and their correlation with cognitive performance were analyzed. Twelve HMM states were identified in this study. Compared with HCs, acute mTBI patients and those with cognitive impairment exhibited distinct changes in dynamics, including fractional occupancy, lifetime, and interval time. Furthermore, the switching rate and probability across HMM states were significantly different between acute mTBI patients and patients with cognitive impairment (all p < 0.05). The temporal reconfiguration of states in acute mTBI patients and those with cognitive impairment was associated with several brain networks (including the high-order cognition network [DMN], subcortical network [SUB], and sensory and motor network [SMN]). Hidden Markov models provide additional information on the dynamic activity of brain networks in patients with acute mTBI and those with cognitive impairment. Our results suggest that brain network dynamics determined by the HMM could reinforce the understanding of the neuropathological mechanisms of acute mTBI patients and those with cognitive impairment.