bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Adr1 transcription factor directs regulation of the ergosterol pathway and azole resistance in
Candida albicans
Authors: Shrivastava Manjari , Kouyoumdjian Gaëlle S. , Kirbizakis Eftyhios , Ruiz Daniel , Henry Manon , Vincent Antony T. , Sellam Adnane , Whiteway Malcolm 
Published: October 2023

ABSTRACT

Transcription factors (TFs) play key roles in cellular regulation and are critical in the control of drug resistance in the fungal pathogen
Candida albicans
. We found that activation of the transcription factor C4_02500C_A (Adr1) conferred significant resistance against fluconazole. In
Saccharomyces cerevisiae
, Adr1 is a carbon-source-responsive zinc-finger transcription factor required for transcription of the glucose-repressed gene
ADH1
and of genes required for ethanol, glycerol, and fatty acid utilization. Motif scanning of promoter elements suggests that Adr1 may be rewired in fungi and govern the ergosterol synthesis pathway in
C. albicans
. Because previous studies have identified the zinc-cluster transcription factor Upc2 as a regulator of the ergosterol pathway in both fungi, we examined the relationship between Adr1 and Upc2 in sterol biosynthesis in
C. albicans
. Phenotypic profiles of either
ADR1
or
UPC2
modulation in
C. albicans
showed differential growth in the presence of fluconazole; either
adr1
or
upc2
homozygous deletion results in sensitivity to the drug, while their activation generates a fluconazole-resistant strain. The rewiring from ergosterol synthesis to fatty acid metabolism involved all members of the Adr1 regulon except the alcohol dehydrogenase Adh1, which remains under Adr1 control in both circuits and may have been driven by the lifestyle of
S
.
cerevisiae
, which requires the ability to both tolerate and process high concentrations of ethanol.

Importance

Research often relies on well-studied orthologs within related species, with researchers using a well-studied gene or protein to allow prediction of the function of the ortholog. In the opportunistic pathogen
Candida albicans
, orthologs are usually compared with
Saccharomyces cerevisiae
, and this approach has been very fruitful. Many transcription factors (TFs) do similar jobs in the two species, but many do not, and typically changes in function are driven not by modifications in the structures of the TFs themselves but in the connections between the transcription factors and their regulated genes. This strategy of changing TF function has been termed transcription factor rewiring. In this study, we specifically looked for rewired transcription factors, or
Candida
-specific TFs, that might play a role in drug resistance. We investigated 30 transcription factors that were potentially rewired or were specific to the
Candida
clade. We found that the Adr1 transcription factor conferred resistance to drugs like fluconazole, amphotericin B, and terbinafine when activated. Adr1 is known for fatty acid and glycerol utilization in
Saccharomyces
, but our study reveals that it has been rewired and is connected to ergosterol biosynthesis in
Candida albicans
.
Discovery of a glucocorticoid receptor (GR) activity signature correlates with immune cell infiltration in adrenocortical carcinoma
Authors: Wu Kan , Liu Zhihong , Liang Jiayu , Zhu Yuchun , Wang Xianding , Li Xiang 
Published: October 2023

BackgroundAdrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy, of which >40% present with glucocorticoid excess. Glucocorticoids and glucocorticoid receptor (GR) signaling have long been thought to suppress immunity and promote tumor progression by acting on immune cells. Here, we provide new insights into the interaction between GR signaling activity and the immune signature of ACC as a potential explanation for immune escape and resistance to immunotherapy.MethodsFirst, GR immunohistochemical staining and immunofluorescence analysis of tumor-infiltrating lymphocyte (CD4 T, CD8 T cells, natural killer (NK) cells, dendritic cells and macrophages) were performed in 78 primary ACC tissue specimens. Quantitative data of immune cell infiltration in ACC were correlated with clinical characteristics. Second, we discovered a GR activity signature (GRsig) using GR-targeted gene networks derived from global gene expression data of primary ACC. Finally, we identified two GRsig-related subtypes based on the GRsig and assessed the differences in immune characteristics and prognostic stratification between the two subtypes.ResultsGR was expressed in 90% of the ACC tumors, and CD8+ cytotoxic T lymphocytes were the most common infiltrating cell type in ACC specimens (88%, 8.6 cells/high power field). GR expression positively correlated with CD8+ T cell (Phi=0.342, p<0.001), CD4+ T cell (Phi=0.280, p<0.001), NK cell (Phi=0.280, p<0.001), macrophage (Phi=0.285, p<0.001), and dendritic cell (Phi=0.397, p<0.001) infiltration. Clustering heatmap analysis also displayed high immune cell infiltration in GR high-expressing tumors and low immune cell infiltration in GR-low tumors. High GR expression and high immune cell infiltration were significantly associated with better survival. Glucocorticoid excess is associated with low immune cell abundance and unfavorable prognosis. A GRsig comprizing n=34 GR-associated genes was derived from Gene Expression Omnibus/The Cancer Genome Atlas (TCGA) data sets and used to define two GRsig-related subtypes in the TCGA cohort. We demonstrated distinct differences in the immune landscape and clinical outcomes between the two subtypes.ConclusionGR expression positively correlates with tumor-infiltrating immune cells in ACC. The GRsig could serve as a prognostic biomarker and may be helpful for prognosis prediction and response to immunotherapy. Consequently, targeting the GR signaling pathway might be pivotal and should be investigated in clinical studies.
SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models
Authors: Gray Elizabeth , Ulrich Michelle , Epp Angela , Younan Patrick , Sahetya Disha , Hensley Kelly , Allred Sean , Huang Li-Ya , Hahn Julie , Gahnberg Kristen , Treuting Piper M , Trueblood Esther S , Gosink John J , Thurman Robert , Wo Serena , Spahr Kellie , Haass Evgenia Jane , Snead Katie , Miller Dannah , Padilla Mary , Smith Alyson J , Frantz Chris , Schrum Jason P , Nazarenko Natalya , Gardai Shyra J 
Published: October 2023

BackgroundSGN-B7H4V is a novel investigational vedotin antibody–drug conjugate (ADC) comprising a B7-H4-directed human monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine citrulline (mc-vc) linker. This vedotin linker-payload system has been clinically validated in multiple Food and Drug Administration approved agents including brentuximab vedotin, enfortumab vedotin, and tisotumab vedotin. B7-H4 is an immune checkpoint ligand with elevated expression on a variety of solid tumors, including breast, ovarian, and endometrial tumors, and limited normal tissue expression. SGN-B7H4V is designed to induce direct cytotoxicity against target cells by binding to B7-H4 on the surface of target cells and releasing the cytotoxic payload MMAE upon internalization of the B7-H4/ADC complex.MethodsB7-H4 expression was characterized by immunohistochemistry across multiple solid tumor types. The ability of SGN-B7H4V to kill B7-H4-expressing tumor cells in vitro and in vivo in a variety of xenograft tumor models was also evaluated. Finally, the antitumor activity of SGN-B7H4V as monotherapy and in combination with an anti-programmed cell death-1 (PD-1) agent was evaluated using an immunocompetent murine B7-H4-expressing Renca tumor model.ResultsImmunohistochemistry confirmed B7-H4 expression across multiple solid tumors, with the highest prevalence in breast, endometrial, and ovarian tumors. In vitro, SGN-B7H4V killed B7-H4-expressing tumor cells by MMAE-mediated direct cytotoxicity and antibody-mediated effector functions including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. In vivo, SGN-B7H4V demonstrated strong antitumor activity in multiple xenograft models of breast and ovarian cancer, including xenograft tumors with heterogeneous B7-H4 expression, consistent with the ability of vedotin ADCs to elicit a bystander effect. In an immunocompetent murine B7-H4-expressing tumor model, SGN-B7H4V drove robust antitumor activity as a monotherapy that was enhanced when combined with an anti-PD-1 agent.ConclusionThe immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates robust antitumor activity in preclinical models through multiple potential mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies.
MHD hybrid nanofluid flow over a stretched surface with convective boundary conditions: Applications of heat transfer
Authors: Alnahdi Abeer S. , Gul Taza 
Published: October 2023

The main objective of this research is to analytically study an innovative, viscous, time-independent, and incompressible (HFN) hybrid nanofluid flow on a slanderous stretched surface. This study examines thermal conductivity, heat absorption/omission, thermal radiation, and the magnetic effect of in the existence of HFN. Incorporating an external heat source into the heat transfer process increases the effect of the dissipative heat and thermal radiation. The flow characteristics are governed by the mathematical form which is further transferred to ordinary differential equations (ODEs) via appropriate assumptions regarding similarity variables and stream functions. The strong nonlinearity was successfully solved using the analytical technique homotopy analysis method (HAM) for these nonlinear equations. The results and discussion section provides a thorough explanation of the main outcomes of the study. This research focuses on the enhancement of heat transfer and the effects.
Machine Learning for Nonorographic Gravity Waves in a Climate Model
Authors: Hardiman Steven C. , Scaife Adam A. , van Niekerk Annelize , Prudden Rachel , Owen Aled , Adams Samantha V. , Dunstan Tom , Dunstone Nick J. , Madge Sam 
Published: October 2023

Abstract
There is growing use of machine learning algorithms to replicate subgrid parameterization schemes in global climate models. Parameterizations rely on approximations; thus, there is potential for machine learning to aid improvements. In this study, a neural network is used to mimic the behavior of the nonorographic gravity wave scheme used in the Met Office climate model, important for stratospheric climate and variability. The neural network is found to require only two of the six inputs used by the parameterization scheme, suggesting the potential for greater efficiency in this scheme. Use of a one-dimensional mechanistic model is advocated, allowing neural network hyperparameters to be chosen based on emergent features of the coupled system with minimal computational cost, and providing a testbed prior to coupling to a climate model. A climate model simulation, using the neural network in place of the existing parameterization scheme, is found to accurately generate a quasi-biennial oscillation of the tropical stratospheric winds, and correctly simulate the nonorographic gravity wave variability associated with El Niño–Southern Oscillation and stratospheric polar vortex variability. These internal sources of variability are essential for providing seasonal forecast skill, and the gravity wave forcing associated with them is reproduced without explicit training for these patterns.

Significance Statement
Climate simulations are required for providing advice to government, industry, and society regarding the expected climate on time scales of months to decades. Machine learning has the potential to improve the representation of some sources of variability in climate models that are too small to be directly simulated by the model. This study demonstrates that a neural network can simulate the variability due to atmospheric gravity waves that is associated with El Niño–Southern Oscillation and with the tropical and polar regions of the stratosphere. These details are important for a model to produce more accurate predictions of regional climate.
Vertical Exchange Induced by Mixed Layer Instabilities
Authors: Luo Yangcheng , Callies Jörn 
Published: October 2023

Abstract
Submesoscale turbulence in the upper ocean consists of fronts, filaments, and vortices that have horizontal scales on the order of 100 m to 10 km. High-resolution numerical simulations have suggested that submesoscale turbulence is associated with strong vertical motion that could substantially enhance the vertical exchange between the thermocline and mixed layer, which may have an impact on marine ecosystems and climate. Theoretical, numerical, and observational work indicates that submesoscale turbulence is energized primarily by baroclinic instability in the mixed layer, which is most vigorous in winter. This study demonstrates how such mixed layer baroclinic instabilities induce vertical exchange by drawing filaments of thermocline water into the mixed layer. A scaling law is proposed for the dependence of the exchange on environmental parameters. Linear stability analysis and nonlinear simulations indicate that the exchange, quantified by how much thermocline water is entrained into the mixed layer, is proportional to the mixed layer depth, is inversely proportional to the Richardson number of the thermocline, and increases with increasing Richardson number of the mixed layer. The results imply that the tracer exchange between the thermocline and mixed layer is more efficient when the mixed layer is thicker, when the mixed layer stratification is stronger, when the lateral buoyancy gradient is stronger, and when the thermocline stratification is weaker. The scaling suggests vigorous exchange between the permanent thermocline and deep mixed layers in winter, especially in mode water formation regions.

Significance Statement
This study examines how instabilities in the surface layer of the ocean bring interior water up from below. This interior–surface exchange can be important for dissolved gases such as carbon dioxide and oxygen as well as nutrients fueling biological growth in the surface ocean. A scaling law is proposed for the dependence of the exchange on environmental parameters. The results of this study imply that the exchange is particularly strong if the well-mixed surface layer is thick, lateral density gradients are strong (such as at fronts), and the stratification below the surface layer is weak. These theoretical findings can be implemented in boundary layer parameterization schemes in global ocean models and improve our understanding of the marine ecosystem and how the ocean mediates climate change.
Multi-omics analysis reveals the molecular basis of flavonoid accumulation in fructus of Gardenia (Gardenia jasminoides Ellis)
Authors: Chen Jianrong , Tang Weizhuo , Li Chunyan , Kuang Ding , Xu Xiaojiang , Gong Yuan , Liu Fang , Gao Song 
Published: October 2023

Abstract
Background
The fruits of Gardenia are rich in flavonoids and geniposides, which have various pharmacological effects such as antioxidant, anti-inflammatory and anticancer. In this study, we analyzed the transcriptome and metabolome of gardenia peel and kernel at different growth stages, revealed the regulatory network related to flavonoid synthesis, and identified the key regulatory genes.

Results
The results showed that in terms of flavonoid metabolic pathways, gardenia fruits mainly synthesized cinnamic acid through the phenylpropanoid pathway, and then synthesized flavonoids through the action of catalytic enzymes such as 4-coumaroyl-CoA ligase, chalcone synthase, chalcone isomerase and flavanol synthase, respectively. In addition, we found that the metabolomics data showed a certain spatial and temporal pattern in the expression of genes related to the flavonoid metabolism pathway and the relative content of metabolites, which was related to the development and ripening process of the fruit.

Conclusions
In summary, this study successfully screened out the key genes related to the biosynthesis metabolism of flavonoids in gardenia through the joint analysis of transcriptome and metabolome. This is of certain significance to the in-depth study of the formation mechanism of gardenia efficacy components and the improvement of quality.
Hordeum vulgare differentiates its response to beneficial bacteria
Authors: Duan Yongming , Han Min , Grimm Maja , Schierstaedt Jasper , Imani Jafargholi , Cardinale Massimiliano , Le Jean Marie , Nesme Joseph , Sørensen Søren J. , Schikora Adam 
Published: October 2023

Abstract
Background
In nature, beneficial bacteria triggering induced systemic resistance (ISR) may protect plants from potential diseases, reducing yield losses caused by diverse pathogens. However, little is known about how the host plant initially responds to different beneficial bacteria. To reveal the impact of different bacteria on barley (Hordeum vulgare), bacterial colonization patterns, gene expression, and composition of seed endophytes were explored.

Results
This study used the soil-borne Ensifer meliloti, as well as Pantoea sp. and Pseudomonas sp. isolated from barley seeds, individually. The results demonstrated that those bacteria persisted in the rhizosphere but with different colonization patterns. Although root-leaf translocation was not observed, all three bacteria induced systemic resistance (ISR) against foliar fungal pathogens. Transcriptome analysis revealed that ion- and stress-related genes were regulated in plants that first encountered bacteria. Iron homeostasis and heat stress responses were involved in the response to E. meliloti and Pantoea sp., even if the iron content was not altered. Heat shock protein-encoding genes responded to inoculation with Pantoea sp. and Pseudomonas sp. Furthermore, bacterial inoculation affected the composition of seed endophytes. Investigation of the following generation indicated that the enhanced resistance was not heritable.

Conclusions
Here, using barley as a model, we highlighted different responses to three different beneficial bacteria as well as the influence of soil-borne Ensifer meliloti on the seed microbiome. In total, these results can help to understand the interaction between ISR-triggering bacteria and a crop plant, which is essential for the application of biological agents in sustainable agriculture.
Index of consciousness monitoring during general anesthesia may effectively enhance rehabilitation in elderly patients undergoing laparoscopic urological surgery: a randomized controlled clinical trial
Authors: Qi Fengling , Fan Long , Wang Chunxiu , Liu Yang , Yang Shuyi , Fan Zhen , Miao Fangfang , Kan Minhui , Feng Kunpeng , Wang Tianlong 
Published: October 2023

Abstract
Background
Based on electroencephalogram (EEG) analysis, index of consciousness (IoC) monitoring is a new technique for monitoring anesthesia depth. IoC is divided into IoC1 (depth of sedation) and IoC2 (depth of analgesia). The potential for concurrent monitoring of IoC1 and IoC2 to expedite postoperative convalescence remains to be elucidated. We investigated whether combined monitoring of IoC1 and IoC2 can effectively enhances postoperative recovery compared with bispectral index (BIS) in elderly patients undergoing laparoscopic urological surgery under general anesthesia.

Methods
In this prospective, controlled, double-blinded trail, 120 patients aged 65 years or older were arbitrarily assigned to either the IoC group or the control group (BIS monitoring). All patients underwent blood gas analysis at T1 (before anesthesia induction) and T2 (the end of operation). The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were administered to all patients at T0 (1 day before surgery) and T4 (7 days after surgery). Serum concentrations of C-reactive protein (CRP) and glial fibrillary acid protein (GFAP) were assessed at T1, T2, and T3 (24 h after surgery). Postoperative complications and the duration of hospitalization were subjected to comparative evaluation.

Results
The incidence of postoperative cognitive dysfunction (POCD) was notably lower in the IoC group (10%) than in the control group (31.7%) (P = 0.003). Postoperative serum CRP and GFAP concentrations exhibited significant differences at time points T2 (CRP: P = 0.000; GFAP: P = 0.000) and T3 (CRP: P = 0.003; GFAP: P = 0.008). Postoperative blood glucose levels (P = 0.000) and the overall rate of complications (P = 0.037) were significantly lower in Group IoC than in Group control.

Conclusion
The employment of IoC monitoring for the management of elderly surgical patients can accelerate postoperative convalescence by mitigating intraoperative stress and reducing peripheral and central inflammatory injury.

Trial registration
Chinese Clinical Trial Registry Identifier: ChiCTR1900025241 (17/08/2019).