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Mitochondrial ATP synthesis is essential for efficient gametogenesis in Plasmodium falciparum.

Plasmodium male and female gametocytes are the gatekeepers of human-to-mosquito transmission, therefore essential for propagation of malaria within a population. Whilst dormant in humans, their divergent roles during transmission become apparent soon after mosquito feeding with a rapid transformation into gametes - males forming eight motile sperm-like cells aiming to fertilise a single female gamete. Little is known about how the parasite fuels this abrupt change, and the potential role played by their large and elaborate cristate mitochondrion. Using a sex-specific antibody and functional mitochondrial labelling, we show that the male gametocyte mitochondrion is less active than that of female gametocytes and more sensitive to antimalarials targeting mitochondrial energy metabolism. Rather than a vestigial organelle discarded during male gametogenesis, we demonstrate that mitochondrial ATP synthesis is essential for its completion. Additionally, using a genetically encoded ratiometric ATP sensor, we show that gametocytes can maintain cytoplasmic ATP homeostasis in the absence of mitochondrial respiration, indicating the essentiality of the gametocyte mitochondrion for transmission alone. Together, this reveals how gametocytes responsively balance the conflicting demands of a dormant and active lifestyle, highlighting the mitochondria as a rich source of transmission-blocking targets for future drug development.

IMMU-55. TUMOR-WIDE RNA SPLICING ABERRATIONS GENERATE IMMUNOGENIC PUBLIC NEOANTIGENS IN GLIOBLASTOMAS AND OTHER CANCER TYPES

Abstract BACKGROUND Immunotherapy in gliomas is limited by tumor heterogeneity and low mutational burden. Aberrant RNA-splicing (neojunctions) offers a new source for targets, and our neoantigen discovery platform (SNIPP) characterizes a novel class of clonally-expressed splicing-derived neoantigens that elicit a CD8+ T-cell-mediated tumor killing response. METHODS SNIPP identified public neojunctions expressed in TCGA RNA-seq (positive sample rate (PSR) > 10%) and not in GTEx normal tissue RNA-seq data (PSR < 1%) across 12 cancer types. To characterize intratumorally-conserved neojunctions, we performed maximally-distanced multi-site biopsies (n=535) within glioma patients (n=56) and obtained RNA-seq data from each intratumoral site. Two independent algorithms then predicted peptide processing likelihood and HLA-binding affinity of ASN candidates. Neoantigen-specific TCR sequences characterized from subsequent PBMC in vitro sensitization and 10x V(D)J scRNA-seq were transduced into CD8+ T-cells for immunogenicity and cytotoxicity assays against glioma cell lines. RESULTS Our pipeline identified 789 public neojunctions, with 32 neojunctions concurrently identified in transcriptomic and proteomic glioma data and predicted to be presented by HLA-A*02:01 with high confidence. IVS and subsequent 10x VDJ scRNA-seq identified TCR clonotypes reactive against neojunctions in RPL22 (n=7) and GNAS (n=1), the latter being highly intratumorally-conserved (detected in > 90% of spatially-mapped biopsies across 17/56 patients (26.78%)). TCR-transduced T-cells demonstrated recognition and immunogenic activation against endogenously processed and presented neoantigens in multiple GBM PDX cell lines, and co-culturing these T-cells against both glioblastoma and melanoma cell lines demonstrated tumor-specific cytotoxicity. Furthermore, IDH1-mutant oligodendroglioma samples demonstrated significantly elevated expression of neojunctions over IDH1-mutant astrocytoma and IDH1wt subtypes. Differential gene expression (DESeq2) identified decreased expression of splicing factors due to oligodendroglioma-specific co-deletion of Chromosomes 1p/19q. siRNA knockdown of these splicing factors (e.g. SF3A3, SNRPD2) in IDH1wt glioma cells resulted in significantly increased expression of corresponding neojunctions. CONCLUSION Our unique SNIPP neoantigen discovery platform identified novel public tumor-wide splice-derived neoantigens and reactive TCRs, and its pan-cancer application characterized candidates that are targetable across multiple diseases.

STEM-09. A GROUP 3 MEDULLOBLASTOMA STEM CELL PROGRAM IS MAINTAINED BY OTX2-MEDIATED ALTERNATIVE SPLICING

Abstract Group 3 medulloblastomas (MBs) are highly metastatic pediatric brain tumors with limited therapeutic options. The transcription factor orthodenticle homeobox 2 (OTX2) is a known driver and molecular hallmark of Group 3 MB. We previously demonstrated that OTX2 regulates Group 3 MB cell fate decisions that favor self-renewal or stemness and the retention of a primitive cerebellar rhombic lip signature. Here, we show that OTX2-regulated alternative splicing (AS) is a major driver of Group 3 MB progression. Surprisingly, the functional role of post-transcriptional events, such as AS, in Group 3 MB development has never been explored. This gene regulatory layer represents an untapped source of therapeutic targets. Using a combination of TurboID, RNA-sequencing and single cell RNA-seq, we characterized the Group 3 primary MB AS landscape with a focus on genes that control MB stem cells. OTX2 associates with the multimeric Large Assembly of Splicing Regulators (LASR) complex through protein-protein interactions and can directly or indirectly bind RNA. Together, OTX2 and LASR complex proteins oversee a pro-tumorigenic splicing program that is mirrored in the human cerebellar rhombic lip origins and is associated with Group 3γ MBs that exhibit the worst prognosis. Among our core set of OTX2-regulated spliced genes, periphilin 1 (PPHLN1) is expressed in the most primitive cerebellar rhombic lip stem cells, and mimicking PPHLN1 AS by pre-treating cells with a splice blocking antisense morpholino reduces tumor growth while increasing survival in vivo. We propose that OTX2-mediated AS is a key determinant of cell fate decisions favoring the maintenance of the stem cell state. Targeting transcription factors like OTX2 is notoriously difficult; thus, our work offers fresh opportunities to exploit MB-specific AS events therapeutically to abrogate tumor progression.

FluxCT V2.0: Updates to a Web Tool Identifying Contaminating Flux in Space Telescope Data

We present FluxCT V2.0, an updated web tool for identifying contaminating flux in Kepler and TESS target pixel files. FluxCT V2.0 focuses on enhancing functionality, user experience, and data processing capabilities. We resolved existing issues to allow for an extended user base, removed known bugs, and extended the tool to any TESS pixel file, allowing the user to search any TESS point object. A batch code for TESS is now available on the companion GitHub. Additional output parameters, such as amplitude dilution and a magnitude cut, have been added to the tool, allowing users more freedom to analyze the possible effects of target sources.

Deep joint subdomain alignment for unsupervised domain adaptation

Domain adaptation (DA) aims to transfer knowledge of the labeled source domain to the unlabeled target domain. Current DA methods learn domain-invariant features by aligning source and target feature spaces by distribution discrepancy minimization or adversarial training. However, existing DA methods fail to consider the semantic-level alignment, which can lead to the distortion of semantic feature structures for the target tasks. In this paper, we propose a novel domain adaptation method, called Deep Joint Subdomain Alignment (DJSA), which jointly conducts intra-subdomain and inter-subdomain alignment for fine-grained classification of target tasks. DJSA obtains the pseudo labels of unlabeled target samples by measuring the similarity between the target samples and source category centers, and then DJSA calculates an intra-subdomain loss to reduce the difference within the same class and increase the difference between different classes in both the source domain and the target domain, and DJSA utilizes a Local Maximum Mean Discrepancy (LMMD) metric to measure the inter-subdomain discrepancy between the source and target domain, and minimizes the discrepancy to align different domains. Furthermore, extensive experimental results demonstrate the effectiveness and superiority of our proposed method in unsupervised domain adaptation.

KINOME-WIDE SYNTHETIC LETHAL SCREEN IDENTIfiES PANK4 AS A MODULATOR OF TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA

Abstract AIMS Temozolomide (TMZ) represents the cornerstone of glioblastoma (GBM) therapy. However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains confined to a limited fraction of it, with a multitude of under-investigated proteins yet to be characterised. We aimed to uncover synthetic lethal partners of TMZ in GBM that could enhance the effect of TMZ, thus improving TMZ therapy response. METHOD A kinome-wide RNAi screen was performed in a TMZ-resistant GBM cell model. A panel of several TMZ-resistant and patient-derived GBM cell lines was implemented for in vitro validation of our findings through several phenotypic assays. In vivo TMZ-resistant GBM xenografts and immunohistochemical (IHC) analysis of IDH- wildtype GBM specimens were employed to assess the clinical relevance of our findings. Tandem Mass Tag (TMT)-based quantitative proteomic studies were undertaken to elucidate the underlying mechanisms. RESULTS Following a kinome-wide RNAi screen, pantothenate kinase 4 (PANK4) was uncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ-resistant GBM cell models, patient-derived GBM cell lines, tissue samples, as well as in vivo studies, corroborated the potential translational significance of these findings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. A Tandem Mass Tag (TMT)-based quantitative proteomic approach revealed that PANK4 abrogation leads to a significant downregulation of numerous proteins with central roles in cellular detoxification and cellular response to oxidative stress. Mechanistically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death. CONCLUSION Our study provides novel insights into chemoresistance in GBM and unveils a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM.

A multi-source domain feature adaptation network for potato disease recognition in field environment.

Accurate identification of potato diseases is crucial for reducing yield losses. To address the issue of low recognition accuracy caused by the mismatch between target domain and source domain due to insufficient samples, the effectiveness of Multi-Source Unsupervised Domain Adaptation (MUDA) method in disease identification is explored. A Multi-Source Domain Feature Adaptation Network (MDFAN) is proposed, employing a two-stage alignment strategy. This method first aligns the distribution of each source-target domain pair within multiple specific feature spaces. In this process, multi-representation extraction and subdomain alignment techniques are utilized to further improve alignment performance. Secondly, classifier outputs are aligned by leveraging decision boundaries within specific domains. Taking into account variations in lighting during image acquisition, a dataset comprising field potato disease images with five distinct disease types is created, followed by comprehensive transfer experiments. In the corresponding transfer tasks, MDFAN achieves an average classification accuracy of 92.11% with two source domains and 93.02% with three source domains, outperforming all other methods. These results not only demonstrate the effectiveness of MUDA but also highlight the robustness of MDFAN to changes in lighting conditions.

Differentially expressed lncRNAs in SOD1G93A mice skeletal muscle: H19, Myhas and Neat1 as potential biomarkers in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor function and muscle mass loss. Despite extensive research in the field, the underlying causes of ALS remain incompletely understood, contributing to the absence of specific diagnostic and prognostic biomarkers and effective therapies. This study investigates the expression of long-non-coding RNAs (lncRNAs) in skeletal muscle as a potential source of biomarkers and therapeutic targets for the disease. The expression profiles of 12 lncRNAs, selected from the literature, were evaluated across different disease stages in tissue and muscle biopsies from the SOD1G93A transgenic mouse model of ALS. Nine out of the 12 lncRNAs were differentially expressed, with Pvt1, H19 and Neat1 showing notable increases in the symptomatic stages of the disease, and suggesting their potential as candidate biomarkers to support diagnosis and key players in muscle pathophysiology in ALS. Furthermore, the progression of Myhas and H19 RNA levels across disease stages correlated with longevity in the SOD1G93A animal model, effectively discriminating between long- and short-term survival individuals, thereby highlighting their potential as prognostic indicators. These findings underscore the involvement of lncRNAs, especially H19 and Myhas, in ALS pathophysiology, offering novel insights for diagnostic, prognostic and therapeutic targets.

Graph Agent Transformer Network With Contrast Learning for Cross-Domain Recommendation of E-Commerce

Cross-domain recommendation(CDR) system is a kind of recommendation system based on multiple data fields, its core idea is to integrate data from different fields, so as to provide users with more accurate and personalized recommendation services. This paper constructs a hybrid contrast learning graph agent transformer network for CDR of e-commerce. In this method, data in target domain and source domain are first constructed into a multi-part graph structure, and then data mining is carried out by double-branch graph agent transformer. The final embedding of each node in the graph is obtained by training the model through mixed supervised learning and comparative learning. This method not only increases the recommended performance of the model through comparative learning, but also improves the transformer structure through agent and reduces the calculation cost of the model. Simulation results on two real cross-domain recommendation datasets of e-commerce demonstrate the effectiveness of the proposed method.

Size-based spectrophotometric analysis of the Polana-Eulalia Complex

The Polana-Eulalia Complex (PEC) is an Inner Main Belt, C-complex asteroid population that may be the source of the near-Earth asteroid spacecraft mission targets (101955) Bennu and (162173) Ryugu. Here, we report a size-based investigation of the visible (VIS; 0.47 —0.89 μm) spectrophotometric slopes of the PEC's constituent families, the “New Polana” and Eulalia Families. Using two releases of the Sloan Digital Sky Survey's Moving Object Catalog as well as the 3rd data release of the Gaia catalog, we present evidence of size-based slope variability within each family. We find that Eulalia family members exhibit lower average slopes than Polana family members in all catalogs' samples, particularly for objects <9 km in diameter. We are unable to conclude that VIS slope distinguishability between the families is statistically significant, but we explore a potential cause of the bulk slope differences between the PEC families, in addition to providing commentary on size-slope trends generally.

Comparative analysis of LAG3 antibodies shows differential binding patterns by flow cytometry

BackgroundLAG3 is an immune checkpoint molecule with emerging therapeutic use. Expression of LAG3 is well studied on T cells, but the proportion of LAG3-expressing cells varies greatly by study and its comparative expression between non-T cells is lacking. Methods/objectivesThis study uses flow cytometry to compare surface LAG3 expression between T cells, NK cells, B cells, pDCs and monocytes of healthy donors. This study also compares three monoclonal LAG3 antibodies to a commonly used polyclonal LAG3 antibody on ex vivo and PHA-blasts from healthy donors and LAG3+ and LAG3- cell lines. ResultsLAG3 was most highly expressed on classical and intermediate monocytes (25 % and 32 %, respectively), while LAG3 expression on B cells, NK cells and iNKT cells was negligible. Notably, the polyclonal antibody stained a higher proportion of all cell types than the monoclonal antibodies, which had similar staining patterns to one another. Further study using LAG3+ and LAG3- cell lines showed greater specificity and similar sensitivity of the monoclonal antibody T47–530 than the polyclonal antibody. ConclusionMonocytes may represent an unappreciated source of LAG3 and target of LAG3 checkpoint inhibitors. Furthermore, the discrepancies between monoclonal and polyclonal LAG3 antibodies warrants consideration when designing future studies and interpreting past studies, and may explain discrepancies in the literature.

From proteome to pathogenesis: investigating polycystic ovary syndrome with Mendelian randomization analysis.

Polycystic ovary syndrome (PCOS) is defined by oligo/anovulation, hyperandrogenism, and polycystic ovaries with uncertain pathogenesis. The proteome represents a substantial source of therapeutic targets, and their coding genes may elucidate the mechanisms underlying PCOS. However, reports on the profiles of the human plasma protein-coding genes and PCOS are limited. Here, we aimed to investigate novel biomarkers or drug targets for PCOS by integrating genetics and the human plasma proteome. Our study acquired the protein quantitative trait loci from DECODE Genetics, offering 4,907 proteins in 35,559 individuals while obtaining PCOS summary statistics by accessing the FinnGen biobank (1,639 cases and 218,970 controls) and the genome-wide association study catalog (797 cases and 140,558 controls). Herein, we sequentially used two-sample Mendelian randomization (MR) analyses and colocalization to verify the causal link between candidate proteins, their coding genes, and PCOS. Further PCOS data download was conducted by accessing the Gene Expression Omnibus and Zenodo platforms. Gene expression level analysis, pathway enrichment analysis, immune cell infiltration, and transcription factor prediction were performed, aiming at detecting specific cell types with enriched expression and exploring potential optimized treatments for PCOS. MR analysis revealed 243 protein-coding genes with a causal relationship to PCOS risk, of which 12 were prioritized with the most significant evidence. Through colocalization analysis, three key genes, CUB domain-containing protein 1 (CDCP1), glutaredoxin 2 (GLRX2), and kirre-like nephrin family adhesion molecule 2 (KIRREL2), were identified. Subsequently, the three genes were strongly related to immune function and metabolism in terms of biological significance. In single-cell analysis, the expression levels of genes in ovarian theca cells were explored. Overall, three protein-coding genes (CDCP1, GLRX2, and KIRREL2) may be related to a higher PCOS risk, suggesting that they may be entry points for exploration of PCOS pathogenesis and treatment, warranting further clinical investigations.

Likely Detection of GeV γ-Ray Emission from Pulsar Wind Nebula G32.64+0.53 with Fermi-LAT

Abstract In this study, we report the likely GeV γ-ray emissions originating from the pulsar PSR J1849-0001's pulsar wind nebula (PWN) G32.64+0.53. Our analysis covers approximately 14.7 yr of data from the Fermi Large Area Telescope Pass 8. The position of the source and its spectrum matches those in X-ray and TeV energy bands, so we propose that the GeV γ-ray source is indicative of PWN G32.64+0.53. We interpret the broadband spectral energy distribution (SED) using a time-dependent one-zone model, which assumes that the multiband nonthermal emission of the target source can be generated by synchrotron radiation and inverse Compton scattering (ICS) of the electrons/positrons. Our findings demonstrate that the model substantially elucidates the observed SED. These results lend support to the hypothesis that the γ-ray source originates from the PWN G32.64+0.53 powered by PSR J1849-0001. Furthermore, the γ-rays in TeV bands are likely generated by electrons/positrons within the nebula through ICS.

Closed-Form Method for Unified Far-Field and Near-Field Localization Based on TDOA and FDOA Measurements

When the near-field and far-field information of a target is uncertain, it is necessary to choose a suitable localization method. The modified polar representation (MPR) method integrates the two scenarios and achieves a unified localization with direction of arrival (DOA) estimation in the far field and position estimation in the near field. Previous studies have only proposed solutions for stationary environments and have not considered the motion factor. Therefore, this paper proposes a new unified positioning algorithm using multi-sensor time difference of arrival (TDOA) and frequency difference of arrival (FDOA) measurements without prior target source information. The method represents the position of the target source using MPR and describes the localization problem as a weighted least squares (WLS) problem with two constraints. We first obtain the initial estimates by WLS without considering the constraints and then investigate a two-step error correction method based on the constraints. The first step corrects the initial estimate using the Taylor series expansion technique, and the second step corrects the DOA estimate in the previous step using the direct error compensation technique based on the properties of the second constraint. Simulation experiments show that the method is effective for the unified positioning of moving targets and can achieve the Cramer–Rao lower bound (CRLB).

Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach.

The lack of effective vaccines and the development of resistance to the current treatments highlight the urgent need for new anti-leishmanials. Sphingolipid metabolism has been proposed as a promising source of Leishmania-specific targets as these lipids are key structural components of the eukaryotic plasma membrane and are involved in distinct cellular events. Inositol phosphorylceramide (IPC) is the primary sphingolipid in the Leishmania species and is the product of a reaction mediated by IPC synthase (IPCS). The antihistamine clemastine fumarate has been identified as an inhibitor of IPCS in L. major and a potent anti-leishmanial in vivo. Here we sought to further examine the target of this compound in the more tractable species L. mexicana, using an approach combining genomic, proteomic, metabolomic and lipidomic technologies, with molecular and biochemical studies. While the data demonstrated that the response to clemastine fumarate was largely conserved, unexpected disturbances beyond sphingolipid metabolism were identified. Furthermore, while deletion of the gene encoding LmxIPCS had little impact in vitro, it did influence clemastine fumarate efficacy and, importantly, in vivo pathogenicity. Together, these data demonstrate that clemastine does inhibit LmxIPCS and cause associated metabolic disturbances, but its primary target may lie elsewhere.

Quality control for serological testing

ObjectivesThe quality control of serological assays remains controversial. The aim of this project was to describe the problems associated with a working model for controlling these assays and solutions, including using a source of well-defined targets and acceptable limits, a process to identify lot-to-lot reagent variation and an interpretation of the result that accounted for the clinical situation. False-negative results are problematic but can be reduced by identifying and comparing reagent lot variation with previous results. MethodsThe components of the Quality Assurance strategy are the following: Lot-to-lot reagent and calibrator variation assessment; dynamic, big-data approach to determine accurate targets and acceptable limits for manufacturer-provided QC material; negative QC monitoring process; use of commutable EQA with a sufficient method subgroup size to assess bias; clinical assessment of any statistically flagged error; and provision of support to the clinician for the interpretation of results. ResultsThe model described has been used for twelve months, and acceptable variation has been maintained. ConclusionsThe paper presents a solution that emphasizes the early detection of reagent lot variation and patient risk rather than instrument control.Reducing the risk of a false result to patients requires optimal assay quality control and an effective mechanism to support the clinician’s use of these results in diagnosis and monitoring. The problems of serological assays are well-known, but there remain few integrated solutions in the literature.

Optical Detection of Underwater Propeller Wake Based on a Position-Sensitive Detector

The study of underwater vehicle wake detection is of significant importance within the field of target detection, localisation, and tracking of underwater vehicles. Given that propellers are the propellers of modern ships and underwater vehicles, the propeller wake field represents the principal target source for wake detection in underwater vehicles. The objective of this paper is to propose a method for measuring the wake of an underwater propeller based on a position-sensitive detector. A theoretical model of the relationship between the laser spot displacement and the change in the refractive index of the wake field is established on the basis of the principle of laser beam deflection. A prototype experimental setup for underwater propeller wake measurement was constructed based on the aforementioned optical measurement method. Furthermore, the simulation of the propeller wake flow field with strong density stratification and linear density stratification was conducted based on the experimental setup. Furthermore, experiments were conducted to detect the flow field of a propeller wake. The experimental results indicate that the wake dissipation times of the propeller in a strong density-stratified water environment are approximately 800 s and 750 s. Following the stabilisation of the wake field density, the laser spot position is observed to be stable at 0.341 mm and 0.441 mm, respectively, with a corresponding refractive index change of 2.99 × 10−6 RIU (refractive index unit) and 3.87 × 10−6 RIU, respectively. These experimental results are found to be in general agreement with the simulation results of the propeller wake field. A comparison of the experimental wake measurements based on the device with the wake measurements based on a CTD (conductivity–temperature–depth) device reveals a consistent trend. The realisation of this detection technique is of great significance for the advancement of research in the field of optical detection of underwater vehicle wake streams.

Lombard speech detection in case of spatial separation between noise source and talkers of different genders

The spatial selectivity of hearing to speech signals was studied when the target signal and interference were separated by distance between their sources and the listener. In the work, the hypothesis about the improvement of hearing selectivity due to more intensive activation of the high-frequency binaural mechanism due to the shift of the speaker’s voice spectrum occurs in noisy environment towards high frequencies, was tested. The thresholds for detecting the target signal – a two-syllable word uttered by male or female, were evaluated in the two-alternative two-interval forced choice paradigm in 4 series. Series differed by the type of target signal (ordinary or Lombard speech) and the location of target source and noise (multi-talker noise) one. The both sources were located at a distance of 1 and 4 m opposite the subject at the level of his head. The detection threshold was defined as the ratio of signal and noise levels at the listener’s place (S/N). The threshold for detecting the target signal (male and female speaker voices together) was -11 dB S/N for ordinary as well as Lombard speech. It did not depend on which of the sources - the target signal or noise, was closer to the listener. In normal speech, the detection thresholds on average differed for male and female voices, but the difference was not significant. In Lombard speech, these thresholds were significantly different: for a male voice, the threshold at a detection level of 0.67 was -10 dB S/N, and for a female voice – -12.5 dB S/N.

Towards targeting the breast cancer immune microenvironment.

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, itis also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.

Reliability of In-band and Broadband Spectral Index Measurement: Systematic Study of the Effect of Signal-to-noise Ratio for uGMRT Data

Low-radio-frequency spectral index measurements are a powerful tool for distinguishing between different emission mechanisms and, in turn, understanding the nature of the sources. Besides the standard method of estimating the “broadband” spectral index of sources from observations in two different frequency “bands,” if the observations were made with large instantaneous bandwidth, the “in-band” spectral index can be determined, either using images of emission at multiple frequency ranges within a band or using the novel Multi Term-Multi Frequency Synthesis (MT-MFS) imaging algorithm. Here, using simulated upgraded Giant Metrewave Radio Telescope (uGMRT) data, we have systematically studied the reliability of various methods of spectral index estimation for sources with a wide range of signal-to-noise ratios (S/Ns). It is found that for synthetic uGMRT point-source data, the MT-MFS imaging algorithm produces in-band spectral indices for S/N ≲ 100 that have errors ≳0.2, making them unreliable. However, at a similar S/N, the sub-band splitting method produces errors ≲0.2, which are more accurate and unbiased than the in-band spectral indices. The broadband spectral indices produce errors ≲0.2 even for S/N ≳ 15, and hence they are most reliable if there are no higher-order variations in the spectral index. These results may be used to improve the uGMRT observation and data analysis strategies, depending on the brightness of the target source.