Intrinsic Response Research Articles

Workloads of Emergency Call Types in Active-Duty Firefighters

Firefighting is an occupation with high injury risks, particularly when conducting fireground operations. The fire service generally quantifies the job demands of firefighting through tracking emergency call volume across 24 h shifts; however, volume alone does not account for the specific work completed in response to different call types. Utilization of external (i.e., objective work) and internal (i.e., intrinsic responses to work) training load measures have the potential to quantify the multifaceted workload demands of responses to medical and fire emergencies and inform injury prevention strategies. Therefore, the purpose of this study was to utilize training load measures to quantify the workloads across emergency call types. For medical emergencies and fire emergencies, the external load and the physiological, perceived, and cumulative internal loads were quantified. The results indicate that the magnitude of objective work required for fire emergency responses that include fire suppression and/or auto-extrication is approximately three times greater than that of medical and other fire emergency (i.e., no suppression or extrication) responses. Further, in response to the objective work for fire suppression and/or auto-extrication calls, the intrinsic workloads are six times more physiologically and perceptually demanding than—as well as double, cumulatively—those of medical and other fire emergency responses.

Unconventional Piezoelectricity of Two-Dimensional Materials Driven by the Hall Effect.

Piezoelectricity has been widely explored for nanoelectromechanical applications, yet its working modes are mainly limited in polar directions. Here we discover the intrinsic electro-mechanical response in crystal materials that is transverse to the conventional polarized direction, which is named unconventional piezoelectricity. A Hall-like mechanism is proposed to interpret unconventional piezoelectricity as charge polarization driven by a built-in electric field for systems with asymmetric Berry curvature distributions. Density functional theory simulations and statistical analyses justify such a mechanism and confirm that unconventional piezoelectricity is a general property for various two-dimensional materials with spin splitting or valley splitting. An empirical formula is derived to connect the conventional and unconventional piezoelectricity. The extended understanding of the piezoelectric tensor in quantum materials opens an opportunity for applications in multidirectional energy conversion, broadband operation, and multifunctional sensing.

Abstract B092: CDK8 and CXCL2 remodel the tumor microenvironment to contribute to KRASG12D small molecule inhibition resistance in pancreatic ductal adenocarcinoma

Abstract Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 50% of PDAC patients presenting with KRASG12D mutations. The recent development of small molecule inhibitors targeting KRASG12D has enabled effective targeting of mutant KRAS signaling and suppression of tumor growth; however, the contribution of the tumor microenvironment to the therapeutic efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D suppression remain to be fully elucidated. Here, we employed spatial transcriptomics and proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12D inhibition with MRTX1133. MRTX1133 treatment was associated with increased antigen presenting cells (APCs), T cells, and putative tumor-restraining fibroblasts within proximity to cancer cells, suggesting that antigen presentation and remodeling of the local microenvironment facilitates an effective response to KRASG12D inhibition. In the context of relapsed MRTX1133 treated tumors, single cell RNA sequencing and validation identified CDK8 as an intrinsic mediator of resistance and CXCL2 as an extrinsic mediator of resistance. Together, these studies identify APCs and CDK8 as therapeutic targets for enabling long term responses to small molecule KRASG12D inhibition with MRTX1133. Citation Format: Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li, Amari M. Sockwell, Sami J. Morse, Patience J. Kelly, Michelle L. Kirtley, Meagan R. Conner, Sarah I. Patel, Shreyasee V. Khumbar, Kent A. Arian, Yasaman Barekatain, Barbara A. Moreno Diaz, Hengyu Lyu, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Navid Sobhani, Francesca Paradiso, Vincent Bernard, Paola Guerrero, Haoqiang Ying, Anirban Maitra, Timothy P. Heffernan, Raghu Kalluri. CDK8 and CXCL2 remodel the tumor microenvironment to contribute to KRASG12D small molecule inhibition resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B092.

Dose-dependent changes in orientation amplitude maps in the cat visual cortex after propofol bolus injections

A general intravenous anesthetic propofol (2,6-diisopropylphenol) is widely used in clinical, veterinary practice and animal experiments. It activates gamma- aminobutyric acid (GABAa) receptors. Though the cerebral cortex is one of the major targets of propofol action, no study of dose dependency of propofol action on cat visual cortex was performed yet. Also, no such investigation was done until now using intrinsic signal optical imaging. Here, we report for the first time on the dependency of optical signal in the visual cortex (area 17/area 18) on the propofol dose. Optical imaging of intrinsic responses to visual stimuli was performed in cats before and after propofol bolus injections at different doses on the background of continuous propofol infusion. Orientation amplitude maps were recorded. We found that amplitude of optical signal significantly decreased after a bolus dose of propofol. The effect was dose- and time-dependent producing stronger suppression of optical signal under the highest bolus propofol doses and short time interval after injection. In each hemisphere, amplitude at cardinal and oblique orientations decreased almost equally. However, surprisingly, amplitude at cardinal orientations in the ipsilateral hemisphere was depressed stronger than in contralateral cortex at most time intervals. As the magnitude of optical signal represents the strength of orientation tuned component, these our data give new insights on the mechanisms of generation of orientation selectivity. Our results also provide new data toward understanding brain dynamics under anesthesia and suggest a recommendation for conducting intrinsic signal optical imaging experiments on cortical functioning under propofol anesthesia.

"I want to be there. I have to be there.": Parents' perceived barriers and facilitators to bedside presence in the pediatric intensive care unit.

Parental presence at the bedside during a stressful pediatric intensive care unit (PICU) admission may improve child comfort, reduce parental anxiety, and enable family engagement. We performed this study to identify factors that parents perceive impact their capability, opportunity, and motivation to be at the bedside in PICU. We conducted a qualitative descriptive study using semi-structured interviews based on the Theoretical Domains Framework (TDF). We included parents of children admitted to the PICU for at least 24 h at IWK Health in Nova Scotia, Canada. Interviews were coded independently by two researchers using a directed content approach based on the TDF. We generated themes and subthemes, with the subthemes identified as factors impacting parental presence, and assigned TDF domains to each of the subthemes. Fourteen primary caregivers (8 mother figures, 6 father figures) participated in 11 interviews. The factors associated with parental presence were captured by 6 themes: Understanding the Medicalized Child; Maintaining the Parent Role; Life Beyond the Hospital; Parental Intrinsic Responses and Coping; Support Structures; and The PICU Environment. Fifty-two barriers and enablers were identified within 13 TDF domains; 10 TDF domains were determined to be relevant to parental presence, which may be used to guide design of future interventions. Participants emphasized the importance of self-care to enable them to remain physically at their child's bedside and to be engaged in their care. Parents perceive multiple factors within 6 themes act as barriers or enablers to presence with their critically ill child in the PICU. Guided by relevant TDF domains, interventions may be designed to optimize presence, particularly engaged presence, which may improve health-related outcomes of children and their parents.

PRMT6-mediated ADMA promotes p62 phase separation to form a negative feedback loop in ferroptosis.

Purpose: Due to intrinsic defensive response, ferroptosis-activating targeted therapy fails to achieve satisfactory clinical benefits. Though p62-Keap1-Nrf2 axis is activated to form a negative feedback loop during ferroptosis induction, how p62 is activated remains largely unknown. Methods: MTS assay was applied to measure cell growth. Lipid ROS was detected with C11-BODIPY reagent by flow cytometer. Quantitative real-time PCR (qPCR) and western blotting were performed to determine mRNA and protein level. Immunofluorescence (IF) was performed to examine the distribution of proteins. Fluorescence recovery after photobleaching (FRAP) was adopted to evaluate p62 phase separation. Immunoprecipitation (IP), co-IP and Proximal ligation assay (PLA) were performed to detected protein posttranslational modifications and protein-protein interactions. Tumor xenograft model was employed to inspect in vivo growth of pancreatic cancer cells. Results: Upon ferroptosis induction, Nuclear Factor E2 Related Factor 2 (Nrf2) protein and its downstream genes such as HMOX1 and NQO1 were upregulated. Knockdown of p62 significantly reversed Nrf2 upregulation and Keap1 decrease after ferroptosis induction. Knockdown of either p62 or Nrf2 remarkably sensitized ferroptosis induction. Due to augmented p62 phase separation, formation of p62 bodies were increased to recruit Keap1 after ferroptosis induction. Protein arginine methyltransferase 6 (PRMT6) mediated asymmetric dimethylarginine (ADMA) of p62 to increase its oligomerization, promoting p62 phase separation and p62 body formation. Knockdown of p62 or PRMT6 notably sensitized pancreatic cancer cells to ferroptosis both in vitro and in vivo through suppressing Nrf2 signaling. Conclusion: During ferroptosis induction, PRMT6 mediated p62 ADMA to promote its phase separation, sequestering Keap1 to activate Nrf2 signaling and inhibit ferroptosis. Therefore, targeting PRMT6-mediated p62 ADMA could be a new option to sensitize ferroptosis for cancer treatment.

Ubiquitin Signaling in the Immune System.

Protein ubiquitination is a post-translational modification of proteins that is widespread in eukaryotic cells. It was identified initially while investigating the mechanisms of intracellular protein degradation. There is mounting evidence that ubiquitination and its reverse process, deubiquitination, play a critical regulatory role in the process of intrinsic and adaptive immune responses by regulating the function of various immune cell types, thereby influencing the development of a variety of major human diseases such as autoimmune diseases, infectious diseases, and malignancies. This article will discuss current advances in protein ubiquitination-mediated control of several immune cell functions and its significance in multiple sclerosis (MS).

The preparation of pH-sensitive doxorubicin prodrug for enhanced antitumor efficacy

We have produced a micelle nanoparticle with intrinsic pH response, which is formed by self-assembled amphiphilic polyethylene glycol-Schiff-doxorubicin (PEG-Schiff-DOX) prodrug. These nanoparticles can maintain stability well under normal conditions and last for more than a week, but they will rapidly decompose in slightly acidic environments. The concentration of DOX in the nano solution is high with the drug loading ratio of 49.4%. This pH-responsive drug release behavior may lead to higher intracellular drug concentrations and prolonged action times. CCK-8 assays have shown that the nanosuspension exhibits superior anti-tumor activity against HeLa cells compared to free DOX. It is believed that these nanoparticle-based prodrug have great potential for developing DOX formulations for cancer therapy.

Antiviral Activity of Zinc Finger Antiviral Protein (ZAP) in Different Virus Families.

The CCCH-type zinc finger antiviral protein (ZAP) in humans, specifically isoforms ZAP-L and ZAP-S, is a crucial component of the cell's intrinsic immune response. ZAP acts as a post-transcriptional RNA restriction factor, exhibiting its activity during infections caused by retroviruses and alphaviruses. Its function involves binding to CpG (cytosine-phosphate-guanine) dinucleotide sequences present in viral RNA, thereby directing it towards degradation. Since vertebrate cells have a suppressed frequency of CpG dinucleotides, ZAP is capable of distinguishing foreign genetic elements. The expression of ZAP leads to the reduction of viral replication and impedes the assembly of new virus particles. However, the specific mechanisms underlying these effects have yet to be fully understood. Several questions regarding ZAP's mechanism of action remain unanswered, including the impact of CpG dinucleotide quantity on ZAP's activity, whether this sequence is solely required for the binding between ZAP and viral RNA, and whether the recruitment of cofactors is dependent on cell type, among others. This review aims to integrate the findings from studies that elucidate ZAP's antiviral role in various viral infections, discuss gaps that need to be filled through further studies, and shed light on new potential targets for therapeutic intervention.

Phase-incorporation-induced electromagnetic coupling of NFS@1T/2H–MoS2 for enhanced microwave absorption

Herein, we propose a combination strategy to induce robust room-temperature electromagnetic coupling in non-magnetic MoS2 semiconductor (2H–MoS2). The introduction of ascorbic acid (AA) is intended to introduce sulfur vacancies (sv) in the process of 2H–MoS2 nano-sheet shells coating on the surface of three-dimensional (3D) matrix. It promotes the transformation of local lattice (2H–MoS2) into metal phase (1T-MoS2). The transformed 1T-MoS2 phase improves the conductivity (σ) of the composite by 1.48 times. Due to the Mo4+4d energy state within the bandgap, the exchange interaction between the sv and the Mo4+4d bandgap state produces a robust intrinsic electromagnetic response of more than 1.2 emu/g. Density functional theory (DFT) calculations are used to analyze the above results, and a novel electromagnetic-coupling-enhanced microwave absorption mechanism is proposed. The results indicates that microwave absorption performance can be effectively improved by the phase-incorporation effect. The minimum reflection loss (RLmin) reaches −53.1 dB (1.7 mm) and the adjustable effective absorption bandwidth (EAB) covers 14.5 GHz (3.5–18 GHz) at the various matching thicknesses. This work might shed light on a new possibility of manipulating electromagnetic interaction to promote microwave absorption.

Phase-change metasurfaces for dynamic control of chiral quasi-bound states in the continuum

Chiral quasi-bound states in the continuum (QBIC) offer novel mechanisms to achieve intrinsic chiroptical responses. However, current studies on chiral QBIC metasurfaces are restricted to the excitation of intrinsic chirality and fail to dynamically control its circular dichroism (CD) responses. Herein, we construct a phase-change metasurface based on paired Ge2Sb2Te5 (GST) bars to demonstrate the dynamic control of the CD responses of chiral QBIC. The modified coupled mode theory (CMT) is proposed to evaluate the intrinsic chirality, and the predicted results are in good agreement with the finite–difference time-domain (FDTD) results. The maximal intrinsic chirality is associated with the spin-selected dipole mode, i.e., the coupled magnetic dipole (MD) QBIC mode for the left-handed circularly polarized (LCP) light and the decoupled electric dipole (ED) QBIC mode for the right-handed circularly polarized (RCP) light. By varying the volume fraction of GST, the location of chiral BIC can be tuned linearly, and the corresponding chiral response can be switched.

Inhibition of SARS-CoV-2 infection and replication by Petasites hybridus CO2-extract (Ze 339)

BackgroundThe intensified search for low-threshold herbal anti-viral drugs would be of great advantage in prevention of early stages of infection. Since the SARS-CoV-2 Omicron variant has prevailed in western countries, the course has only been mild, but there are still no widely available drugs that can alleviate or shorten disease progression and counteract the development of Long-COVID. This study aimed to investigate the antiviral effects of a CO2-extract from Petasites hybridus (Ze 339). MethodsWe analyzed the infection and replication rate of SARS-CoV-2 in primary normal human bronchial epithelial cells (NHBEs) using a GFP-expressing version of the wild-type SARS-CoV-2 virus and live cell imaging. Upon infection with a clinical isolate of the Omicron variant, viral RNA content was quantified, and plaque assays were performed. In addition, the human transcriptome was analyzed after 4- and 24-hours post infection using whole genome microarrays. ResultsZe 339 had a protective effect on primary airway epithelial cells during SARS-CoV-2 infection and impeded SARS-CoV-2 infection and replication in NHBE. Notably, Ze 339 inhibited the expression of infection-induced IFNA10 by 8.6-fold (p < 0.05) and additionally reduced a wide range of other interferons (IFNA6, IFNA7, IFNA8, IFNA21, IFNE, IFNW1). ConclusionThereby, Ze 339 attenuated epithelial infection by SARS-CoV-2 and modeled the IFN response. In conclusion, this study highlights Ze 339 as a potential treatment option for COVID-19 that limits infection-associated cell intrinsic immune responses.

Gate-tunable anomalous Hall effect in Bernal tetralayer graphene

Large spin-orbit coupling is often thought to be critical in realizing magnetic order-locked charge transport such as the anomalous Hall effect (AHE). Recently, artificial stacks of two-dimensional materials, e.g., magic-angle twisted bilayer graphene on hexagonal boron-nitride heterostructures and dual-gated rhombohedral trilayer graphene, have become platforms for realizing AHE without spin-orbit coupling. However, these stacking arrangements are not energetically favorable, impeding experiments and further device engineering. Here we report an anomalous Hall effect in Bernal-stacked tetralayer graphene devices (BTG), the most stable configuration of four-layer graphene. BTG AHE is switched on by a displacement field and is most pronounced at low carrier densities. The onset of AHE occurs in tandem with a full metal to a broken isospin transition indicating an orbital origin of the itinerant ferromagnetism. At lowest densities, BTG exhibits an unconventional hysteresis with step-like anomalous Hall plateaus. Persisting to several tens of kelvin, AHE in BTG demonstrates the ubiquity and robustness of magnetic order in readily available and stable multilayer Bernal graphene stacks—a new venue for intrinsic non-reciprocal responses.

Verbal and nonverbal fluency in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multi-system disorder that commonly affects cognition and behaviour. Verbal fluency impairments are consistently reported in ALS patients, and we aimed to investigate whether this deficit extends beyond the verbal domain. We further aimed to determine whether deficits are underpinned by a primary intrinsic response generation impairment (i.e., a global reduction across tasks), potentially related to apathy, or an inability to maintain responding over time (i.e., a 'drop off' pattern). Twenty-two ALS patients and 21 demographically-matched controls completed verbal and nonverbal fluency tasks (phonemic/semantic word fluency, design fluency, gesture fluency and ideational fluency), requiring the generation of responses over a specified time period. Fluency performance was analysed in terms of the overall number of novel items produced, as well as the number of items produced in the first 'initiation' and the remaining 'maintenance' time periods. ALS patients' overall performance was not globally reduced across tasks. Patients were impaired only on meaningful gesture fluency, which requires the generation of gestures that communicate meaning (e.g., waving). On phonemic fluency, ALS patients showed a 'drop off' pattern of performance, where they had difficulty maintaining responding over time, but this pattern was not evident on the other fluency tasks. Apathy did not appear to be related to fluency performance. The selective meaningful gesture fluency deficit, in the context of preserved meaningless gesture fluency, highlights that the retrieval of action knowledge may be weakened in early ALS.

Cell Intrinsic Determinants of Alpha Herpesvirus Latency and Pathogenesis in the Nervous System.

Alpha herpesvirus infections (α-HVs) are widespread, affecting more than 70% of the adult human population. Typically, the infections start in the mucosal epithelia, from which the viral particles invade the axons of the peripheral nervous system. In the nuclei of the peripheral ganglia, α-HVs establish a lifelong latency and eventually undergo multiple reactivation cycles. Upon reactivation, viral progeny can move into the nerves, back out toward the periphery where they entered the organism, or they can move toward the central nervous system (CNS). This latency-reactivation cycle is remarkably well controlled by the intricate actions of the intrinsic and innate immune responses of the host, and finely counteracted by the viral proteins in an effort to co-exist in the population. If this yin-yang- or Nash-equilibrium-like balance state is broken due to immune suppression or genetic mutations in the host response factors particularly in the CNS, or the presence of other pathogenic stimuli, α-HV reactivations might lead to life-threatening pathologies. In this review, we will summarize the molecular virus-host interactions starting from mucosal epithelia infections leading to the establishment of latency in the PNS and to possible CNS invasion by α-HVs, highlighting the pathologies associated with uncontrolled virus replication in the NS.

Impaired intracellular Ca2+ signaling contributes to age-related cerebral small vessel disease in Col4a1 mutant mice.

Humans and mice with mutations in COL4A1 and COL4A2 manifest hallmarks of cerebral small vessel disease (cSVD). Mice with a missense mutation in Col4a1 at amino acid 1344 (Col4a1+/G1344D) exhibit age-dependent intracerebral hemorrhages (ICHs) and brain lesions. Here, we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential for the autoregulation of cerebral blood flow. Electrophysiological analyses showed that the loss of myogenic constriction resulted from blunted pressure-induced smooth muscle cell (SMC) membrane depolarization. Furthermore, we found that dysregulation of membrane potential was associated with impaired Ca2+-dependent activation of large-conductance Ca2+-activated K+ (BK) and transient receptor potential melastatin 4 (TRPM4) cation channels linked to disruptions in sarcoplasmic reticulum (SR) Ca2+ signaling. Col4a1 mutations impair protein folding, which can cause SR stress. Treating Col4a1+/G1344D mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins and alleviates SR stress, restored SR Ca2+ signaling, maintained BK and TRPM4 channel activity, prevented loss of myogenic tone, and reduced ICHs. We conclude that alterations in SR Ca2+ handling that impair ion channel activity result in dysregulation of SMC membrane potential and loss of myogenic tone and contribute to age-related cSVD in Col4a1+/G1344D mice.

Effects of Annealing and Domain Structure on the Photovoltaic Response in Pb[(Mg1/3Nb2/3)0.70Ti0.30]O3 Single Crystal

Crystalline acentricity leading to the photovoltaic (PV) effect in ferroelectrics (FEs) emerges these materials as important candidates for the PV cells potentially overcoming the Shockley–Queisser limit of semiconductors. However, this research direction still requires more investigations to develop reliable pathways for PV efficiency optimization. Herein, it is reported that due to the sample annealing above the Curie point the PV effect asymmetry with respect to the poling sign can be compensated and intrinsic PV response of the FE crystal can be increased by more than 20% in comparison with the pristine sample. It is also reported how the orientation of domain walls can be used to engineer the PV effect in the subcoercive electric field region. The reported results contribute to better understanding of PV effect tuning in the FEs paving the way for more efficient and sustainable solar energy utilization.

Integrated multi-wavelength lasers for all-optical processing of ultra-high frequency signals

Semiconductor lasers are nowadays simply unavoidable and essential light sources. While their complexity and dynamical behavior have attracted some attention from a fundamental viewpoint, these special properties remain largely left aside in applications outside the lab. The development of multi-wavelength or multi-color lasers may be a turning point in this regard. On the one hand, multi-color lasers allow for simultaneous emission at multiple and controllable modes, thus adding extra versatility to the lasers. On the other hand, the coupling between the different modes may lead to exciting new functionalities and applications exploiting directly the intrinsic dynamical response of the laser itself. In this perspective letter, we describe the role that multi-wavelength lasers may, in our opinion, play in the future in signal processing applications, especially at the mm-wave and subterahertz frequencies.

Vibration characteristic analysis of three-dimensional sandwich cylindrical shell based on the Spectro-Geometric method

This paper presents the numerical investigations on the free and random vibration properties of thick cylindrical shells under the three-dimensional (3-D) elasticity theory. The analysis of these properties is conducted using the Rayleigh-Ritz method in conjunction with the Spectro-Geometric method (SGM). The cylindrical shell considered in this study is composed of fiber-reinforced composite and functionally graded porous graphene platelet reinforced composites (FGP-GPLRC). To simulate different boundary conditions, an artificial spring technique is utilized. The displacement components, as determined by SGM, are incorporated into the energy expression of the cylindrical shell. By applying the Rayleigh-Ritz method, the intrinsic frequencies and vibration modes of the cylindrical shell are obtained. Additionally, the power spectral density (PSD) function of the cylindrical shell under random excitation is obtained by the Pseudo-Excitation method (PEM). The accuracy and effectiveness of the present method are verified through comparative studies with existing literature and finite element method (FEM). Furthermore, an investigation on the effects of various parameters on the intrinsic frequency and random response of the cylindrical shell is conducted.

CDS-DB, an omnibus for patient-derived gene expression signatures induced by cancer treatment.

Patient-derived gene expression signatures induced by cancer treatment, obtained from paired pre- and post-treatment clinical transcriptomes, can help reveal drug mechanisms of action (MOAs) in cancer patients and understand the molecular response mechanism of tumor sensitivity or resistance. Their integration and reuse may bring new insights. Paired pre- and post-treatment clinical transcriptomic data are rapidly accumulating. However, a lack of systematic collection makes data access, integration, and reuse challenging. We therefore present the Cancer Drug-induced gene expression Signature DataBase (CDS-DB). CDS-DB has collected 78 patient-derived, paired pre- and post-treatment transcriptomic source datasets with uniformly reprocessed expression profiles and manually curated metadata such as drug administration dosage, sampling time and location,and intrinsic drug response status. From these source datasets, 2012 patient-level gene perturbation signatures were obtained, covering 85 therapeutic regimens, 39 cancer subtypesand 3628 patient samples. Besides data browsing, downloadand search, CDS-DB also supports single signature analysis (including differential gene expression, functional enrichment, tumor microenvironmentand correlation analyses), signature comparative analysisand signature connectivity analysis. This provides insights into drug MOA and its heterogeneity in patients, drug resistance mechanisms, drug repositioningand drug (combination) discovery, etc. CDS-DB is available at http://cdsdb.ncpsb.org.cn/.