M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity

A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or ß-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or ß-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection

Transposable elements are associated with the variable response to influenza infection

インフルエンザ重症度に関連する転移因子を特定: マルチオミクス解析で見えた「動く遺伝子」の新たな役割. 京都大学プレスリリース. 2023-05-11.A multiomics approach provides insights into flu severity. 京都大学プレスリリース. 2023-05-11.Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity

Decreased galectin-3 expression in prostate cancer

BACKGROUND Galectin-3 is a carbohydrate-binding protein whose level of expression has been shown to be correlated with metastatic potential in a number of different tumor types. The purpose of this investigation was to examine galectin-3 expression in several tumorigenic and nontumorigenic prostate cell lines and prostate tissue samples. METHODS The expression of galectin-3 in cell lines and tissue samples was evaluated by tissue immunohistochemistry and Western blot analysis. RESULTS Human cell lines PC-3M, PC-3, DU-145, PrEC-1, and MCF10A demonstrated the presence of galectin-3. Galectin-3 was not detected in TSU-pr1 and LNCaP by Western blot analysis. We furthered our studies by examining a series of human prostate tissue samples for expression of galectin-3. Overall, approximately 60–70% of the normal tissue examined demonstrated heterogenous expression of galectin-3. In stage II tumors, however, there was a dramatic decrease in galectin-3 expression in both PIN and tumor sections, with only 10.5% (2/19) of these samples expressing this protein. Stage III tumors also demonstrated a decreased expression of galectin-3, although this downregulation was not as dramatic, with 35% of PIN samples and 52% of tumor tissue expressing galectin-3 ( P < 0.01). CONCLUSIONS These data demonstrate that galectin-3 is downregulated in prostate cancer. The altered downregulation pattern of galectin-3 observed between tumor stages suggests different roles for galectin-3 in the progression of prostate cancer. Prostate 44:118–123, 2000. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34754/1/4_ftp.pd

ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis(1). Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α(1)-adrenergic receptor (AR) and β(3)-AR signalling induces the expression of thermogenic genes of the futile creatine cycle(2,3), and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α(1)-AR subtype (ADRA1A) and Gα(q) to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gα(q) and Gα(s) signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A–Gα(q)–futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis

Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment

Prostate cancer will develop chemoresistance following a period of chemotherapy. This is due, in part, to the acquisition of antiapoptotic properties by the cancer cells and, therefore, development of novel strategies for treatment is of critical need. Here, we attempt to clarify the role of the antiapoptotic molecule galectin-3 in prostate cancer cells using siRNA and antagonist approaches. The data showed that Gal-3 inhibition by siRNA or its antagonist GCS-100/modified citrus pectin (MCP) increased cisplatin-induced apoptosis of PC3 cells. Recent studies have indicated that cisplatin-induced apoptosis may be mediated by calpain, a calcium-dependent protease, as its activation leads to cleavage of androgen receptor into an androgen-independent isoform in prostate cancer cells. Thus, we examined whether calpain activation is associated with the Gal-3 function of regulating apoptosis. Here, we report that Gal-3 inhibition by siRNA or GCS-100/MCP enhances calpain activation, whereas Gal-3 overexpression inhibits it. Inhibition of calpain using its inhibitor and/or siRNA attenuated the proapoptotic effect of Gal-3 inhibition, suggesting that calpain activation may be a novel mechanism for the proapoptotic effect of Gal-3 inhibition. Thus, a paradigm shift for treating prostate cancer is suggested whereby a combination of a non-toxic anti-Gal-3 drug together with a toxic chemotherapeutic agent could serve as a novel therapeutic modality for chemoresistant prostate cancers

Using Advanced Computer Vision Algorithms on Small Mobile Robots

The Technology Transfer project employs a spiral development process to enhance the functionality and autonomy of mobile robot systems in the Joint Robotics Program (JRP) Robotic Systems Pool by converging existing component technologies onto a transition platform for optimization. An example of this approach is the implementation of advanced computer vision algorithms on small mobile robots. We demonstrate the implementation and testing of the following two algorithms useful on mobile robots: 1) object classification using a boosted Cascade of classifiers trained with the Adaboost training algorithm, and 2) human presence detection from a moving platform. Object classification is performed with an Adaboost training system developed at the University of California, San Diego (UCSD) Computer Vision Lab. This classification algorithm has been used to successfully detect the license plates of automobiles in motion in real-time. While working towards a solution to increase the robustness of this system to perform generic object recognition, this paper demonstrates an extension to this application by detecting soda cans in a cluttered indoor environment. The human presence detection from a moving platform system uses a data fusion algorithm which combines results from a scanning laser and a thermal imager. The system is able to detect the presence of humans while both the humans and the robot are moving simultaneously. In both systems, the two aforementioned algorithms were implemented on embedded hardware and optimized for use in real-time. Test results are shown for a variety of environments

Towards a warfighter’s associate: eliminating the operator control unit

In addition to the challenges of equipping a mobile robot with the appropriate sensors, actuators, and processing electronics necessary to perform some useful function, there coexists the equally important challenge of effectively controlling the system’s desired actions. This need is particularly critical if the intent is to operate in conjunction with human forces in a military application, as any low-level distractions can seriously reduce a warfighter’s chances of survival in hostile environments. Historically there can be seen a definitive trend towards making the robot smarter in order to reduce the control burden on the operator, and while much progress has been made in laboratory prototypes, all equipment deployed in theatre to date has been strictly teleoperated. There exists a definite tradeoff between the value added by the robot, in terms of how it contributes to the performance of the mission, and the loss of effectiveness associated with the operator control unit. From a command-and-control perspective, the ultimate goal would be to eliminate the need for a separate robot controller altogether, since it represents an unwanted burden and potential liability from the operator’s perspective. This paper introduces the long-term concept of a supervised autonomous Warfighter’s Associate, which employs a natural-language interface for communication with (and oversight by) its human counterpart. More realistic near-term solutions to achieve intermediate success are then presented, along with actual results to date. The primary application discussed is military, but the concept also applies to law enforcement, space exploration, and search-and-rescue scenarios

Enhancing Functionality and Autonomy in Man-Portable Robots

Current man-portable robotic systems are too heavy for troops to pack during extended missions in rugged terrain and typically require more user support than can be justified by their limited return in force multiplication or improved effectiveness. As a consequence, today’s systems appear organically attractive only in life-threatening scenarios, such as detection of chemical/biological/radiation hazards, mines, or improvised explosive devices. For the long term, significant improvements in both functionality (i.e., perform more useful tasks) and autonomy (i.e., with less human intervention) are required to increase the level of general acceptance and, hence, the number of units deployed by the user. In the near term, however, the focus must remain on robust and reliable solutions that reduce risk and save lives. This paper describes ongoing efforts to address these needs through a spiral development process that capitalizes on technology transfer to harvest applicable results of prior and ongoing activities throughout the technical community