Bacteria expressing an activating mutant of human chemokine CXCL16 (hCXCL16K42A) led to a therapeutic effect in multiple mouse tumor models, a consequence of CD8+ T cell recruitment. Moreover, our strategy centers on tumor-derived antigen presentation by dendritic cells, executed using a second engineered bacterial strain to express CCL20. The recruitment of conventional type 1 dendritic cells followed, and it acted in conjunction with the T cell recruitment stimulated by hCXCL16K42A, contributing to improved therapeutic outcomes. In short, we develop bacteria to recruit and activate both innate and adaptive immune responses against tumors, which represents a novel cancer immunotherapy approach.
The Amazon rainforest's long-standing ecological conditions are intrinsically linked to the transmission of a multitude of tropical diseases, especially those transmitted by vectors. The wide array of pathogenic organisms likely fuels strong selective pressures necessary for human endurance and propagation in this location. Still, the genetic blueprint for human adaptation to this complex environmental setting remains shrouded in mystery. This investigation into the genetic adaptations to the Amazonian rainforest environment leverages the genomic data of 19 native populations. Natural selection was intensely observed within genes related to Trypanosoma cruzi infection in genomic and functional analyses, the pathogen behind Chagas disease, a neglected tropical parasitic affliction endemic to the Americas and now spreading internationally.
The movement of the intertropical convergence zone (ITCZ) plays a critical role in shaping weather, climate, and social structures. Despite significant study of the ITCZ's shifts in current and future warmer climates, its migration across past geological time scales remains poorly understood. Utilizing an ensemble of climate models simulating the past 540 million years, we establish that the movement of the Intertropical Convergence Zone (ITCZ) is chiefly governed by continental configurations, operating via two opposing pathways: hemispheric radiation disparity and trans-equatorial ocean heat circulation. Uneven absorption of solar radiation between hemispheres is principally due to the contrasting reflectivities of land and ocean surfaces, which are predictable based solely on the distribution of land. The hemispheric asymmetry of ocean surface area fundamentally influences the hemispheric asymmetry of surface wind stress, a key driver of the strong cross-equatorial ocean heat transport. These results expose simple mechanisms that explain the influence of continental evolution on global ocean-atmosphere circulations, wherein the latitudinal distribution of land plays a key role.
Despite the presence of ferroptosis in acute cardiac/kidney injuries (ACI/AKI) caused by anticancer drugs, molecular imaging methods for identifying this form of cell death within ACI/AKI remain a significant hurdle. To enable contrast-enhanced magnetic resonance imaging (feMRI) of ferroptosis, we present an artemisinin-based probe (Art-Gd), utilizing the redox-active Fe(II) as a vivid chemical marker. The Art-Gd probe displayed a high degree of feasibility for early diagnosis of anticancer drug-induced acute cellular injury (ACI)/acute kidney injury (AKI) within vivo settings, anticipating standard clinical assessments by at least 24 and 48 hours, respectively. Furthermore, the feMRI provided illustrative imaging data on the various operational pathways of ferroptosis-directed therapies, which include either the cessation of lipid oxidation or the reduction of iron concentrations. A feMRI strategy, with its simple chemistry and robust efficacy, is presented in this study for the early evaluation of anticancer drug-induced ACI/AKI. The potential applications for the theranostics of a wide variety of ferroptosis-related diseases are highlighted.
Lipofuscin, a byproduct of lipids and misfolded proteins, is an autofluorescent (AF) pigment that accumulates in postmitotic cells over time. We immunophenotyped brain microglia from old (greater than 18 months) C57BL/6 mice, revealing that a third of these displayed atypical features (AF) compared with those of young mice. These atypical microglia showed remarkable changes in lipid and iron content, phagocytic activity, and oxidative stress response. Microglia, depleted pharmacologically in old mice, saw the elimination of AF microglia after repopulation, which reversed their dysfunction. Following traumatic brain injury (TBI), older mice without AF microglia exhibited attenuated age-related neurological deficits and neurodegeneration. SCH58261 Furthermore, phagocytic activity, lysosomal burden, and lipid buildup in microglia, enduring up to one year post-TBI, demonstrated variations dependent on APOE4 genotype, and were constantly driven by oxidative stress mediated by phagocytes. Consequently, age-related microglial dysfunction, characterized by heightened neuronal and myelin phagocytosis, alongside inflammatory neurodegenerative processes, may be exacerbated by traumatic brain injury (TBI), potentially mirroring a pathological state within the aging microglia (AF).
The necessity of direct air capture (DAC) is undeniable in reaching the target of net-zero greenhouse gas emissions by 2050. The low atmospheric CO2 concentration, roughly 400 parts per million, acts as a formidable obstacle to optimizing CO2 capture through sorption-desorption processes. A polyamine-Cu(II) complex-based hybrid sorbent, formed via Lewis acid-base interactions, is presented. This sorbent exhibits a CO2 capture capacity of over 50 moles per kilogram, significantly exceeding the capacity of most current DAC sorbents by a factor of roughly two to three. The hybrid sorbent, like other amine-based sorbents, is responsive to thermal desorption procedures that involve temperatures less than 90°C. SCH58261 Moreover, seawater's function as a regenerant was substantiated, and the desorbed CO2 is simultaneously incorporated into a safe, chemically stable alkalinity (NaHCO3). Dual-mode regeneration's distinctive flexibility facilitates the utilization of oceans as decarbonizing sinks, increasing the diversity of applications for Direct Air Capture (DAC).
In real-time El Niño-Southern Oscillation (ENSO) predictions, process-based dynamical models are still plagued by substantial biases and uncertainties; recent innovations in data-driven deep learning algorithms provide a promising means of achieving superior skill in modeling the tropical Pacific sea surface temperature (SST). This paper introduces the 3D-Geoformer, a novel self-attention-based neural network model. This model is built using the Transformer architecture for ENSO predictions, targeting three-dimensional upper-ocean temperature and wind stress anomalies. This time-space attention-enhanced, purely data-driven model impressively predicts Nino 34 SST anomalies 18 months in advance, beginning in boreal spring, with high correlation scores. Sensitivity tests highlight the 3D-Geoformer model's ability to illustrate the evolution of upper-ocean temperature and coupled ocean-atmosphere dynamics, conforming to the Bjerknes feedback mechanism during ENSO cycles. Successful self-attention model applications in ENSO prediction indicate a strong potential for modeling complex, multidimensional spatiotemporal phenomena in geoscience.
The precise mechanisms that underlie bacterial acquisition of tolerance, and later resistance to antibiotics, are poorly understood. Glucose levels are observed to diminish progressively in ampicillin-resistant strains derived from initially ampicillin-sensitive strains. SCH58261 Ampicillin's mechanism for initiating this event involves the targeting of the pts promoter and pyruvate dehydrogenase (PDH), ultimately promoting glucose transport and inhibiting glycolysis, respectively. Glucose's metabolic route leads it to the pentose phosphate pathway, where it catalyzes the formation of reactive oxygen species (ROS) and consequently causes genetic mutations. Simultaneously, PDH activity recovers gradually owing to the competitive binding of accumulated pyruvate and ampicillin, which diminishes glucose levels and stimulates the cyclic adenosine monophosphate (cAMP)/cyclic AMP receptor protein (CRP) complex. Glucose transport and reactive oxygen species (ROS) are negatively regulated by cAMP/CRP, while DNA repair is enhanced, ultimately contributing to ampicillin resistance. The presence of glucose and manganese ions inhibits the acquisition of resistance, providing a viable approach to managing it effectively. This identical effect is observable in the intracellular bacterium Edwardsiella tarda. Thus, the regulation of glucose metabolism warrants investigation as a means to block or delay the transition from tolerance to resistance.
Disseminated tumor cells (DTCs), reactivating from dormancy, are posited as the source of late breast cancer recurrences, particularly in estrogen receptor-positive (ER+) breast cancer cells (BCCs) residing in bone marrow (BM). It is posited that the relationship between the BM niche and BCCs is essential to recurrence, and thus, the development of appropriate model systems is crucial for gaining mechanistic understanding and improving treatment efficacy. In vivo studies of dormant DTCs revealed their localization near bone-lining cells, coupled with autophagy. We established a well-defined, bio-inspired dynamic indirect coculture system to investigate the underlying cell-cell interactions. This system consisted of ER+ basal cell carcinomas (BCCs), bone marrow (BM) niche cells, human mesenchymal stem cells (hMSCs), and fetal osteoblasts (hFOBs). hFOBs promoted a state of dormancy and autophagy, in contrast to hMSCs' promotion of BCC growth, with the tumor necrosis factor- and monocyte chemoattractant protein 1 receptor signaling pathways partly driving these effects. The reversible dormancy state, resulting from dynamic shifts in the microenvironment or the inhibition of autophagy, offers additional avenues for investigating the mechanisms and identifying potential therapeutic targets to prevent late recurrence.