In multiple mouse tumor models, bacteria expressing the activating mutant of the human chemokine, CXCL16 (hCXCL16K42A), proved to be therapeutically beneficial due to the recruitment of CD8+ T cells. Additionally, we concentrate on the presentation of tumor-sourced antigens by dendritic cells, accomplished through a second engineered bacterial strain producing CCL20. This resulted in the recruitment of conventional type 1 dendritic cells, which further complemented the hCXCL16K42A-induced T cell recruitment, thereby producing an additional therapeutic benefit. Generally speaking, we design bacteria to recruit and activate innate and adaptive anticancer immune responses, thus establishing a new strategy for cancer immunotherapy.
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. Pathogen diversity in this region is probably a key factor in generating strong selective pressures that impact human survival and reproductive success. Yet, the genetic foundations of human adaptation to this multifaceted ecosystem remain unknown. Employing genomic data from 19 native populations of the Amazon rainforest, this study explores the potential genetic adaptations in response to the environment. Genomic and functional data underscored a profound impact of natural selection on a group of genes critical to Trypanosoma cruzi infection, the agent of Chagas disease, a neglected tropical parasitic affliction endemic to the Americas and now spreading globally.
Variations in the intertropical convergence zone (ITCZ) placement hold substantial influence on weather, climate, and human societies. Extensive research has been conducted on the shifts of the ITCZ in current and future warmer climates, but the historical migration of the ITCZ over geological time spans remains largely unknown. By examining a collection of climate simulations over the past 540 million years, we demonstrate that continental configurations primarily dictate the migration patterns of the ITCZ, operating through two competing processes: hemispheric radiative imbalance and cross-equatorial ocean heat transfer. The differing absorption of solar radiation across hemispheres is primarily a consequence of the disparity in albedo between land and water, a pattern readily inferred from the configuration of landmasses. The hemispheric asymmetry of ocean surface area dictates the uneven distribution of surface wind stress, which is intrinsically linked to the substantial cross-equatorial ocean heat transport. These results underscore how the influence of continental evolution on global ocean-atmosphere circulations can be comprehended through simple mechanisms, with the latitudinal distribution of land playing a crucial role.
Anticancer drug-induced acute cardiac/kidney injuries (ACI/AKI) have demonstrated ferroptosis; however, the utilization of molecular imaging to pinpoint ferroptosis in these cases is a considerable hurdle. We introduce an artemisinin-based probe (Art-Gd) for contrast-enhanced magnetic resonance imaging of ferroptosis (feMRI), utilizing the redox-active Fe(II) as a visually distinct chemical target. The Art-Gd probe's in vivo application facilitated early diagnosis of anticancer drug-induced acute cellular injury (ACI) and acute kidney injury (AKI), demonstrating a significant advantage of at least 24 and 48 hours, respectively, over standard clinical tests. Using feMRI, the varying mechanisms of action for ferroptosis-targeted agents were demonstrated, with either the inhibition of lipid peroxidation or the removal of iron ions highlighted in the imagery. This feMRI strategy, featuring straightforward chemistry and dependable efficacy, is presented in this study to facilitate early assessment of anticancer drug-induced ACI/AKI. This approach may illuminate the theranostic potential for a range of ferroptosis-related illnesses.
Lipofuscin, an autofluorescent (AF) pigment made up of lipids and misfolded proteins, progressively accumulates in postmitotic cells undergoing senescence. Using immunophenotyping, we examined microglia within the brains of senior C57BL/6 mice (18 months and above). The results indicated that a third of the microglia in these old mice showed atypical features (AF), characterized by substantial changes to lipid and iron levels, reduced phagocytic activity, and elevated oxidative stress levels. Upon repopulation, the pharmacological depletion of microglia in aged mice successfully eliminated AF microglia, leading to a reversal of microglial dysfunction. Age-related neurological deficits and neurodegenerative conditions, brought on by traumatic brain injury (TBI), were less severe in older mice devoid of AF microglia. Nivolumab mouse Moreover, the sustained phagocytic activity, lysosomal strain, and lipid buildup within microglia, persisting for up to one year post-TBI, were modulated by APOE4 genotype and continually fueled by phagocyte-induced oxidative stress. Moreover, a pathological condition in aging microglia, characterized by heightened phagocytosis of neurons and myelin, and inflammatory neurodegenerative changes, potentially signified by AF, could be exacerbated by traumatic brain injury (TBI).
Direct air capture (DAC) is critical to ensuring net-zero greenhouse gas emissions are attained by the year 2050. The atmospheric CO2 concentration, albeit low at around 400 parts per million, presents a formidable hurdle to achieving high capture capacities through sorption-desorption processes. We introduce a hybrid sorbent, constructed using polyamine-Cu(II) complex Lewis acid-base interactions. This sorbent shows a remarkable CO2 capture capacity exceeding 50 moles per kilogram, which represents roughly two to three times the capacity of most previously reported DAC sorbents. The hybrid sorbent, like other amine-based sorbents, is responsive to thermal desorption procedures that involve temperatures less than 90°C. Nivolumab mouse In addition, seawater was verified to be a functional regenerant, and the desorbed carbon dioxide is concurrently stored as a safe, chemically stable alkalinity, sodium bicarbonate (NaHCO3). Using oceans as decarbonizing sinks is facilitated by the unique adaptability of dual-mode regeneration, which broadens the opportunities available for Direct Air Capture (DAC).
The accuracy of process-based dynamical models' real-time predictions of El Niño-Southern Oscillation (ENSO) is currently constrained by substantial biases and uncertainties; recent developments in data-driven deep learning algorithms suggest a promising path to achieving superior skill in tropical Pacific sea surface temperature (SST) modeling. A self-attention neural network model, called 3D-Geoformer, is developed for predicting ENSO using the Transformer architecture. This model's focus is on forecasting three-dimensional upper-ocean temperature and wind stress anomalies. Remarkably high correlation is achieved in 18-month-ahead predictions of Nino 34 SST anomalies using a time-space attention-enhanced model, purely data-driven, beginning in boreal spring. Sensitivity analyses show that the 3D-Geoformer model can represent the temporal development of upper-ocean temperature and the integrated ocean-atmosphere dynamics governed by the Bjerknes feedback during El Niño-Southern Oscillation cycles. The effective implementation of self-attention-based models in ENSO forecasting underscores their substantial capacity for multidimensional, spatiotemporal modeling in the discipline of geoscience.
The biological processes by which bacteria gain tolerance to antibiotics and subsequently become resistant still pose considerable scientific challenges. Glucose abundance progressively decreases in parallel with the acquisition of ampicillin resistance in strains initially sensitive to ampicillin. Nivolumab mouse Through targeting the pts promoter and pyruvate dehydrogenase (PDH), ampicillin initiates this event, resulting in the promotion of glucose transport and inhibition of 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. The mechanism by which cAMP/CRP mediates resistance to ampicillin involves negatively regulating glucose transport and ROS, and positively modulating DNA repair. Glucose and manganese ions create a delay in the acquisition of resistance, thereby forming a powerful tool to control it. This identical effect is also observed within the intracellular pathogen Edwardsiella tarda. Therefore, glucose metabolic pathways offer a promising avenue to impede or decelerate 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). Recurrence of BCCs is suspected to be closely related to interactions occurring between BCCs and the BM niche, which demands the development of informative model systems for mechanistic insights and refined treatment approaches. Within an in vivo context, we examined dormant DTCs, finding them positioned near bone-lining cells and displaying signs of 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. Inhibition of autophagy or modifications to the microenvironment allowed the reversal of this dormancy, thereby creating further opportunities to explore the underlying mechanisms and identify therapeutic targets to prevent the late recurrence of the condition.