From out-competing grandmasters in chess to informing high-stakes healthcare decisions, emerging methods from artificial intelligence are increasingly capable of making complex and strategic ...decisions in diverse, high-dimensional and uncertain situations. But can these methods help us devise robust strategies for managing environmental systems under great uncertainty? Here we explore how reinforcement learning (RL), a subfield of artificial intelligence, approaches decision problems through a lens similar to adaptive environmental management: learning through experience to gradually improve decisions with updated knowledge. We review where RL holds promise for improving evidence-informed adaptive management decisions even when classical optimization methods are intractable and discuss technical and social issues that arise when applying RL to adaptive management problems in the environmental domain. Our synthesis suggests that environmental management and computer science can learn from one another about the practices, promises and perils of experience-based decision-making. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.
While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used ...for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.
Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete ...activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.
The advancement of nanoscale electronics has been limited by energy dissipation challenges for over a decade. Such limitations could be particularly severe for two-dimensional (2D) semiconductors ...integrated with flexible substrates or multilayered processors, both being critical thermal bottlenecks. To shed light into fundamental aspects of this problem, here we report the first direct measurement of spatially resolved temperature in functioning 2D monolayer MoS2 transistors. Using Raman thermometry, we simultaneously obtain temperature maps of the device channel and its substrate. This differential measurement reveals the thermal boundary conductance of the MoS2 interface with SiO2 (14 ± 4 MW m–2 K–1) is an order magnitude larger than previously thought, yet near the low end of known solid–solid interfaces. Our study also reveals unexpected insight into nonuniformities of the MoS2 transistors (small bilayer regions) which do not cause significant self-heating, suggesting that such semiconductors are less sensitive to inhomogeneity than expected. These results provide key insights into energy dissipation of 2D semiconductors and pave the way for the future design of energy-efficient 2D electronics.
Two-dimensional (2D) semimetals beyond graphene have been relatively unexplored in the atomically thin limit. Here, we introduce a facile growth mechanism for semimetallic WTe2 crystals and then ...fabricate few-layer test structures while carefully avoiding degradation from exposure to air. Low-field electrical measurements of 80 nm to 2 μm long devices allow us to separate intrinsic and contact resistance, revealing metallic response in the thinnest encapsulated and stable WTe2 devices studied to date (3–20 layers thick). High-field electrical measurements and electrothermal modeling demonstrate that ultrathin WTe2 can carry remarkably high current density (approaching 50 MA/cm2, higher than most common interconnect metals) despite a very low thermal conductivity (of the order ∼3 Wm–1 K–1). These results suggest several pathways for air-stable technological viability of this layered semimetal.
Life history trade-offs lead to various strategies that maximize fitness, but the developmental mechanisms underlying these alternative strategies continue to be poorly understood. In insects, ...trade-offs exist between size and developmental time. Recent studies in the fruit fly Drosophila melanogaster have suggested that the steroidogenic prothoracic glands play a key role in determining the timing of metamorphosis. In this study, the nutrient-dependent growth and transcriptional activation of prothoracic glands were studied in D. melanogaster and the tobacco hornworm Manduca sexta. In both species, minimum viable weight (MVW) was associated with activation of ecdysteroid biosynthesis genes and growth of prothoracic gland cells. However, the timing of MVW attainment in M. sexta is delayed by the presence of the sesquiterpenoid hormone, juvenile hormone (JH), whereas in D. melanogaster it is not. Moreover, in D. melanogaster, the transcriptional regulation of ecdysteroidogenesis becomes nutrient-independent at the MVW/critical weight (CW) checkpoint. In contrast, in M. sexta, starvation consistently reduced transcriptional activation of ecdysteroid biosynthesis genes even after CW attainment, indicating that the nature of CW differs fundamentally between the two species. In D. melanogaster, the prothoracic glands dictate the timing of metamorphosis even in the absence of nutritional inputs, whereas in M. sexta, prothoracic gland activity is tightly coupled to the nutritional status of the body, thereby delaying the onset of metamorphosis before CW attainment. We propose that selection for survival under unpredictable nutritional availability leads to the evolution of increased modularity in both morphological and endocrine traits.
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•Minimum viable weight (MVW) involves ecdysteroid biosynthesis gene activation in Manduca sexta and Drosophila melanogaster.•Timing of MVW attainment in Manduca sexta is delayed by the presence of juvenile hormone.•Transcriptional regulation of ecdysteroidogenesis becomes nutrient-independent at MVW/critical weight in D. melanogaster.•In M. sexta, prothoracic gland activity is tightly coupled to the nutritional status of the body.•The differential regulation of prothoracic glands may underlie alternative life history strategies.
Background There is increased risk of hypertension, early cardiovascular disease, and premature mortality in women who have had preeclampsia. This study was undertaken to determine the upper limit of ...normal blood pressure (BP) 6 months postpartum and the frequency of women with prior preeclampsia who had BP above these limits, as part of the P4 (Post-Partum Physiology, Psychology and Pediatric) follow-up study. Methods and Results BP was measured by sphygmomanometer, 24-hour ambulatory BP monitoring, and non-invasive central BP at 6 months postpartum in 302 women who had normotensive pregnancy and 90 who had preeclampsia. The upper limit of normal BP (mean+2 SD) for women with normotensive pregnancy was 122/79 mm Hg for routine BP, 115/81 mm Hg for central BP, and 121/78 mm Hg for 24-hour ambulatory BP monitoring. Traditional normal values detected only 3% of women who had preeclampsia as having high BP 6 months postpartum whereas these new values detected between 13% and 19%. Women with preeclampsia had greater body mass index (27.8 versus 25.0,
<0.001) and left ventricular wall thickness but similar augmentation index. They also had lower high-density lipoprotein (59±15 versus 65±16 mg/dL,
=0.002), higher triglycerides (77±51 versus 61±35 mg/dL,
=0.005), and higher homeostatic model assessment score (2.1±1.8 versus 1.3±1.9,
<0.001). Conclusions Clinicians wishing to detect high BP in these women should be aware of the lower than usual upper limit of normal for this young cohort and where possible should use 24-hour ambulatory BP monitoring to detect these changes. This may define a subgroup of women who had preeclampsia for whom targeted BP lowering therapy would be successful. Registration URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365295&isReview=true; Unique identifier: ACTRN12613001260718.
Centrally located hepatocellular carcinoma(HCC)is sited in the central part of the liver and adjacent to main hepatic vascular structures.This special location is associated with an increase in the ...difficulty of surgery,aggregation of the recurrence disease,and greater challenge in disease management.This review summarizes the evolution of our understanding for centrally located HCC and discusses the development of treatment strategies,surgical approaches and recurrence prevention methods.To improve patient survival,a multi-disciplinary modality is greatly needed throughout the whole treatment period.
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