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Miniaturization has been an everlasting theme in the development of semiconductor lasers. One important breakthrough in this process in recent years is the use of metal-dielectric composite structures that made truly subwavelength lasers possible. Many different designs of metallic cavity semiconductor nanolasers have been proposed and demonstrated. In this article, we will review some of the most exciting progresses in this newly emerging field. In particular, we will focus on metallic-cavity nanolasers with volume smaller than wavelength cubed under electrical injection with emphasis on high-temperature operation. Such devices will serve as an important component in the future integrated nanophotonic systems due to its ultra-small size. Lasers: Rise of the nanolaser Semiconductor nanolasers based on subwavelength-scale metal cavities could become important light sources for integrated optical circuitry on silicon. In this paper, Kang Ding and Cun-Zheng Ning from Arizona State University in the USA review progress in this exciting and rapidly evolving field. They cover the achievement of milestones such as the reduction of cavity sizes to below the scale of one wavelength, operation at room temperature, continuous-wave emission and the use of electrical injection. They describe the design and operating principles of nanolasers, as well as the challenges faced in terms of device fabrication, overcoming cavity loss, high-temperature operation and waveguide integration. Future improvements in fabrication technology to address issues such as surface passivation and material deposition will bring further advances in device performance.

The ASEAN region is one of the most susceptible regions to climate change, with three of its countries—Myanmar, the Philippines, and Thailand—among those that have suffered the greatest fatalities and economic losses because of climate-related disasters. This paper reveals that the ASEAN’s environmental performance is sorely lagging other regions despite evidence of its cohesive and comprehensive efforts to mitigate emissions and build up adaptive capacity to climate-related disasters. Within the ASEAN, there exist gaps in environmental performance between each country. This suggests that increased cooperation between individual ASEAN countries is pertinent for the region to collectively combat climate change. In addition, we show that government effectiveness has a positive influence on a country’s climate performance, signifying that a government’s strong commitment to governance is necessary in the fight against climate change.

Galectin-3 (Gal-3) has been implicated in pancreatic ductal adenocarcinoma (PDAC), and its candidacy as a therapeutic target has been evaluated. Gal-3 is widely upregulated in tumors, and its expression is associated with the development and malignancy of PDAC. In the present study, we demonstrate that a polysaccharide, RN1, purified from the flower of Panax notoginseng binds to Gal-3 and suppresses its expression. In addition, RN1 markedly inhibits PDAC cells growth in vitro , in vivo and in patient-derived xenografts. Mechanistically, RN1 binds to epidermal growth factor receptor (EGFR) and Gal-3, thereby disrupting the interaction between Gal-3 and EGFR and downregulating extracellular-related kinase (ERK) phosphorylation and the transcription factor of Gal-3, Runx1 expression. Inhibiting the expression of Runx1 by RN1, suppresses Gal-3 expression and inactivates Gal-3-associated signaling pathways, including the EGFR/ERK/Runx1, BMP/smad/Id-3 and integrin/FAK/JNK signaling pathways. In addition, RN1 can also bind to bone morphogenetic protein receptors (BMPR1A and BMPR2) and block the interaction between Gal-3 and the BMPRs. Thus, our results suggest that a novel Gal-3 inhibitor RN1 may be a potential candidate for human PDAC treatment via multiple targets and multiple signaling pathways.

As primarily an electronic observable, the room-temperature thermopower S in cuprates provides possibilities for a quantitative assessment of the Hubbard model. Using determinant quantum Monte Carlo, we demonstrate agreement between Hubbard model calculations and experimentally measured room-temperature S across multiple cuprate families, both qualitatively in terms of the doping dependence and quantitatively in terms of magnitude. We observe an upturn in S with decreasing temperatures, which possesses a slope comparable to that observed experimentally in cuprates. From our calculations, the doping at which S changes sign occurs in close proximity to a vanishing temperature dependence of the chemical potential at fixed density. Our results emphasize the importance of interaction effects in the systematic assessment of the thermopower S in cuprates. High-temperature behaviour of thermopower is special in cuprates, allowing for theory-experiment comparisons. Wang et al. use quantum Monte Carlo to compute high temperature thermopower in the Hubbard model, demonstrating qualitative and quantitative agreement with experiments across multiple cuprate families.

With the approval of the antibody-drug conjugate enfortumab vedotin (EV), NECTIN4 has emerged as a bona fide therapeutic target in urothelial carcinoma (UC). Here, we report the development of a NECTIN4-directed chimeric antigen receptor (CAR) T cell, which exhibits reactivity across cells expressing a range of endogenous NECTIN4, with enhanced activity in high expressors. We demonstrate that the PPARγ pathway, critical for luminal differentiation, transcriptionally controls NECTIN4 , and that the PPARγ agonist rosiglitazone primes and augments NECTIN4 expression, thereby increasing sensitivity to NECTIN4-CAR T cell-mediated killing. NECTIN4-CAR T cells have potent anti-tumor activity even against EV resistant cells, which largely retain NECTIN4 expression, including in a post-EV biopsy cohort. Our results elucidate a therapeutically actionable mechanism that UC cells use to control NECTIN4 expression and suggest therapeutic approaches that leverage PPARγ agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients. Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

East Asia has experienced rapid development with increasing carbon monoxide (CO) emission in the past decades. Therefore, uplifting CO from the boundary layer to the free troposphere in East Asia can have great implications on regional air quality around the world. It can also influence global climate due to the longer lifetime of CO at higher altitudes. In this study, three cases of high CO episodes in the East China Sea and the Sea of Japan from 2003 to 2005 are examined with spaceborne Measurements of Pollution in the Troposphere (MOPITT) data, in combination with aircraft measurements from the Measurement of Ozone and Water Vapor by Airbus In-Service Aircraft (MOZAIC) program. High CO abundances of 300–550 ppbv are observed in MOZAIC data in the free troposphere during these episodes. These are among the highest CO abundances documented at these altitudes. On average, such episodes with CO over 400 ppbv (in the 2003 and 2004 cases) and between 200 and 300 ppbv (in the 2005 case) may occur 2–5 and 10–20% in time, respectively, in the respective altitudes over the region. Correspondingly, elevated CO is shown in MOPITT daytime data in the middle to upper troposphere in the 2003 case, in the lower to middle troposphere in the 2004 case, and in the upper troposphere in the 2005 case. Through analyses of the simulations from a chemical transport model GEOS-Chem and a trajectory dispersion model FLEXPART, we found different CO signatures in the elevated CO and distinct transport pathways and mechanisms for these cases. In the 2003 case, emissions from large forest fires near Lake Baikal dominated the elevated CO, which had been rapidly transported upward by a frontal system from the fire plumes. In the 2004 case, anthropogenic CO from the North China Plain experienced frontal lifting and mostly reached ~ 700 hPa near the East China Sea, while CO from biomass burning over Indochina experienced orographic lifting, lee-side-trough-induced convection, and frontal lifting through two separate transport pathways, leading to two distinct CO enhancements around 700 and 300 hPa. In the 2005 case, the observed CO of ~ 300 ppbv around 300 hPa originated from anthropogenic sources over the Sichuan Basin and the North China Plain and from forest fires over Indochina. The high CO was transported to such altitudes through strong frontal lifting, interacting with convection and orographic lifting. These cases show that topography affects vertical transport of CO in East Asia via different ways, including orographic uplifting over the Hengduan Mountains, assisting frontal lifting in the North China Plain, and facilitating convection in the Sichuan Basin. In particular, topography-induced lee-side troughs over Indochina led to strong convection that assisted CO uplifting to the upper troposphere. This study shows that the new daytime MOPITT near-infrared (NIR) and thermal-infrared (TIR) data (version 5 or above) have enhanced vertical sensitivity in the free troposphere and may help qualitative diagnosis of vertical transport processes in East Asia.

Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable. To identify such a nutrient, we performed a nutrigenetic screen by removing individual amino acids to identify possible addictions across a panel of breast cancer cells. This screen revealed that cystine deprivation triggered rapid programmed necrosis, but not apoptosis, in the basal-type breast cancer cells mostly seen in TNBC tumors. In contrast, luminal-type breast cancer cells are cystine-independent and exhibit little death during cystine deprivation. The cystine addiction phenotype is associated with a higher level of cystine-deprivation signatures noted in the basal type breast cancer cells and tumors. We found that the cystine-addicted breast cancer cells and tumors have strong activation of TNFα and MEKK4-p38-Noxa pathways that render them susceptible to cystine deprivation-induced necrosis. Consistent with this model, silencing of TNFα and MEKK4 dramatically reduces cystine-deprived death. In addition, the cystine addiction phenotype can be abrogated in the cystine-addictive cells by miR-200c, which converts the mesenchymal-like cells to adopt epithelial features. Conversely, the introduction of inducers of epithelial-mesenchymal transition (EMT) in cystine-independent breast cancer cells conferred the cystine-addiction phenotype by modulating the signaling components of cystine addiction. Together, our data reveal that cystine-addiction is associated with EMT in breast cancer during tumor progression. These findings provide the genetic and mechanistic basis to explain how cystine deprivation triggers necrosis by activating pre-existing oncogenic pathways in cystine-addicted TNBC with prominent mesenchymal features.

One of the most promising approaches to reach a high gain in inertial confinement fusion is the fast ignition scheme. In this scheme, a relativistic electron beam is generated; this passes through the imploded plasma and deposits parts of its energy in the core. However, the large angular spread of the relativistic electron beam and the poorly controlled compression of the target affect realization of the fast ignition technique. Here, we demonstrate that indirectly driven (that is, driven by X-rays generated inside a gold hohlraum) implosions with a ‘high-foot’ and a short-coast time of less than 200 ps allow us to tightly compress the shell. Furthermore, we show the ability to optimize the symmetry of the imploding shell by changing the hohlraum length, successfully tuning a suitable tube-shaped shell to compensate for the large angular spread of the relativistic electron beam and to enhance the electron-to-core coupling efficiency via resistive magnetic fields. Benefiting from those experimental techniques, a significant enhancement in neutron yield was achieved in our indirectly driven fast ignition experiments. These results pave the way towards high-coupling fast ignition experiments with indirectly driven targets similar to those at the National Ignition Facility. Experiments realizing the indirect-drive fast ignition scheme for inertial confinement fusion are reported. Enabled by a tightly compressed target, an increase of neutron yield is observed.

Background Secukinumab has demonstrated sustained improvement in the signs and symptoms of psoriatic arthritis (PsA) over 2 years in the FUTURE 2 study (NCT01752634). This post hoc analysis assessed the ability of secukinumab to achieve Psoriatic Arthritis Disease Activity Score (PASDAS)-based remission or low disease activity (LDA) through 2 years among patients with PsA in the FUTURE 2 study. Methods PASDAS (cut-off scores: remission ≤ 1.9; LDA > 1.9 and < 3.2; Moderate Disease Activity ≥ 3.2 and < 5.4; and high disease activity [HDA] ≥ 5.4) was assessed in the overall population (tumour necrosis factor inhibitor [TNFi]-naïve and TNFi-experienced), in patients stratified by prior TNFi use and by disease duration at weeks 16, 52 and 104. The impact of secukinumab on individual PASDAS core components and on the relationship between PASDAS states and patient-reported outcomes (PROs), including physical function, health-related quality of life (HRQoL) and work productivity, were also assessed. Data for the approved doses of secukinumab (300 and 150 mg) are reported. PASDAS scores and core components were reported as observed, and PROs were analysed using mixed models for repeated measures. Results In the overall population, PASDAS remission and LDA were achieved in 15.6% and 22.9%, respectively, of patients treated with secukinumab 300 mg and in 15.2% and 19.2%, respectively, in the secukinumab 150 mg group versus 2.3% and 13.8%, respectively, with placebo at week 16. In the TNFi-naïve group, a higher proportion of patients achieved remission + LDA at week 16 with secukinumab 300 and 150 mg (46.2% and 42.9%, respectively) versus placebo (17.5%), with corresponding responses in TNFi-experienced patients being 22.6% and 19.4% versus 13.3%. Remission/LDA responses with secukinumab were sustained through 2 years. Patients achieving remission/LDA reported greater improvements in PROs than patients in HDA through 2 years. Conclusions Secukinumab-treated patients achieved higher PASDAS-defined remissions or LDA compared with placebo at week 16, which were sustained through 2 years. Remission/LDA was achieved by both TNFi-naïve and TNFi-experienced patients treated with secukinumab, with higher rates in TNFi-naïve patients. Secukinumab-treated patients achieving remission/LDA reported significantly greater improvements in PROs, including physical function and different dimensions of health-related quality of life and work, than patients in HDA. Trial registration ClinicalTrials.gov, NCT01752634 . Registered on December 19, 2012. EUDRACT, 2012-004439-22 . Registered on December 12, 2012.