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Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction., (© 2023. The Author(s).)

Membrane-based alkaline water electrolyser is promising for cost-effective green hydrogen production. One of its key technological obstacles is the development of active catalyst-materials for alkaline hydrogen-evolution-reaction (HER). Here, we show that the activity of platinum towards alkaline HER can be significantly enhanced by anchoring platinum-clusters onto two-dimensional fullerene nanosheets. The unusually large lattice distance (~0.8 nm) of the fullerene nanosheets and the ultra-small size of the platinum-clusters (~2 nm) leads to strong confinement of platinum clusters accompanied by pronounced charge redistributions at the intimate platinum/fullerene interface. As a result, the platinum-fullerene composite exhibits 12 times higher intrinsic activity for alkaline HER than the state-of-the-art platinum/carbon black catalyst. Detailed kinetic and computational investigations revealed the origin of the enhanced activity to be the diverse binding properties of the platinum-sites at the interface of platinum/fullerene, which generates highly active sites for all elementary steps in alkaline HER, particularly the sluggish Volmer step. Furthermore, encouraging energy efficiency of 74% and stability were achieved for alkaline water electrolyser assembled using platinum-fullerene composite under industrially relevant testing conditions., (© 2023. The Author(s).)

Attempts to develop photocatalysts for hydrogen production from water usually result in low efficiency. Here we report the finding of photocatalysts by integrated interfacial design of stable covalent organic frameworks. We predesigned and constructed different molecular interfaces by fabricating ordered or amorphous π skeletons, installing ligating or non-ligating walls and engineering hydrophobic or hydrophilic pores. This systematic interfacial control over electron transfer, active site immobilisation and water transport enables to identify their distinct roles in the photocatalytic process. The frameworks, combined ordered π skeletons, ligating walls and hydrophilic channels, work under 300-1000 nm with non-noble metal co-catalyst and achieve a hydrogen evolution rate over 11 mmol g -1 h -1 , a quantum yield of 3.6% at 600 nm and a three-order-of-magnitude-increased turnover frequency of 18.8 h -1 compared to those obtained with hydrophobic networks. This integrated interfacial design approach is a step towards designing solar-to-chemical energy conversion systems., (© 2023. The Author(s).)

Despite knowledge of the presence of the Tibetan Plateau (TP) in reorganizing large-scale atmospheric circulation, it remains unclear how surface albedo darkening over TP will impact local glaciers and remote Asian monsoon systems. Here, we use a coupled land-atmosphere global climate model and a glacier model to address these questions. Under a high-emission scenario, TP surface albedo darkening will increase local temperature by 0.24 K by the end of this century. This warming will strengthen the elevated heat pump of TP, increasing South Asian monsoon precipitation while exacerbating the current "South Flood-North Drought" pattern over East Asia. The albedo darkening-induced climate change also leads to an accompanying TP glacier volume loss of 6.9%, which further increases to 25.2% at the equilibrium, with a notable loss in western TP. Our findings emphasize the importance of land-surface change responses in projecting future water resource availability, with important implications for water management policies., (© 2023. The Author(s).)

Evaporative loss of interception (E i ) is the first process occurring during rainfall, yet its role in large-scale surface water balance has been largely underexplored. Here we show that E i can be inferred from flux tower evapotranspiration measurements using physics-informed hybrid machine learning models built under wet versus dry conditions. Forced by satellite and reanalysis data, this framework provides an observationally constrained estimate of E i , which is on average 84.1 ± 1.8 mm per year and accounts for 8.6 ± 0.2% of total rainfall globally during 2000-2020. Rainfall frequency regulates long-term average E i changes, and rainfall intensity, rather than vegetation attributes, determines the fraction of E i in gross precipitation (E i /P). Rain events have become less frequent and more intense since 2000, driving a global decline in E i (and E i /P) by 4.9% (6.7%). This suggests that ongoing rainfall changes favor a partitioning towards more soil moisture and runoff, benefiting ecosystem functions but simultaneously increasing flood risks., (© 2022. The Author(s).)

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5 + DM) is an autoimmune condition associated with rapidly progressive interstitial lung disease and high mortality. The aetiology and pathogenesis of MDA5 + DM are still largely unknown. Here we describe the immune signatures of MDA5 + DM via single-cell RNA sequencing, flow cytometry and multiplex immunohistochemistry in peripheral B and T cells and in affected lung tissue samples from one patient. We find strong peripheral antibody-secreting cell and CD8 + T cell responses as cellular immune hallmarks, and over-stimulated type I interferon signaling and associated metabolic reprogramming as molecular immune signature in MDA5 + DM. High frequency of circulating ISG15 + CD8 + T cells at baseline predicts poor one-year survival in MDA5 + DM patients. In affected lungs, we find profuse immune cells infiltration, which likely contributes to the pro-fibrotic response via type I interferon production. The importance of type I interferons in MDA5 + DM pathology is further emphasized by our observation in a retrospective cohort of MDA5 + DM patients that combined calcineurin and Janus kinase inhibitor therapy show superior efficacy to calcineurin inhibitor monotherapy. In summary, this study reveals key immune-pathogenic features of MDA5 + DM and provides a potential basis for future tailored therapies., (© 2022. The Author(s).)

Water availability plays a critical role in shaping terrestrial ecosystems, particularly in low- and mid-latitude regions. The sensitivity of vegetation growth to precipitation strongly regulates global vegetation dynamics and their responses to drought, yet sensitivity changes in response to climate change remain poorly understood. Here we use long-term satellite observations combined with a dynamic statistical learning approach to examine changes in the sensitivity of vegetation greenness to precipitation over the past four decades. We observe a robust increase in precipitation sensitivity (0.624% yr -1 ) for drylands, and a decrease (-0.618% yr -1 ) for wet regions. Using model simulations, we show that the contrasting trends between dry and wet regions are caused by elevated atmospheric CO 2 (eCO 2 ). eCO 2 universally decreases the precipitation sensitivity by reducing leaf-level transpiration, particularly in wet regions. However, in drylands, this leaf-level transpiration reduction is overridden at the canopy scale by a large proportional increase in leaf area. The increased sensitivity for global drylands implies a potential decrease in ecosystem stability and greater impacts of droughts in these vulnerable ecosystems under continued global change., (© 2022. The Author(s).)

Precipitation-based assessments show a lengthening of tropical dry seasons under climate change, without considering simultaneous changes in ecosystem water demand. Here, we compare changes in tropical dry season length and timing when dry season is defined as the period when precipitation is less than: its climatological average, potential evapotranspiration, or actual evapotranspiration. While all definitions show more widespread tropical drying than wetting for 1983-2016, we find the largest fraction (48.7%) of tropical land probably experiencing longer dry seasons when dry season is defined as the period when precipitation cannot meet the need of actual evapotranspiration. Southern Amazonia (due to delayed end) and central Africa (due to earlier onset and delayed end) are hotspots of dry season lengthening, with greater certainty when accounting for water demand changes. Therefore, it is necessary to account for changing water demand when characterizing changes in tropical dry periods and ecosystem water deficits., (© 2022. The Author(s).)

The seasonal greening of Northern Hemisphere (NH) ecosystems, due to extended growing periods and enhanced photosynthetic activity, could modify near-surface warming by perturbing land-atmosphere energy exchanges, yet this biophysical control on warming seasonality is underexplored. By performing experiments with a coupled land-atmosphere model, here we show that summer greening effectively dampens NH warming by -0.15 ± 0.03 °C for 1982-2014 due to enhanced evapotranspiration. However, greening generates weak temperature changes in spring (+0.02 ± 0.06 °C) and autumn (-0.05 ± 0.05 °C), because the evaporative cooling is counterbalanced by radiative warming from albedo and water vapor feedbacks. The dwindling evaporative cooling towards cool seasons is also supported by state-of-the-art Earth system models. Moreover, greening-triggered energy imbalance is propagated forward by atmospheric circulation to subsequent seasons and causes sizable time-lagged climate effects. Overall, greening makes winter warmer and summer cooler, attenuating the seasonal amplitude of NH temperature. These findings demonstrate complex tradeoffs and linkages of vegetation-climate feedbacks among seasons., (© 2022. The Author(s).)

Cloning quantitative trait locus (QTL) is time consuming and laborious, which hinders the understanding of natural variation and genetic diversity. Here, we introduce RapMap, a method for rapid multi-QTL mapping by employing F 2 gradient populations (F 2 GPs) constructed by minor-phenotypic-difference accessions. The co-segregation standard of the single-locus genetic models ensures simultaneous integration of a three-in-one framework in RapMap i.e. detecting a real QTL, confirming its effect, and obtaining its near-isogenic line-like line (NIL-LL). We demonstrate the feasibility of RapMap by cloning eight rice grain-size genes using 15 F 2 GPs in three years. These genes explain a total of 75% of grain shape variation. Allele frequency analysis of these genes using a large germplasm collection reveals directional selection of the slender and long grains in indica rice domestication. In addition, major grain-size genes have been strongly selected during rice domestication. We think application of RapMap in crops will accelerate gene discovery and genomic breeding., (© 2021. The Author(s).)

Photocatalytic hydrogen peroxide (H 2 O 2 ) generation represents a promising approach for artificial photosynthesis. However, the sluggish half-reaction of water oxidation significantly limits the efficiency of H 2 O 2 generation. Here, a benzylamine oxidation with more favorable thermodynamics is employed as the half-reaction to couple with H 2 O 2 generation in water by using defective zirconium trisulfide (ZrS 3 ) nanobelts as a photocatalyst. The ZrS 3 nanobelts with disulfide (S 2 2- ) and sulfide anion (S 2- ) vacancies exhibit an excellent photocatalytic performance for H 2 O 2 generation and simultaneous oxidation of benzylamine to benzonitrile with a high selectivity of >99%. More importantly, the S 2 2- and S 2- vacancies can be separately introduced into ZrS 3 nanobelts in a controlled manner. The S 2 2- vacancies are further revealed to facilitate the separation of photogenerated charge carriers. The S 2- vacancies can significantly improve the electron conduction, hole extraction, and kinetics of benzylamine oxidation. As a result, the use of defective ZrS 3 nanobelts yields a high production rate of 78.1 ± 1.5 and 32.0 ± 1.2 μmol h -1 for H 2 O 2 and benzonitrile, respectively, under a simulated sunlight irradiation.

The state of ecosystems is influenced strongly by their past, and describing this carryover effect is important to accurately forecast their future behaviors. However, the strength and persistence of this carryover effect on ecosystem dynamics in comparison to that of simultaneous environmental drivers are still poorly understood. Here, we show that vegetation growth carryover (VGC), defined as the effect of present states of vegetation on subsequent growth, exerts strong positive impacts on seasonal vegetation growth over the Northern Hemisphere. In particular, this VGC of early growing-season vegetation growth is even stronger than past and co-occurring climate on determining peak-to-late season vegetation growth, and is the primary contributor to the recently observed annual greening trend. The effect of seasonal VGC persists into the subsequent year but not further. Current process-based ecosystem models greatly underestimate the VGC effect, and may therefore underestimate the CO 2 sequestration potential of northern vegetation under future warming.

The global monsoon is characterised by transitions between pronounced dry and wet seasons, affecting food security for two-thirds of the world's population. Rising atmospheric CO 2 influences the terrestrial hydrological cycle through climate-radiative and vegetation-physiological forcings. How these two forcings affect the seasonal intensity and characteristics of monsoonal precipitation and runoff is poorly understood. Here we use four Earth System Models to show that in a CO 2 -enriched climate, radiative forcing changes drive annual precipitation increases for most monsoon regions. Further, vegetation feedbacks substantially affect annual precipitation in North and South America and Australia monsoon regions. In the dry season, runoff increases over most monsoon regions, due to stomatal closure-driven evapotranspiration reductions and associated atmospheric circulation change. Our results imply that flood risks may amplify in the wet season. However, the lengthening of the monsoon rainfall season and reduced evapotranspiration will shorten the water resources scarcity period for most monsoon regions.

The functionality and performance of a semiconductor is determined by its bandgap. Alloying, as for instance in In x Ga 1-x N, has been a mainstream strategy for tuning the bandgap. Keeping the semiconductor alloys in the miscibility gap (being homogeneous), however, is non-trivial. This challenge is now being extended to halide perovskites - an emerging class of photovoltaic materials. While the bandgap can be conveniently tuned by mixing different halogen ions, as in CsPb(Br x I 1-x ) 3 , the so-called mixed-halide perovskites suffer from severe phase separation under illumination. Here, we discover that such phase separation can be highly suppressed by embedding nanocrystals of mixed-halide perovskites in an endotaxial matrix. The tuned bandgap remains remarkably stable under extremely intensive illumination. The agreement between the experiments and a nucleation model suggests that the size of the nanocrystals and the host-guest interfaces are critical for the photo-stability. The stabilized bandgap will be essential for the development of perovskite-based optoelectronics, such as tandem solar cells and full-color LEDs.

Most studies of the northern hemisphere carbon cycle based on atmospheric CO 2 concentration have focused on spring and autumn, but the climate change impact on summer carbon cycle remains unclear. Here we used atmospheric CO 2 record from Point Barrow (Alaska) to show that summer CO 2 drawdown between July and August, a proxy of summer carbon uptake, is significantly negatively correlated with terrestrial temperature north of 50°N interannually during 1979-2012. However, a refined analysis at the decadal scale reveals strong differences between the earlier (1979-1995) and later (1996-2012) periods, with the significant negative correlation only in the later period. This emerging negative temperature response is due to the disappearance of the positive temperature response of summer vegetation activities that prevailed in the earlier period. Our finding, together with the reported weakening temperature control on spring carbon uptake, suggests a diminished positive effect of warming on high-latitude carbon uptake.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1's active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers.

While climate warming reduces the occurrence of frost events, the warming-induced lengthening of the growing season of plants in the Northern Hemisphere may actually induce more frequent frost days during the growing season (GSFDs, days with minimum temperature < 0 °C). Direct evidence of this hypothesis, however, is limited. Here we investigate the change in the number of GSFDs at latitudes greater than 30° N using remotely-sensed and in situ phenological records and three minimum temperature (T min ) data sets from 1982 to 2012. While decreased GSFDs are found in northern Siberia, the Tibetan Plateau, and northwestern North America (mainly in autumn), ~43% of the hemisphere, especially in Europe, experienced a significant increase in GSFDs between 1982 and 2012 (mainly during spring). Overall, regions with larger increases in growing season length exhibit larger increases in GSFDs. Climate warming thus reduces the total number of frost days per year, but GSFDs nonetheless increase in many areas.

Enhancing or restoring enzymatic function in cells is highly desirable in applications ranging from ex vivo cellular manipulations to enzyme replacement therapies in humans. However, because enzymes degrade in biological milieus, achieving long-term enzymatic activities can be challenging. Herein we report on the in cellulo properties of nanofactories that consist of antioxidative enzymes encapsulated in metal-organic frameworks (MOFs). We demonstrate that, while free enzymes display weak activities for only a short duration, these efficient nanofactories protect human cells from toxic reactive oxygen species for up to a week. Remarkably, these results are obtained in spite of the nanofactories being localized in lysosomes, acidic organelles that contain a variety of proteases. The long-term persistence of the nanofactories is attributed to the chemical stability of MOF in low pH environment and to the protease resistance provided by the protective cage formed by the MOF around the encapsulated enzymes.

Coronary arteriogenesis is a central step in cardiogenesis, requiring coordinated generation and integration of endothelial cell and vascular smooth muscle cells. At present, it is unclear whether the cell fate programme of cardiac progenitors to generate complex muscular or vascular structures is entirely cell autonomous. Here we demonstrate the intrinsic ability of vascular progenitors to develop and self-organize into cardiac tissues by clonally isolating and expanding second heart field cardiovascular progenitors using WNT3A and endothelin-1 (EDN1) human recombinant proteins. Progenitor clones undergo long-term expansion and differentiate primarily into endothelial and smooth muscle cell lineages in vitro, and contribute extensively to coronary-like vessels in vivo, forming a functional human-mouse chimeric circulatory system. Our study identifies EDN1 as a key factor towards the generation and clonal derivation of ISL1(+) vascular intermediates, and demonstrates the intrinsic cell-autonomous nature of these progenitors to differentiate and self-organize into functional vasculatures in vivo.

Enzymatic catalytic processes possess great potential in chemical manufacturing, including pharmaceuticals, fuel production and food processing. However, the engineering of enzymes is severely hampered due to their low operational stability and difficulty of reuse. Here, we develop a series of stable metal-organic frameworks with rationally designed ultra-large mesoporous cages as single-molecule traps (SMTs) for enzyme encapsulation. With a high concentration of mesoporous cages as SMTs, PCN-333(Al) encapsulates three enzymes with record-high loadings and recyclability. Immobilized enzymes that most likely undergo single-enzyme encapsulation (SEE) show smaller Km than free enzymes while maintaining comparable catalytic efficiency. Under harsh conditions, the enzyme in SEE exhibits better performance than free enzyme, showing the effectiveness of SEE in preventing enzyme aggregation or denaturation. With extraordinarily large pore size and excellent chemical stability, PCN-333 may be of interest not only for enzyme encapsulation, but also for entrapment of other nanoscaled functional moieties.

Even as the study of plant genomics rapidly develops through the use of high-throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits.

Grains from cereals contribute an important source of protein to human food, and grain protein content (GPC) is an important determinant of nutritional quality in cereals. Here we show that the quantitative trait locus (QTL) qPC1 in rice controls GPC by regulating the synthesis and accumulation of glutelins, prolamins, globulins, albumins and starch. qPC1 encodes a putative amino acid transporter OsAAP6, which functions as a positive regulator of GPC in rice, such that higher expression of OsAAP6 is correlated with higher GPC. OsAAP6 greatly enhances root absorption of a range of amino acids and has effects on the distribution of various amino acids. Two common variations in the potential cis-regulatory elements of the OsAAP6 5'-untranslated region seem to be associated with GPC diversity mainly in indica cultivars. Our results represent the first step toward unravelling the mechanism of regulation underlying natural variation of GPC in rice.