The prostate epithelial lineage hierarchy remains inadequately defined. Recent lineage-tracing studies have implied the existence of prostate luminal epithelial progenitors with extensive regenerative capacity. However, this capacity has not been demonstrated in prostate stem cell activity assays, probably owing to the strong susceptibility of luminal progenitors to anoikis. Here we show that constitutive expression of Notch1 intracellular domain impairs secretory function of mouse prostate luminal cells, suppresses anoikis of luminal epithelial cells by augmenting NF-κB activity independent of Hes1, stimulates luminal cell proliferation by potentiating PI3K-AKT signalling, and rescues the capacities of the putative prostate luminal progenitors for unipotent differentiation in vivo and short-term self-renewal in vitro. Epithelial cell autonomous AR signalling is dispensable for the Notch-mediated effects. As Notch activity is increased in prostate cancers, and anoikis resistance is a hallmark for metastatic cancer cells, this study suggests a pro-metastatic function of Notch signalling during prostate cancer progression.

Hyperactivation of the transcriptional factor E2F1 occurs frequently in human cancers and contributes to malignant progression. E2F1 activity is regulated by proteolysis mediated by the ubiquitin-proteasome system. However, the deubiquitylase that controls E2F1 ubiquitylation and stability remains undefined. Here we demonstrate that the deubiquitylase POH1 stabilizes E2F1 protein through binding to and deubiquitylating E2F1. Conditional knockout of Poh1 alleles results in reduced E2F1 expression in primary mouse liver cells. The POH1-mediated regulation of E2F1 expression strengthens E2F1-downstream prosurvival signals, including upregulation of Survivin and FOXM1 protein levels, and efficiently facilitates tumour growth of liver cancer cells in nude mice. Importantly, human hepatocellular carcinomas (HCCs) recapitulate POH1 regulation of E2F1 expression, as nuclear abundance of POH1 is increased in HCCs and correlates with E2F1 overexpression and tumour growth. Thus, our study suggests that the hyperactivated POH1-E2F1 regulation may contribute to the development of liver cancer.

Inhibition of the Wnt antagonist sclerostin increases bone mass in patients with osteoporosis and in preclinical animal models. Here we show increased levels of the Wnt antagonist Dickkopf-1 (DKK-1) in animals treated with sclerostin antibody, suggesting a negative feedback mechanism that limits Wnt-driven bone formation. To test our hypothesis that co-inhibition of both factors further increases bone mass, we engineer a first-in-class bispecific antibody with single residue pair mutations in the Fab region to promote efficient and stable cognate light-heavy chain pairing. We demonstrate that dual inhibition of sclerostin and DKK-1 leads to synergistic bone formation in rodents and non-human primates. Furthermore, by targeting distinct facets of fracture healing, the bispecific antibody shows superior bone repair activity compared with monotherapies. This work supports the potential of this agent both for treatment and prevention of fractures and offers a promising therapeutic approach to reduce the burden of low bone mass disorders.

Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/β-catenin and TGF-β pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/β-catenin and TGF-β activities. Notably, correlations among miR-128-3p levels, activated β-catenin and TGF-β signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.

Echovirus 30 (E30), a serotype of Enterovirus B (EV-B), recently emerged as a major causative agent of aseptic meningitis worldwide. E30 is particularly devastating in the neonatal population and currently no vaccine or antiviral therapy is available. Here we characterize two highly potent E30-specific monoclonal antibodies, 6C5 and 4B10, which efficiently block binding of the virus to its attachment receptor CD55 and uncoating receptor FcRn. Combinations of 6C5 and 4B10 augment the sum of their individual anti-viral activities. High-resolution structures of E30-6C5-Fab and E30-4B10-Fab define the location and nature of epitopes targeted by the antibodies. 6C5 and 4B10 engage the capsid loci at the north rim of the canyon and in-canyon, respectively. Notably, these regions exhibit antigenic variability across EV-Bs, highlighting challenges in development of broad-spectrum antibodies. Our structures of these neutralizing antibodies of E30 are instructive for development of vaccines and therapeutics against EV-B infections.

Abiotic stresses, including drought and salinity, trigger a complex osmotic-stress and abscisic acid (ABA) signal transduction network. The core ABA signalling components are snf1-related protein kinase2s (SnRK2s), which are activated by ABA-triggered inhibition of type-2C protein-phosphatases (PP2Cs). SnRK2 kinases are also activated by a rapid, largely unknown, ABA-independent osmotic-stress signalling pathway. Here, through a combination of a redundancy-circumventing genetic screen and biochemical analyses, we have identified functionally-redundant MAPKK-kinases (M3Ks) that are necessary for activation of SnRK2 kinases. These M3Ks phosphorylate a specific SnRK2/OST1 site, which is indispensable for ABA-induced reactivation of PP2C-dephosphorylated SnRK2 kinases. ABA-triggered SnRK2 activation, transcription factor phosphorylation and SLAC1 activation require these M3Ks in vitro and in plants. M3K triple knock-out plants show reduced ABA sensitivity and strongly impaired rapid osmotic-stress-induced SnRK2 activation. These findings demonstrate that this M3K clade is required for ABA- and osmotic-stress-activation of SnRK2 kinases, enabling robust ABA and osmotic stress signal transduction.

Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.

Controlling the biodistribution of nanoparticles upon intravenous injection is the key to achieving target specificity. One of the impediments in nanoparticle-based tumor targeting is the inability to limit the trafficking of nanoparticles to liver and other organs leading to smaller accumulated amounts in tumor tissues, particularly via passive targeting. Here we overcome both these challenges by designing nanoparticles that combine the specificity of antibodies with favorable particle biodistribution profiles, while not exceeding the threshold for renal filtration as a combined vehicle. To that end, ultrasmall silica nanoparticles are functionalized with anti-human epidermal growth factor receptor 2 (HER2) single-chain variable fragments to exhibit high tumor-targeting efficiency and efficient renal clearance. This ultrasmall targeted nanotheranostics/nanotherapeutic platform has broad utility, both for imaging a variety of tumor tissues by suitably adopting the targeting fragment and as a potentially useful drug delivery vehicle.

Inflammasome activation is essential for host defence against invading pathogens, but is also involved in various forms of inflammatory diseases. The processes that control inflammasome activity are thus important for averting excessive immune responses and tissue damage. Here we show that the deubiquitinase POH1 negatively regulates the immune response triggered by inflammasome activation. POH1 deficiency in macrophages enhances mature IL-1β production without significant alterations in inflammasome priming and ASC-caspase-1 activation. In WT macrophages, POH1 interacts with and deubiquitinates pro-IL-1β by decreasing the K63-linked polyubiquitin chains, as well as decreases the efficacy of pro-IL-1β cleavage. Furthermore, myeloid cell-specific deletion of POH1 aggravates lipopolysaccharide-induced systemic inflammation and alum-induced peritonitis inflammatory responses in vivo. Our study thereby reveals that POH1-mediated deubiquitination of pro-IL-1β is an important regulatory event that restrains inflammatory responses for the maintenance of immune homeostasis.

Much of the world's Li deposits occurs as basinal brines in magmatic orogens, particularly in continental volcanic arcs. However, the exact origin of Li enrichment in arc magmatic systems is not clear. Here, we show that, globally, primitive arc magmas have Li contents and Li/Y ratios similar to mid-ocean ridge basalts, indicating that the subducting slab has limited contribution to Li enrichment in arc magmas. Instead, we find that Li enrichment is enhanced by lower degrees of sub-arc mantle melting and higher extents of intracrustal differentiation. These enrichment effects are favored in arcs with thick crust, which explains why magmatism and differentiation in continental arcs, like the Andes, reach greater Li contents than their island arc counterparts. Weathering of these enriched source rocks mobilizes and transports such Li into the hydrologic system, ultimately developing Li brines with the combination of arid climate and the presence of landlocked extensional basins in thickened orogenic settings.

Constraining thickness and geothermal gradient of Archean continental crust are crucial to understanding geodynamic regimes of the early Earth. Archean crust-sourced tonalitic-trondhjemitic-granodioritic gneisses are ideal lithologies for reconstructing the thermal state of early continental crust. Integrating experimental results with petrochemical data from the Eastern Block of the North China Craton allows us to establish temporal-spatial variations in thickness, geothermal gradient and basal heat flow across the block, which we relate to cooling mantle potential temperature and resultant changing geodynamic regimes from vertical tectonics in the late Mesoarchean (~2.9 Ga) to plate tectonics with hot subduction in the early to late Neoarchean (~2.7-2.5 Ga). Here, we show the transition to a plate tectonic regime plays an important role in the rapid cooling of the mantle, and thickening and strengthening of the lithosphere, which in turn prompted stabilization of the cratonic lithosphere at the end of the Archean.

Cryptochromes are blue light receptors that regulate plant growth and development. They also act as the core components of the central clock oscillator in animals. Although plant cryptochromes have been reported to regulate the circadian clock in blue light, how they do so is unclear. Here we show that Arabidopsis cryptochrome 2 (CRY2) forms photobodies with the TCP22 transcription factor in response to blue light in plant cells. We provide evidence that PPK kinases influence the characteristics of these photobodies and that together these components, along with LWD transcriptional regulators, can positively regulate the expression of CCA1 encoding a central component of the circadian oscillator.

Chemoresistance limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an EGFR/HER2 targeted conjugate, dual-targeting ligand-based lidamycin (DTLL), which shows a highly potent antitumor effect. To overcome chemoresistance in PDAC, we aim to study DTLL efficacy when combined with gemcitabine and explore its mechanisms of action. DTLL in combination with gemcitabine show a superior inhibitory effect on the growth of gemcitabine-resistant/sensitive tumors. DTLL sensitizes gemcitabine efficacy via distinct action mechanisms mediated by mothers against decapentaplegic homolog 4 (SMAD4). It not only prevents neoplastic proliferation via ATK/mTOR blockade and NF-κB impaired function in SMAD4-sufficient PDACs, but also restores SMAD4 bioactivity to trigger downstream NF-κB-regulated signaling in SMAD4-deficient tumors and to overcome chemoresistance. DTLL seems to act as a SMAD4 module that normalizes its function in PDAC, having a synergistic effect in combination with gemcitabine. Our findings provide insight into a rational SMAD4-directed precision therapy in PDAC.

How the genetic landscape governs a tumor's response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by KrasG12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.

The greater wax moth (GWM), Galleria mellonella (Lepidoptera: Pyralidae), is a major bee pest that causes significant damage to beehives and results in economic losses. Bacillus thuringiensis (Bt) appears as a potential sustainable solution to control this pest. Here, we develop a novel Bt strain (designated BiotGm) that exhibits insecticidal activity against GWM larvae with a LC50 value lower than 2 μg/g, and low toxicity levels to honey bee with a LC50 = 20598.78 μg/mL for larvae and no observed adverse effect concentration = 100 μg/mL for adults. We design an entrapment method consisting of a lure for GWM larvae, BiotGm, and a trapping device that prevents bees from contacting the lure. We find that this method reduces the population of GWM larvae in both laboratory and field trials. Overall, these results provide a promising direction for the application of Bt-based biological control of GWM in beehives, although further optimization remain necessary.

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

The mid-Pleistocene transition (MPT) is widely recognized as a shift in paleoclimatic periodicity from 41- to 100-kyr cycles, which largely reflects integrated changes in global ice volume, sea level, and ocean temperature from the marine realm. However, much less is known about monsoon-induced terrestrial vegetation change across the MPT. Here, on the basis of a 1.7-million-year δ13C record of loess carbonates from the Chinese Loess Plateau, we document a unique MPT reflecting terrestrial vegetation changes from a dominant 23-kyr periodicity before 1.2 Ma to combined 100, 41, and 23-kyr cycles after 0.7 Ma, very different from the conventional MPT characteristics. Model simulations further reveal that the MPT transition likely reflects decreased sensitivity of monsoonal hydroclimate to insolation forcing as the Northern Hemisphere became increasingly glaciated through the MPT. Our proxy-model comparison suggests varied responses of temperature and precipitation to astronomical forcing under different ice/CO2 boundary conditions, which greatly improves our understanding of monsoon variability and dynamics from the natural past to the anthropogenic future.

The mid-infrared (mid-IR) is a strategically important band for numerous applications ranging from night vision to biochemical sensing. Here we theoretically analyzed and experimentally realized a Huygens metasurface platform capable of fulfilling a diverse cross-section of optical functions in the mid-IR. The meta-optical elements were constructed using high-index chalcogenide films deposited on fluoride substrates: the choices of wide-band transparent materials allow the design to be scaled across a broad infrared spectrum. Capitalizing on a two-component Huygens' meta-atom design, the meta-optical devices feature an ultra-thin profile (λ0/8 in thickness) and measured optical efficiencies up to 75% in transmissive mode for linearly polarized light, representing major improvements over state-of-the-art. We have also demonstrated mid-IR transmissive meta-lenses with diffraction-limited focusing and imaging performance. The projected size, weight and power advantages, coupled with the manufacturing scalability leveraging standard microfabrication technologies, make the Huygens meta-optical devices promising for next-generation mid-IR system applications.

Rapid Auger recombination represents an important challenge faced by quasi-2D perovskites, which induces resulting perovskite light-emitting diodes' (PeLEDs) efficiency roll-off. In principle, Auger recombination rate is proportional to materials' exciton binding energy (Eb). Thus, Auger recombination can be suppressed by reducing the corresponding materials' Eb. Here, a polar molecule, p-fluorophenethylammonium, is employed to generate quasi-2D perovskites with reduced Eb. Recombination kinetics reveal the Auger recombination rate does decrease to one-order-of magnitude lower compared to its PEA+ analogues. After effective passivation, nonradiative recombination is greatly suppressed, which enables resulting films to exhibit outstanding photoluminescence quantum yields in a broad range of excitation density. We herein demonstrate the very efficient PeLEDs with a peak external quantum efficiency of 20.36%. More importantly, devices exhibit a record luminance of 82,480 cd m-2 due to the suppressed efficiency roll-off, which represent one of the brightest visible PeLEDs yet.

As sequencing depth of chromatin studies continually grows deeper for sensitive profiling of regulatory elements or chromatin spatial structures, aligning and preprocessing of these sequencing data have become the bottleneck for analysis. Here we present Chromap, an ultrafast method for aligning and preprocessing high throughput chromatin profiles. Chromap is comparable to BWA-MEM and Bowtie2 in alignment accuracy and is over 10 times faster than traditional workflows on bulk ChIP-seq/Hi-C profiles and than 10x Genomics' CellRanger v2.0.0 pipeline on single-cell ATAC-seq profiles.