Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection.

Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.

ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.

The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA structures recognized by MMR proteins during replication. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors. Interestingly, the antitumor effects of ATRi are partially due to CD8+ T cells. In MMR-d cells, ATRi stimulates the accumulation of nascent DNA fragments in the cytoplasm, activating the cGAS-mediated interferon response. The combination of ATRi and anti-PD-1 antibody reduces the growth of MMR-d tumors more efficiently than ATRi or anti-PD-1 alone, showing the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy.

A mediator lost in the war on cancer.

An unexpected role for a Mediator subunit, MED12, in resistance to multiple anticancer agents is revealed by Huang et al. Loss of MED12 confers drug resistance by activating transforming growth factor b (TGF-b) signaling. Inhibition of the TGF-b pathway resensitizes cells to therapeutic drugs, suggesting a new combinatorial cancer treatment.

PLEKv2: predicting lncRNAs and mRNAs based on intrinsic sequence features and the coding-net model.

BACKGROUND: Long non-coding RNAs (lncRNAs) are RNA transcripts of more than 200 nucleotides that do not encode canonical proteins. Their biological structure is similar to messenger RNAs (mRNAs). To distinguish between lncRNA and mRNA transcripts quickly and accurately, we upgraded the PLEK alignment-free tool to its next version, PLEKv2, and constructed models tailored for both animals and plants. RESULTS: PLEKv2 can achieve 98.7% prediction accuracy for human datasets. Compared with classical tools and deep learning-based models, this is 8.1%, 3.7%, 16.6%, 1.4%, 4.9%, and 48.9% higher than CPC2, CNCI, Wen et al.'s CNN, LncADeep, PLEK, and NcResNet, respectively. The accuracy of PLEKv2 was > 90% for cross-species prediction. PLEKv2 is more effective and robust than CPC2, CNCI, LncADeep, PLEK, and NcResNet for primate datasets (including chimpanzees, macaques, and gorillas). Moreover, PLEKv2 is not only suitable for non-human primates that are closely related to humans, but can also predict the coding ability of RNA sequences in plants such as Arabidopsis. CONCLUSIONS: The experimental results illustrate that the model constructed by PLEKv2 can distinguish lncRNAs and mRNAs better than PLEK. The PLEKv2 software is freely available at https://sourceforge.net/projects/plek2/ .

2D Memory Selectors with Giant Nonlinearity Enabled by Van der Waals Heterostructures.

The integration of one-selector-one-resistor crossbar arrays requires the selectors featured with high nonlinearity and bipolarity to prevent leakage currents and any crosstalk among distinct cells. However, a selector with sufficient nonlinearity especially in the frame of device miniaturization remains scarce, restricting the advance of high-density storage devices. Herein, a high-performance memory selector is reported by constructing a graphene/hBN/WSe2 heterostructure. Within the temperature range of 300-80 K, the nonlinearity of this selector varies from ≈103 - ≈104 under forward bias, and increases from ≈300 - ≈105 under reverse bias, the highest reported nonlinearity among 2D selectors. This improvement is ascribed to direct tunneling at low bias and Fowler-Nordheim tunneling at high bias. The tunneling current versus voltage curves exhibit excellent bipolarity behavior because of the comparable hole and electron tunneling barriers, and the charge transport polarity can be effectively tuned from N-type or P-type to bipolar by simply changing source-drain bias. In addition, the conceptual memory selector exhibits no sign of deterioration after 70 000 switching cycles, paving the way for assembling 2D selectors into modern memory devices.

Ethylene controls three-dimensional growth involving reduced auxin levels in the moss Physcomitrium patens.

The conquest of land by plants was concomitant with, and possibly enabled by, the evolution of three-dimensional (3D) growth. The moss Physcomitrium patens provides a model system for elucidating molecular mechanisms in the initiation of 3D growth. Here, we investigate whether the phytohormone ethylene, which is believed to have been a signal before land plant emergence, plays a role in 3D growth regulation in P. patens. We report ethylene controls 3D gametophore formation, based on results from exogenously applied ethylene and genetic manipulation of PpEIN2, which is a central component in the ethylene signaling pathway. Overexpression (OE) of PpEIN2 activates ethylene responses and leads to earlier formation of gametophores with fewer gametophores produced thereafter, phenocopying ethylene-treated wild-type. Conversely, Ppein2 knockout mutants, which are ethylene insensitive, show initially delayed gametophore formation with more gametophores produced later. Furthermore, pharmacological and biochemical analyses reveal auxin levels are decreased in the OE lines but increased in the knockout mutants. Our results suggest that evolutionarily, ethylene and auxin molecular networks were recruited to build the plant body plan in ancestral land plants. This might have played a role in enabling ancient plants to acclimate to the continental surfaces of the planet.

Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis.

BACKGROUND AND AIMS: Liver fibrosis results from the accumulation of myofibroblasts (MFs) derived from quiescent HSCs, and yes-associated protein (YAP) controls this state transition. Although fibrosis is also influenced by HSC death and senescence, whether YAP regulates these processes and whether this could be leveraged to treat liver fibrosis are unknown. APPROACH AND RESULTS: YAP activity was manipulated in MF-HSCs to determine how YAP impacts susceptibility to pro-apoptotic senolytic agents or ferroptosis. Effects of senescence on YAP activity and susceptibility to apoptosis versus ferroptosis were also examined. CCl 4 -treated mice were treated with a ferroptosis inducer or pro-apoptotic senolytic to determine the effects on liver fibrosis. YAP was conditionally disrupted in MFs to determine how YAP activity in MF-HSC affects liver fibrosis in mouse models. Silencing YAP in cultured MF-HSCs induced HSC senescence and vulnerability to senolytics, and promoted ferroptosis resistance. Conversely, inducing HSC senescence suppressed YAP activity, increased sensitivity to senolytics, and decreased sensitivity to ferroptosis. Single-cell analysis of HSCs from fibrotic livers revealed heterogeneous sensitivity to ferroptosis, apoptosis, and senescence. In mice with chronic liver injury, neither the ferroptosis inducer nor senolytic improved fibrosis. However, selectively depleting YAP in MF-HSCs induced senescence and decreased liver injury and fibrosis. CONCLUSION: YAP determines whether MF-HSCs remain activated or become senescent. By regulating this state transition, Yap controls both HSC fibrogenic activity and susceptibility to distinct mechanisms for cell death. MF-HSC-specific YAP depletion induces senescence and protects injured livers from fibrosis. Clarifying determinants of HSC YAP activity may facilitate the development of novel anti-fibrotic therapies.

Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression.

BACKGROUND AND AIMS: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Senescing cells upregulate thrombomodulin-protease-activated receptor-1 (THBD-PAR1) signaling to remain viable. Vorapaxar blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. APPROACH AND RESULTS: We evaluated the THBD-PAR1 pathway in liver biopsies from patients with NAFLD. Chow-fed mice were treated with viral vectors to overexpress p16 in hepatocytes and induce replicative senescence. Effects on the THBD-PAR1 axis and regenerative capacity were assessed; the transcriptome of p16-overexpressing hepatocytes was characterized, and we examined how conditioned medium from senescent but viable (dubbed "undead") hepatocytes reprograms HSCs. Mouse models of NASH caused by genetic obesity or Western diet/CCl 4 were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Inducing senescence upregulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR1 signaling with vorapaxar interrupts this process, reduces the burden of 'undead' senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress. CONCLUSION: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.

Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.

Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is essential for mitophagy, it is unclear how ubiquitinated mitochondria activate autophagosome assembly locally to ensure efficient destruction. Here, we report that Parkin activates lipid remodeling on mitochondria targeted for autophagic destruction. Mitochondrial Parkin induces the production of phosphatidic acid (PA) and its subsequent conversion to diacylglycerol (DAG) by recruiting phospholipase D2 and activating the PA phosphatase, Lipin-1. The production of DAG requires mitochondrial ubiquitination and ubiquitin-binding autophagy receptors, NDP52 and optineurin (OPTN). Autophagic receptors, via Golgi-derived vesicles, deliver an autophagic activator, EndoB1, to ubiquitinated mitochondria. Inhibition of Lipin-1, NDP52/OPTN, or EndoB1 results in a failure to produce mitochondrial DAG, autophagosomes, and mitochondrial clearance, while exogenous cell-permeable DAG can induce autophagosome production. Thus, mitochondrial DAG production acts downstream of Parkin to enable the local assembly of autophagosomes for the efficient disposal of ubiquitinated mitochondria.

The amino acid sensor methionyl-tRNA synthetase is required for methionine-induced milk protein synthesis in a domestic pigeon model.

This study was conducted to investigate whether methionyl-tRNA synthetase (MetRS) is a mediator of methionine (Met)-induced crop milk protein synthesis via the janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signalling pathway in breeding pigeons. In Experiment 1, a total of 216 pairs of breeding pigeons were divided into three groups (control, Met-deficient, and Met-rescue groups). In Experiments 2 and 3, forty pairs of breeding pigeons from each experiment were allocated into four groups. The second experiment included a control group and three MetRS inhibitor (REP8839) groups. The third experiment included a Met-deficient group, Met-sufficient group, REP8839 + Met-deficient group and REP8839 + Met-sufficient group. Experiment 1 showed that Met supplementation increased crop development, crop milk protein synthesis, the protein expression of MetRS and JAK2/STAT5 signalling pathway, and improved squab growth. Experiment 2 showed that crop development, crop milk protein synthesis and the protein expression of MetRS and the JAK2/STAT5 signalling pathway were decreased, and squab growth was inhibited by the injection of 1·0 mg/kg body weight REP8839, which was the selected dose for the third experiment. Experiment 3 showed that Met supplementation increased crop development, crop milk protein synthesis and the expression of MetRS and JAK2/STAT5 signalling pathway and rescued squab growth after the injection of REP8839. Moreover, the co-immunoprecipitation results showed that there was an interaction between MetRS and JAK2. Taken together, these findings indicate that MetRS mediates Met-induced crop milk protein synthesis via the JAK2/STAT5 signalling pathway, resulting in improved squab growth in breeding pigeons.

Finale: the last minutes of Smads.

TGF-beta ligands induce phosphorylation of receptor-activated Smads at both the C-terminal tail and the linker region. Two papers from Massagué and colleagues (Alarcón et al., 2009; Gao et al., 2009) reveal a dual role for this linker phosphorylation, which is required for activation of Smads and for their degradation.

A Dilated Convolutional Neural Network for Cross-Layers of Contextual Information for Congested Crowd Counting.

Crowd counting is an important task that serves as a preprocessing step in many applications. Despite obvious improvement reported by various convolutional-neural-network-based approaches, they only focus on the role of deep feature maps while neglecting the importance of shallow features for crowd counting. In order to surmount this issue, a dilated convolutional-neural-network-based cross-level contextual information extraction network is proposed in this work, which is abbreviated as CL-DCNN. Specifically, a dilated contextual module (DCM) is constructed by importing cross-level connection between different feature maps. It can effectively integrate contextual information while conserving the local details of crowd scenes. Extensive experiments show that the proposed approach outperforms state-of-the-art approaches using five public datasets, i.e., ShanghaiTech part A, ShanghaiTech part B, Mall, UCF_CC_50 and UCF-QNRF, achieving MAE 52.6, 8.1, 1.55, 181.8, and 96.4, respectively.

The potential role of iron-carbon micro-electrolysis materials in curtailing lag-phase stimulates kitchen waste anaerobic digestion at different solid contents: Performance, synergistic effect and microbial response.

High-solid anaerobic digestion (HSAD) of kitchen waste was generally faced to the common problems such as systemic acidification, prolonged lag-phase time and low methane production. Iron-carbon micro-electrolysis (ICME) materials exhibited advantages that porous structure, large specific surface area and excellent conductivity. It was beneficial for organic compounds to hydrolysis. Moreover, ICME materials could establish direct interspecies electron transfer (DIET) pathway between bacteria and methanogens. ICME materials were commonly used to enhance the AD of wastewater, but they were rarely applied to HSAD of kitchen waste. In this study, ICME materials were utilized to enhance HSAD of kitchen waste at different solid content conditions. The results showed that the highest cumulative biogas yield (705.23 mL/g VS) was obtained in the experimental group (TS = 10%), which was 94.15% higher than that of the control group. At the same time, the addiction of ICME could shorten lag-phase time. Electrochemical characteristics and XPS analysis showed that ICME materials promoted the release of Fe2+ in the AD system and acceleration of direct interspecies electron transfer between microorganisms. Microbial community analysis showed that ICME materials enriched electroactive bacteria (Proteiniphilum), Methanosarcina, Methanobrevibacter and Methanofollis. Functional gene prediction revealed that ICME materials increased the relative abundance of carbohydrate transport and metabolism and coenzyme transport and metabolism. It provided a potential measure to treat kitchen waste.

The evolution of flower-pollinator trait matching, and why do some alpine gingers appear to be mismatched?

BACKGROUND AND AIMS: Morphological matching between flower and pollinator traits has been documented in diverse plant lineages. Indeed, the matching of corolla tube length and pollinator tongue length has been cited repeatedly as a classic case of coevolution. However, there are many possible evolutionary routes to trait matching. Our aim here is both to review the evolutionary mechanisms of plant-pollinator trait matching and to investigate a specific case of trait matching/mismatching in a genus of alpine gingers. METHODS: Roscoea gingers with long corolla tubes in the western Himalayas have pollinators with correspondingly long tongues, but the match between corolla tube and pollinator tongue lengths is not seen in the eastern Himalayas. Six floral traits were measured, including corolla tube depth, an internal trait controlling pollinator access to nectar. We calculated coefficients of variation and phylogenetically controlled correlation patterns of these traits in six Roscoea species in order to gain possible insights into stabilizing selection and modularization of these traits. KEY RESULTS: The distal (nectar-containing) portion of the corolla tube exhibited lower coefficients of variations than did the basal portion. This is consistent with the hypothesis that pollinators mediate stabilizing selection on the distal, but not basal, portion of the corolla tube. This result, combined with phylogenetic data, suggests that the elevated liquid level of nectar in the distal tube evolved subsequent to dispersal into the eastern Himalayan region and loss of long-tongue pollinators. After accounting for phylogeny, corolla tube length, anther length, style length and labellum width were all intercorrelated. Corolla-tube depth was not part of this covariational module, however, suggesting separate adaptation to short-tongued pollinators. CONCLUSIONS: The reduction in functional corolla tube depth in the Roscoea appears to be related to the loss of long-tongued pollinators associated with dispersal to the eastern Himalayas and pollination by short-tongued pollinators. The apparent mismatch between floral tubes and pollinator tongues is a case of cryptic trait matching between flowers and pollinators, underscoring the importance of combining floral anatomy with pollination ecology in assessing plant-pollinator trait matching.

Synthesis of 3-Haloindoles via Cascade Oxidative Cyclization/Halogenation of 2-Alkenylanilines Mediated by PIDA and LiBr/KI.

The treatment of 2-alkenylanilines with phenyliodine(III) diacetate (PIDA) and LiBr or KI in HFIP was found to afford the corresponding 3-haloindoles via cascade oxidative cyclization/halogenation encompassing oxidative C-N/C-X (X = Br, I) bond formations. A plausible mechanism involving the in situ formation of the reactive AcO-X (X = Br, I) from the reaction of PIDA and LiBr/KI was postulated.

A combat game model with inter-network confrontation and intra-network cooperation.

Inter-network combat and intra-network cooperation among structured systems are likely to have been recurrent features of human evolutionary history; however, little research has investigated the combat mechanism between structured systems that the adversarial interactions will cause the disability of agents and agents are prone to seek cooperation with neighbors. Hence, the current study has proposed a two-network combat game model and designed the corresponding rules of how to attack, how to be disabled, how to cooperate, and how to win. First, within the framework of our model, we have simulated the combat among four common network structures-the Erdos-Rényi (ER) random network, the grid graph, the small-world network, and the scale-free network. We found that the grid network always holds the highest winning percentage, while the ER random graph is most likely to lose when combating with the other three network structures. For each structure, we have also simulated the combat between the same network structures with different generating parameters. The simulations reveal that the small-world property and heterogeneity can promote winning a combat. Besides, by broadening and deepening cooperation, we have found that broader cooperation helps defeat the opposite system on grid and scale-free networks, yet hinders it on ER and Watts-Strogatz (WS) networks, while deeper cooperation can benefit to winning except on scale-free networks. These findings inform our understanding of the effects of structure and cooperation in a combat.

Hydrovoltaic technology: from mechanism to applications.

Water is a colossal reservoir of clean energy as it adsorbs thirty-five percent of solar energy reaching the Earth's surface. More than half of the adsorbed energy turns into latent heat for water evaporation, driving the water cycle of the Earth.1 Yet, only very limited energy in the water cycle is harvested by current industrial technologies. The past decade has witnessed the emergence of hydrovoltaic technology, which generates electricity from nanomaterials by direct interaction with water and enables energy harvesting from the water cycle such as from rain, waves, flows, moisture and natural evaporation. Years of efforts have been committed to improve the conversion efficiency of hydrovoltaic devices through chemical synthesis of advanced nanomaterials and innovative design of device structures. Further development of this field, however, still requires in-depth understanding of hydrovoltaic mechanisms and boosting of the electrical outputs for wider applications. Here, we present a tutorial review of different mechanisms of generating electricity from droplets, flows, natural evaporation and ambient moisture by analyzing basic interactions at various water-material interfaces. Key aspects in raising the output power of hydrovoltaic devices are then discussed in terms of material synthesis, structural design, and device optimization. We also provide an outlook on the potential applications of this technology ranging from sensors, power suppliers to multifunctional systems as well as on the scientific and technological challenges in transforming its potential into practical utility. The prospects of this emerging field are considered for future endeavor.

Microbial response behavior to powdered activated carbon in high-solids anaerobic digestion of kitchen waste: Metabolism and functional prediction analysis.

Anaerobic digestion (AD) can not only treat organic waste, but also recycle energy. However, high-solids AD of kitchen waste usually failed due to excessive acidification. In this study, the effect of activated carbon (AC) on kitchen waste AD performance was investigated under high-solids conditions (total solids contents = 15%). The results showed that efficiencies of acidogenesis and methanogenesis were promoted in presence of moderate concentration (50 g/L > AC >5 g/L), but high concentration (AC >70 g/L) weakened AD performance. Moreover, AC addition enhanced the methane production rate from 66.0 mL/g VS to 231.50 mL/g VS, i.e., up to 250.7%. High-throughput sequencing results demonstrated that the abundance of electroactive DMER64 increased from less than 1%-29.7% (20 g/L AC). As AC gradually increased，aceticlastic methanogenesis changed to hydrogenotrophic pathway. Predicted functional analysis indicated that AC can enhance abundances of energy and inorganic ion metabolism, resulting in high methane production.

Paired Oxidative and Reductive Catalysis: Breaking the Potential Barrier of Electrochemical C(sp3 )-H Alkenylation.

Due to the intrinsic inertness of alkanes, strong oxidative conditions are typically required to enable their C(sp3 )-H functionalization. Herein, a paired electrocatalysis strategy was developed by integrating oxidative catalysis with reductive catalysis in one cell without interference, in which earth-abundant iron and nickel are employed as the anodic and cathodic catalysts, respectively. This approach lowers the previously high oxidation potential required for alkane activation, enabling electrochemical alkane functionalization at the ultra-low oxidation potential of ≈0.25 V vs. Ag/AgCl under mild conditions. Structurally diverse alkenes, including challenging all-carbon tetrasubstituted olefins, can be accessed using readily available alkenyl electrophiles.

"Phoenix in Flight": an unique fruit morphology ensures wind dispersal of seeds of the phoenix tree (Firmiana simplex (L.) W. Wight).

BACKGROUND: Many seed plants produce winged diaspores that use wind to disperse their seeds. The morphology of these diaspores is directly related to the seed dispersal potential. The majority of winged diaspores have flat wings and only seeds; however, some angiosperms, such as Firmiana produce winged fruit with a different morphology, whose seed dispersal mechanisms are not yet fully understood. In this study, we observed the fruit development of F. simplex and determined the morphological characteristics of mature fruit and their effects on the flight performance of the fruit. RESULTS: We found that the pericarp of F. simplex dehisced early and continued to unfold and expand during fruit development until ripening, finally formed a spoon-shaped wing with multiple alternate seeds on each edge. The wing caused mature fruit to spin stably during descent to provide a low terminal velocity, which was correlated with the wing loading and the distribution of seeds on the pericarp. When the curvature distribution of the pericarp surface substantially changed, the aerodynamic characteristics of fruit during descent altered, resulting in the inability of the fruit to spin. CONCLUSIONS: Our results suggest that the curved shape and alternate seed distribution are necessary for the winged diaspore of F. simplex to stabilize spinning during wind dispersal. These unique morphological characteristics are related to the early cracking of fruits during development, which may be an adaptation for the wind dispersal of seeds.