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This single-arm, multicenter, phase 2 trial (NCT04106180) investigated the triple combination of sintilimab (anti-PD1 antibody), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic non-small cell lung cancer (NSCLC). With a median follow-up of 32.1 months, 18 (36.7%, 90% CI 25.3%-49.5%) of the 49 evaluable patients had an objective response, meeting the primary endpoint. Secondary endpoints included out-of-field (abscopal) response rate (ASR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ASR was 30.6% (95% CI 18.3%-45.4%). The median PFS and OS were 5.9 (95% CI 2.5-9.3) and 18.4 (95% CI 9.7-27.1) months, respectively. Any grade and grade 3 TRAEs occurred in 44 (86.3%) and 6 (11.8%) patients, without grade 4-5 TRAEs. Moreover, in pre-specified biomarker analyses, SBRT-induced increase of follicular helper T cells (Tfh) in unirradiated tumor lesions and patient's blood, as well as of circulating IL-21 levels, was found associated with improved prognosis. Taken together, the triple combination therapy was well tolerated with promising efficacy and Tfh may play a critical role in SBRT-triggered anti-tumor immunity in metastatic NSCLC., (© 2024. The Author(s).)

Viruses as the prevailing biological entities are poorly understood in underground realms. Here, we establish the first metagenomic Groundwater Virome Catalogue (GWVC) comprising 280,420 viral species ( ≥ 5 kb) detected from 607 monitored wells in seven geo-environmental zones throughout China. In expanding ~10-fold the global portfolio of known groundwater viruses, we uncover over 99% novel viruses and about 95% novel viral clusters. By linking viruses to hosts from 119 prokaryotic phyla, we double the number of microbial phyla known to be virus-infected in groundwater. As keystone ultrasmall symbionts in aquifers, CPR bacteria and DPANN archaea are susceptible to virulent viruses. Certain complete CPR viruses even likely infect non-CPR bacteria, while partial CPR/DPANN viruses harbor cell-surface modification genes that assist symbiont cell adhesion to free-living microbes. This study reveals the unknown viral world and auxiliary metabolism associated with methane, nitrogen, sulfur, and phosphorus cycling in groundwater, and highlights the importance of subsurface virosphere in viral ecology., (© 2024. The Author(s).)

C2'-halogenation has been recognized as an essential modification to enhance the drug-like properties of nucleotide analogs. The direct C2'-halogenation of the nucleotide 2'-deoxyadenosine-5'-monophosphate (dAMP) has recently been achieved using the Fe(II)/α-ketoglutarate-dependent nucleotide halogenase AdaV. However, the limited substrate scope of this enzyme hampers its broader applications. In this study, we report two halogenases capable of halogenating 2'-deoxyguanosine monophosphate (dGMP), thereby expanding the family of nucleotide halogenases. Computational studies reveal that nucleotide specificity is regulated by the binding pose of the phosphate group. Based on these findings, we successfully engineered the substrate specificity of these halogenases by mutating second-sphere residues. This work expands the toolbox of nucleotide halogenases and provides insights into the regulation mechanism of nucleotide specificity., (© 2024. The Author(s).)

Empathy enables understanding and sharing of others' feelings. Human neuroimaging studies have identified critical brain regions supporting empathy for pain, including the anterior insula (AI), anterior cingulate (ACC), amygdala, and inferior frontal gyrus (IFG). However, to date, the precise spatio-temporal profiles of empathic neural responses and inter-regional communications remain elusive. Here, using intracranial electroencephalography, we investigated electrophysiological signatures of vicarious pain perception. Others' pain perception induced early increases in high-gamma activity in IFG, beta power increases in ACC, but decreased beta power in AI and amygdala. Vicarious pain perception also altered the beta-band-coordinated coupling between ACC, AI, and amygdala, as well as increased modulation of IFG high-gamma amplitudes by beta phases of amygdala/AI/ACC. We identified a necessary combination of neural features for decoding vicarious pain perception. These spatio-temporally specific regional activities and inter-regional interactions within the empathy network suggest a neurodynamic model of human pain empathy., (© 2024. The Author(s).)

Oxidative stress-induced lipid accumulation is mediated by lipid droplets (LDs) homeostasis, which sequester vulnerable unsaturated triglycerides into LDs to prevent further peroxidation. Here we identify the upregulation of lipopolysaccharide-binding protein (LBP) and its trafficking through LDs as a mechanism for modulating LD homeostasis in response to oxidative stress. Our results suggest that LBP induces lipid accumulation by controlling lipid-redox homeostasis through its lipid-capture activity, sorting unsaturated triglycerides into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated triglycerides accumulation by phospholipid/triglycerides competition and Peroxiredoxin 4, a redox state sensor of LBP that regulates the shuttle of LBP from LDs. Furthermore, chronic stress upregulates LBP expression, leading to insulin resistance and obesity. Our findings contribute to the understanding of the role of LBP in regulating LD homeostasis and against cellular peroxidative injury. These insights could inform the development of redox-based therapies for alleviating oxidative stress-induced metabolic dysfunction., (© 2024. The Author(s).)

Metagenomic binning is an essential technique for genome-resolved characterization of uncultured microorganisms in various ecosystems but hampered by the low efficiency of binning tools in adequately recovering metagenome-assembled genomes (MAGs). Here, we introduce BASALT (Binning Across a Series of Assemblies Toolkit) for binning and refinement of short- and long-read sequencing data. BASALT employs multiple binners with multiple thresholds to produce initial bins, then utilizes neural networks to identify core sequences to remove redundant bins and refine non-redundant bins. Using the same assemblies generated from Critical Assessment of Metagenome Interpretation (CAMI) datasets, BASALT produces up to twice as many MAGs as VAMB, DASTool, or metaWRAP. Processing assemblies from a lake sediment dataset, BASALT produces ~30% more MAGs than metaWRAP, including 21 unique class-level prokaryotic lineages. Functional annotations reveal that BASALT can retrieve 47.6% more non-redundant opening-reading frames than metaWRAP. These results highlight the robust handling of metagenomic sequencing data of BASALT., (© 2024. The Author(s).)

Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation., (© 2024. The Author(s).)

The regulation of heterogeneous material properties to enhance the peroxymonosulfate (PMS) activation to degrade emerging organic pollutants remains a challenge. To solve this problem, we synthesize S-scheme heterojunction PBA/MoS 2 @chitosan hydrogel to achieve photoexcitation synergistic PMS activation. The constructed heterojunction photoexcited carriers undergo redox conversion with PMS through S-scheme transfer pathway driven by the directional interface electric field. Multiple synergistic pathways greatly enhance the reactive oxygen species generation, leading to a significant increase in doxycycline degradation rate. Meanwhile, the 3D polymer chain spatial structure of chitosan hydrogel is conducive to rapid PMS capture and electron transport in advanced oxidation process, reducing the use of transition metal activator and limiting the leaching of metal ions. There is reason to believe that the synergistic activation of PMS by S-scheme heterojunction regulated by photoexcitation will provide a new perspective for future material design and research on enhancing heterologous catalysis oxidation process., (© 2023. Springer Nature Limited.)

We introduce a new paradigm for generating high-purity vortex beams with metasurfaces. By applying optical neural networks to a system of cascaded phase-only metasurfaces, we demonstrate the efficient generation of high-quality Laguerre-Gaussian (LG) vortex modes. Our approach is based on two metasurfaces where one metasurface redistributes the intensity profile of light in accord with Rayleigh-Sommerfeld diffraction rules, and then the second metasurface matches the required phases for the vortex beams. Consequently, we generate high-purity LG p,l optical modes with record-high Laguerre polynomial orders p = 10 and l = 200, and with the purity in p, l and relative conversion efficiency as 96.71%, 85.47%, and 70.48%, respectively. Our engineered cascaded metasurfaces suppress greatly the backward reflection with a ratio exceeding -17 dB. Such higher-order optical vortices with multiple orthogonal states can revolutionize next-generation optical information processing., (© 2023. Springer Nature Limited.)

The sole situation of semi-crystalline structure induced single performance remarkably limits the green cryogels in the application of soft devices due to uncontrolled freezing field. Here, a facile strategy for achieving multifunctionality of cryogels is proposed using total amorphization of polymer. Through precisely lowering the freezing point of precursor solutions with an antifreezing salt, the suppressed growth of ice is achieved, creating an unusually weak and homogenous aggregation of polymer chains upon freezing, thereby realizing the tunable amorphization of polymer and the coexistence of free and hydrogen bonding hydroxyl groups. Such multi-scale microstructures trigger the integrated properties of tissue-like ultrasoftness (Young's modulus <10 kPa) yet stretchability, high transparency (~92%), self-adhesion, and instantaneous self-healing (<0.3 s) for cryogels, along with superior ionic-conductivity, antifreezing (-58 °C) and water-retention abilities, pushing the development of skin-like cryogel electronics. These concepts open an attractive branch for cryogels that adopt regulated crystallization behavior for on-demand functionalities., (© 2023. Springer Nature Limited.)

Solar-driven photosynthesis is a sustainable process for the production of hydrogen peroxide, the efficiency of which is plagued by side reactions. Metal-free covalent organic frameworks (COFs) that can form suitable intermediates and inhibit side reactions show great promise to photo-synthesize H 2 O 2 . However, the insufficient formation and separation/transfer of photogenerated charges in such materials restricts the efficiency of H 2 O 2 production. Herein, we provide a strategy for the design of donor-acceptor COFs to greatly boost H 2 O 2 photosynthesis. We demonstrate that the optimal intramolecular polarity of COFs, achieved by using suitable amounts of phenyl groups as electron donors, can maximize the free charge generation, which leads to high H 2 O 2 yield rates (605 μmol g -1 h -1 ) from water, oxygen and visible light without sacrificial agents. Combining in-situ characterization with computational calculations, we describe how the triazine N-sites with optimal N 2p states play a crucial role in H 2 O activation and selective oxidation into H 2 O 2 . We further experimentally demonstrate that H 2 O 2 can be efficiently produced in tap, river or sea water with natural sunlight and air for water decontamination., (© 2023. The Author(s).)

Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy., (© 2023. The Author(s).)

A key feature in intestinal immunity is the dynamic intestinal barrier, which separates the host from resident and pathogenic microbiota through a mucus gel impregnated with antimicrobial peptides. Using a forward genetic screen, we have found a mutation in Tvp23b, which conferred susceptibility to chemically induced and infectious colitis. Trans-Golgi apparatus membrane protein TVP23 homolog B (TVP23B) is a transmembrane protein conserved from yeast to humans. We found that TVP23B controls the homeostasis of Paneth cells and function of goblet cells, leading to a decrease in antimicrobial peptides and more penetrable mucus layer. TVP23B binds with another Golgi protein, YIPF6, which is similarly critical for intestinal homeostasis. The Golgi proteomes of YIPF6 and TVP23B-deficient colonocytes have a common deficiency of several critical glycosylation enzymes. TVP23B is necessary for the formation of the sterile mucin layer of the intestine and its absence disturbs the balance of host and microbe in vivo., (© 2023. The Author(s).)

The poor stability of Ru-based acidic oxygen evolution (OER) electrocatalysts has greatly hampered their application in polymer electrolyte membrane electrolyzers (PEMWEs). Traditional understanding of performance degradation centered on influence of bias fails in describing the stability trend, calling for deep dive into the essential origin of inactivation. Here we uncover the decisive role of reaction route (including catalytic mechanism and intermediates binding strength) on operational stability of Ru-based catalysts. Using MRuO x (M = Ce 4+ , Sn 4+ , Ru 4+ , Cr 4+ ) solid solution as structure model, we find the reaction route, thereby stability, can be customized by controlling the Ru charge. The screened SnRuO x thus exhibits orders of magnitude lifespan extension. A scalable PEMWE single cell using SnRuO x anode conveys an ever-smallest degradation rate of 53 μV h -1 during a 1300 h operation at 1 A cm -2 ., (© 2023. The Author(s).)

More than two billion people worldwide have suffered thyroid disorders from either iodine deficiency or excess. By creating the national map of groundwater iodine throughout China, we reveal the spatial responses of diverse health risks to iodine in continental groundwater. Greater non-carcinogenic risks relevant to lower iodine more likely occur in the areas of higher altitude, while those associated with high groundwater iodine are concentrated in the areas suffered from transgressions enhanced by land over-use and intensive anthropogenic overexploitation. The potential roles of groundwater iodine species are also explored: iodide might be associated with subclinical hypothyroidism particularly in higher iodine regions, whereas iodate impacts on thyroid risks in presence of universal salt iodization exhibit high uncertainties in lower iodine regions. This implies that accurate iodine supply depending on spatial heterogeneity and dietary iodine structure optimization are highly needed to mitigate thyroid risks in iodine-deficient and -excess areas globally., (© 2022. The Author(s).)

Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16 INK4A is deficient in the majority of HER2+ BCBMs. p16 INK4A -deficiency as measured by protein immunohistochemistry predicted response to combined tucatinib and abemaciclib in orthotopic patient-derived xenografts (PDXs) of HER2 + BCBMs. Our findings establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2 + BCBM., (© 2022. The Author(s).)

Streams and rivers emit substantial amounts of nitrous oxide (N 2 O) and are therefore an essential component of global nitrogen (N) cycle. Permafrost soils store a large reservoir of dormant N that, upon thawing, can enter fluvial networks and partly degrade to N 2 O, yet the role of waterborne release of N 2 O in permafrost regions is unclear. Here we report N 2 O concentrations and fluxes during different seasons between 2016 and 2018 in four watersheds on the East Qinghai-Tibet Plateau. Thawing permafrost soils are known to emit N 2 O at a high rate, but permafrost rivers draining the East Qinghai-Tibet Plateau behave as unexpectedly minor sources of atmospheric N 2 O. Such low N 2 O fluxes are associated with low riverine dissolved inorganic N (DIN) after terrestrial plant uptake, unfavorable conditions for N 2 O generation via denitrification, and low N 2 O yield due to a small ratio of nitrite reductase: nitrous oxide reductase in these rivers. We estimate fluvial N 2 O emissions of 0.432 - 0.463 Gg N 2 O-N yr -1 from permafrost landscapes on the entire Qinghai-Tibet Plateau, which is marginal (~0.15%) given their areal contribution to global streams and rivers (0.7%). However, we suggest that these permafrost-affected rivers can shift from minor sources to strong emitters in the warmer future, likely giving rise to the permafrost non-carbon feedback that intensifies warming., (© 2022. The Author(s).)

Solute-induced river syndromes have grown in intensity in recent years. Here we investigate seven such river syndromes (salinization, mineralization, desalinization, acidification, alkalization, hardening, and softening) associated with global trends in major solutes (Ca 2+ , Mg 2+ , Na + , K + , SO 4 2- , Cl - , HCO 3 - ) and dissolved silica in the world's large rivers (basin areas ≥ 1000 km 2 ). A comprehensive dataset from 600 gauge stations in 149 large rivers reveals nine binary patterns of co-varying trends in runoff and solute concentration. Solute-induced river syndromes are associated with remarkable increases in total dissolved solids (68%), chloride (81%), sodium (86%) and sulfate (142%) fluxes from rivers to oceans worldwide. The syndromes are most prevalent in temperate regions (30~50°N and 30~40°S based on the available data) where severe rock weathering and active human interferences such as urbanization and agricultural irrigation are concentrated. This study highlights the urgency to protect river health from extreme changes in solute contents., (© 2021. The Author(s).)

Learned fear and safety are associated with distinct oscillatory states in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). To determine if and how these network states support the retrieval of competing memories, we mimicked endogenous oscillatory activity through optogenetic stimulation of parvalbumin-expressing interneurons in mice during retrieval of contextual fear and extinction memories. We found that exogenously induced 4 Hz and 8 Hz oscillatory activity in the BLA exerts bi-directional control over conditioned freezing behavior in an experience- and context-specific manner, and that these oscillations have an experience-dependent ability to recruit distinct functional neuronal ensembles. At the network level we demonstrate, via simultaneous manipulation of BLA and mPFC, that experience-dependent 4 Hz resonance across BLA-mPFC circuitry supports post-extinction fear memory retrieval. Our findings reveal that post-extinction fear memory retrieval is supported by local and interregional experience-dependent resonance, and suggest novel approaches for interrogation and therapeutic manipulation of acquired fear circuitry.

Lipid transport and ATP synthesis are critical for the progression of non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) forms complexes with NAFLD-relevant transcripts. It associates with intron 24 of Apob pre-mRNA, with the 3'UTR of Uqcrb, and with the 5'UTR of Ndufb6 mRNA, thereby regulating the splicing of Apob mRNA and the translation of UQCRB and NDUFB6. Hepatocyte-specific HuR knockout reduces the expression of APOB, UQCRB, and NDUFB6 in mice, reducing liver lipid transport and ATP synthesis, and aggravating high-fat diet (HFD)-induced NAFLD. Adenovirus-mediated re-expression of HuR in hepatocytes rescues the effect of HuR knockout in HFD-induced NAFLD. Our findings highlight a critical role of HuR in regulating lipid transport and ATP synthesis.

Sustainable inland waterways should meet the needs of navigation without compromising the health of riverine ecosystems. Here we propose a hierarchical model to describe sustainable development of the Golden Inland Waterways (GIWs) which are characterized by great bearing capacity and transport need. Based on datasets from 66 large rivers (basin area > 100,000 km 2 ) worldwide, we identify 34 GIWs, mostly distributed in Asia, Europe, North America, and South America, typically following a three-stage development path from the initial, through to the developing and on to the developed stage. For most GIWs, the exploitation ratio, defined as the ratio of actual to idealized bearing capacity, should be less than 80% due to ecological considerations. Combined with the indices of regional development, GIWs exploitation, and riverine ecosystem, we reveal the global diversity and evolution of GIWs' sustainability from 2015 to 2050, which highlights the importance of river-specific strategies for waterway exploitation worldwide.

The need for high-energy batteries has driven the development of binder-free electrode architectures. However, the weak bonding between the electrode particles and the current collector cannot withstand the severe volume change of active materials upon battery cycling, which largely limit the large-scale application of such electrodes. Using tin nanoarrays electrochemically deposited on copper substrate as an example, here we demonstrate a strategy of strengthening the connection between electrode and current collector by thermally alloying tin and copper at their interface. The locally formed tin-copper alloys are electron-conductive and meanwhile electrochemically inactive, working as an ideal "glue" robustly bridging tin and copper to survive harsh cycling conditions in sodium ion batteries. The working mechanism of the alloy "glue" is further characterized through a combination of electrochemical impedance spectroscopy, atomic structural analysis and in situ X-ray diffraction, presenting itself as a promising strategy for engineering binder-free electrode with endurable performance.

The industrial synthesis of ammonia (NH 3 ) using iron-based Haber-Bosch catalyst requires harsh reaction conditions. Developing advanced catalysts that perform well at mild conditions (<400 °C, <2 MPa) for industrial application is a long-term goal. Here we report a Co-N-C catalyst with high NH 3 synthesis rate that simultaneously exhibits dynamic and steady-state active sites. Our studies demonstrate that the atomically dispersed cobalt weakly coordinated with pyridine N reacts with surface H 2 to produce NH 3 via a chemical looping pathway. Pyrrolic N serves as an anchor to stabilize the single cobalt atom in the form of Co 1 -N 3.5 that facilitates N 2 adsorption and step-by-step hydrogenation of N 2 to *HNNH, *NH-NH 3 and *NH 2 -NH 4 . Finally, NH 3 is facilely generated via the breaking of the *NH 2 -NH 4 bond. With the co-existence of dynamic and steady-state single atom active sites, the Co-N-C catalyst circumvents the bottleneck of N 2 dissociation, making the synthesis of NH 3 at mild conditions possible.

Proxy-based reconstructions and modeling of Holocene spatiotemporal precipitation patterns for China and Mongolia have hitherto yielded contradictory results indicating that the basic mechanisms behind the East Asian Summer Monsoon and its interaction with the westerly jet stream remain poorly understood. We present quantitative reconstructions of Holocene precipitation derived from 101 fossil pollen records and analyse them with the help of a minimal empirical model. We show that the westerly jet-stream axis shifted gradually southward and became less tilted since the middle Holocene. This was tracked by the summer monsoon rain band resulting in an early-Holocene precipitation maximum over most of western China, a mid-Holocene maximum in north-central and northeastern China, and a late-Holocene maximum in southeastern China. Our results suggest that a correct simulation of the orientation and position of the westerly jet stream is crucial to the reliable prediction of precipitation patterns in China and Mongolia.

The tumour suppressor PTEN, which antagonizes PI3K signalling, is frequently inactivated in haematologic malignancies. In mice, deletion of PTEN in haematopoietic stem cells (HSCs) causes perturbed haematopoiesis, myeloproliferative neoplasia (MPN) and leukaemia. Although the roles of the PI3K isoforms have been studied in PTEN-deficient tumours, their individual roles in PTEN-deficient HSCs are unknown. Here we show that when we delete PTEN in HSCs using the Mx1-Cre system, p110β ablation prevents MPN, improves HSC function and suppresses leukaemia initiation. Pharmacologic inhibition of p110β in PTEN-deficient mice recapitulates these genetic findings, but suggests involvement of both Akt-dependent and -independent pathways. Further investigation reveals that a p110β-Rac signalling loop plays a critical role in PTEN-deficient HSCs. Together, these data suggest that myeloid neoplasia driven by PTEN loss is dependent on p110β via p110β-Rac-positive-feedback loop, and that disruption of this loop may offer a new and effective therapeutic strategy for PTEN-deficient leukaemia.

Motor coordination is broadly divided into gross and fine motor control, both of which depend on proprioceptive organs. However, the channels that function specifically in fine motor control are unknown. Here we show that mutations in trpγ disrupt fine motor control while leaving gross motor proficiency intact. The mutants are unable to coordinate precise leg movements during walking, and are ineffective in traversing large gaps due to an inability in making subtle postural adaptations that are requisite for this task. TRPγ is expressed in proprioceptive organs, and is required in both neurons and glia for gap crossing. We expressed TRPγ in vitro, and found that its activity is promoted by membrane stretch. A mutation eliminating the Na(+)/Ca(2+) exchanger suppresses the gap-crossing phenotype of trpγ flies. Our findings indicate that TRPγ contributes to fine motor control through mechanical activation in proprioceptive organs, thereby promoting Ca(2+) influx, which is required for function.