DNA methylation in the mouse cochlea promotes maturation of supporting cells and contributes to the failure of hair cell regeneration.

Mammalian hair cells do not functionally regenerate in adulthood but can regenerate at embryonic and neonatal stages in mice by direct transdifferentiation of neighboring supporting cells into new hair cells. Previous work showed loss of transdifferentiation potential of supporting cells is in part due to H3K4me1 enhancer decommissioning of the hair cell gene regulatory network during the first postnatal week. However, inhibiting this decommissioning only partially preserves transdifferentiation potential. Therefore, we explored other repressive epigenetic modifications that may be responsible for this loss of plasticity. We find supporting cells progressively accumulate DNA methylation at promoters of developmentally regulated hair cell genes. Specifically, DNA methylation overlaps with binding sites of Atoh1, a key transcription factor for hair cell fate. We further show that DNA hypermethylation replaces H3K27me3-mediated repression of hair cell genes in mature supporting cells, and is accompanied by progressive loss of chromatin accessibility, suggestive of facultative heterochromatin formation. Another subset of hair cell loci is hypermethylated in supporting cells, but not in hair cells. Ten-eleven translocation (TET) enzyme-mediated demethylation of these hypermethylated sites is necessary for neonatal supporting cells to transdifferentiate into hair cells. We also observe changes in chromatin accessibility of supporting cell subtypes at the single-cell level with increasing age: Gene programs promoting sensory epithelium development loses chromatin accessibility, in favor of gene programs that promote physiological maturation and function of the cochlea. We also find chromatin accessibility is partially recovered in a chronically deafened mouse model, which holds promise for future translational efforts in hearing restoration.

SoxC transcription factors shape the epigenetic landscape to establish competence for sensory differentiation in the mammalian organ of Corti.

The auditory organ of Corti is comprised of only two major cell types-the mechanosensory hair cells and their associated supporting cells-both specified from a single pool of prosensory progenitors in the cochlear duct. Here, we show that competence to respond to Atoh1, a transcriptional master regulator necessary and sufficient for induction of mechanosensory hair cells, is established in the prosensory progenitors between E12.0 and 13.5. The transition to the competent state is rapid and is associated with extensive remodeling of the epigenetic landscape controlled by the SoxC group of transcription factors. Conditional loss of Sox4 and Sox11-the two homologous family members transiently expressed in the inner ear at the time of competence establishment-blocks the ability of prosensory progenitors to differentiate as hair cells. Mechanistically, we show that Sox4 binds to and establishes accessibility of early sensory lineage-specific regulatory elements, including ones associated with Atoh1 and its direct downstream targets. Consistent with these observations, overexpression of Sox4 or Sox11 prior to developmental establishment of competence precociously induces hair cell differentiation in the cochlear progenitors. Further, reintroducing Sox4 or Sox11 expression restores the ability of postnatal supporting cells to differentiate as hair cells in vitro and in vivo. Our findings demonstrate the pivotal role of SoxC family members as agents of epigenetic and transcriptional changes necessary for establishing competence for sensory receptor differentiation in the inner ear.

Novel 15N Metabolic Labeling-Based Large-Scale Absolute Quantitative Proteomics Method for Corynebacterium glutamicum.

With fast growth, synthetic biology powers us with the capability to produce high commercial value products in an efficient resource/energy-consuming manner. Comprehensive knowledge of the protein regulatory network of a bacterial host chassis, e.g., the actual amount of the given proteins, is the key to building cell factories for certain target hyperproduction. Many talent methods have been introduced for absolute quantitative proteomics. However, for most cases, a set of reference peptides with isotopic labeling (e.g., SIL, AQUA, QconCAT) or a set of reference proteins (e.g., commercial UPS2 kit) needs to be prepared. The higher cost hinders these methods for large sample research. In this work, we proposed a novel metabolic labeling-based absolute quantification approach (termed nMAQ). The reference Corynebacterium glutamicum strain is metabolically labeled with 15N, and a set of endogenous anchor proteins of the reference proteome is quantified by chemically synthesized light (14N) peptides. The prequantified reference proteome was then utilized as an internal standard (IS) and spiked into the target (14N) samples. SWATH-MS analysis is performed to obtain the absolute expression levels of the proteins from the target cells. The cost for nMAQ is estimated to be less than 10 dollars per sample. We have benchmarked the quantitative performance of the novel method. We believe this method will help with the deep understanding of the intrinsic regulatory mechanism of C. glutamicum during bioengineering and will promote the process of building cell factories for synthetic biology.

The Synergistic Effect of Zuogui Pill and Eldecalcitol on Improving Bone Mass and Osteogenesis in Type 2 Diabetic Osteoporosis.

Background and Objectives: The incidence of diabetic osteoporosis, an important complication of diabetes mellitus, is increasing gradually. This study investigated the combined effect of the Zuogui pill (ZGP) and eldecalcitol (ED-71), a novel vitamin D analog, on type 2 diabetic osteoporosis (T2DOP) and explored their action mechanism. Materials and Methods: Blood glucose levels were routinely monitored in db/db mice while inducing T2DOP. We used hematoxylin and eosin staining, Masson staining, micro-computed tomography, and serum biochemical analysis to evaluate changes in the bone mass and blood calcium and phosphate levels of mice. Immunohistochemical staining was performed to assess the osteoblast and osteoclast statuses. The MC3T3-E1 cell line was cultured in vitro under a high glucose concentration and induced to undergo osteogenic differentiation. Quantitative real-time polymerase chain reaction, Western blot, immunofluorescence, ALP, and alizarin red staining were carried out to detect osteogenic differentiation and PI3K-AKT signaling pathway activity. Results: ZGP and ED-71 led to a dramatic decrease in blood glucose levels and an increase in bone mass in the db/db mice. The effect was strongest when both were used together. ZGP combined with ED-71 promoted osteoblast activity and inhibited osteoclast activity in the trabecular bone region. The in vitro results revealed that ZGP and ED-71 synergistically promoted osteogenic differentiation and activated the PI3K-AKT signaling pathway. The PI3K inhibitor LY294002 or AKT inhibitor ARQ092 altered the synergistic action of both on osteogenic differentiation. Conclusions: The combined use of ZGP and ED-71 reduced blood glucose levels in diabetic mice and promoted osteogenic differentiation through the PI3K-AKT signaling pathway, resulting in improved bone mass. Our study suggests that the abovementioned combination constitutes an effective treatment for T2DOP.

Natural and human factors influencing urban particulate matter concentrations in central heating areas with long-term wearable monitoring devices.

In northern China, central heating, as an important source of urban particulate matter (UPM), causes more than half of the air pollution during the heating season and has significant spatial-temporal heterogeneity. Owing to the limitations of stationary air monitoring networks, few studies distinguish between heating/non-heating seasons and few have been conducted in urban areas. However, fixed monitoring cannot accurately capture the dynamic exposure of residents to UPM, and there is a lack of comprehensive evaluation of the factors affecting UPM. Therefore, this study used wearable Sniffer 4D equipment to monitor the concentrations of UPM (PM1, PM2.5, and PM10) in selected typical areas of Shenyang City from March 2019 to February 2020. A random forest model was combined with land use and point-of-interest data to analyze the contributions and marginal effects of multiple influences on UPM, in both heating and non-heating seasons. The results showed that in the eastern part of the study area, UPM showed completely opposite spatial distribution characteristics during the two seasons. The concentrations of UPM were higher during the heating season than during the non-heating season. The results indicated that temperature and humidity were important factors in diffusing UPM. The production and operation of boilers were important for the production of UPM. In two-dimensional landscape pattern indices, the percentage of forest and Shannon diversity index were the first and second most important factors, respectively. The three-dimensional pattern of buildings had important effects on the transport and diffusion of UPM (landscape height range >100, floor area ratio >1.3, and landscape volume density >5). Wearable devices could monitor the real situation of residents' exposure to UPM and quantify the factors influencing the spatial-temporal distribution of UPM in an ecological sense. These results provide a scientific basis for urban planning and for health risk reduction for residents.

Development of shuttle vectors for rapid prototyping of engineered Synechococcus sp. PCC7002.

Cyanobacteria are of particular interest for chemical production as they can assimilate CO2 and use solar energy to power chemical synthesis. However, unlike the model microorganism of Escherichia coli, the availability of genetic toolboxes for rapid proof-of-concept studies in cyanobacteria is generally lacking. In this study, we first characterized a set of promoters to efficiently drive gene expressions in the marine cyanobacterium Synechococcus sp. PCC7002. We identified that the endogenous cpcBA promoter represented one of the strongest promoters in PCC7002. Next, a set of shuttle vectors was constructed based on the endogenous pAQ1 plasmid to facilitate the rapid pathway assembly. Moreover, we used the shuttle vectors to modularly optimize the amorpha-4,11-diene synthesis in PCC7002. By modularly optimizing the metabolic pathway, we managed to redistribute the central metabolism toward the amorpha-4,11-diene production in PCC7002 with enhanced product titer. Taken together, the plasmid toolbox developed in this study will greatly accelerate the generation of genetically engineered PCC7002. KEY POINTS: • Promoter characterization revealed that the endogenous cpcBA promoter represented one of the strongest promoters in PCC7002 • A set of shuttle vectors with different antibiotic selection markers was constructed based on endogenous pAQ1 plasmid • By modularly optimizing the metabolic pathway, amorpha-4,11-diene production in PCC7002 was improved.

Nonlinear optical property and application of yttrium oxide in erbium-doped fiber lasers.

Yttrium oxide (Y2O3) has garnered some attention in view of its potential to be integrated into a wide range of high-strength structural components, microelectronic and optoelectronic devices. However, the nonlinear optical research of this promising material has not been implemented yet. In this paper, not only the electronic band structures of Y2O3 are theoretically calculated but also the optical nonlinearity of Y2O3 is validated by using the fiber laser as a platform. Meanwhile, the influence of sample thickness on laser performance is further explored by using Y2O3 saturable absorbers with different thickness. Results indicate that Y2O3 not only has impressive optical nonlinearity but also is beneficial to the investigation of ultrafast photons by adjusting the thickness of Y2O3. Therefore, Y2O3 can be used as a potential saturable absorber candidate for in-depth research and application.

Negative differential resistance effect induced by metal ion implantation in SiO2 film for multilevel RRAM application.

Pt/SiO2:metal nanoparticles/Pt sandwich structure is fabricated with the method of metal ion (Ag) implantation. The device exhibits multilevel storage with appropriate R off/R on ratio, good endurance and retention properties. Based on transmission electron microscopy and energy dispersive spectrometer analysis, we confirm that Pt nanoparticles are spurted into SiO2 film from Pt bottom electrode by Ag implantation; during electroforming, the local electric field can be enhanced by these Pt nanoparticles, meanwhile the Ag nanoparticles constantly migrate toward the Pt nanoparticles. The implantation induced nanoparticles act as trap sites in the resistive switching layer and play critical roles in the multilevel storage, which is evidenced by the negative differential resistance effect in the current-voltage (I-V) measurements.

Scale-up cultivation enhanced arachidonic acid accumulation by red microalgae Porphyridium purpureum.

The present study attempts to cultivate Porphyridium purpureum under different scale-up conditions for further development and commercialization of microalgae-derived PUFAs such as ARA and EPA. Different temperatures (25, 30, and 35 °C) and light intensities (70, 165, and 280 µmol/m2s) were applied to the 50 L pilot-scale cultivation of P. purpureum in ASW. The cultivation under the light intensity of 280 µmol/m2s at 35 °C obtained biomass concentration up to 9.52 g/L, total fatty acid content to 56.82 mg/g, and ARA content to 22.29 mg/g. While the maximum EPA content of 7.00 mg/g was achieved under the light intensity of 280 µmol/m2s at 25 °C and the highest ratio of UFAs to TFAs of 74.66% was also obtained in this trial. Both biomass concentration and TFAs content were improved by increasing light intensity and temperature. Moreover, the ratio of ARA to EPA was enhanced by increasing cultivation temperature under the light intensity of 280 µmol/m2s. In contrast with flask culture, the conversion of linoleic acid (C18:2) to ARA was enhanced in scale-up culture, leading to more ARA content. Phosphate limitation enhanced the synthesis of lipid and LPUFAs. Moreover, the biomass concentration and biosynthesis of palmitic acid were preferred by sufficient C (NaHCO3).

Pt/WO3/FTO memristive devices with recoverable pseudo-electroforming for time-delay switches in neuromorphic computing.

A recoverable pseudo-electroforming process was discovered in Pt/WO3/FTO devices. Unlike conventional electroforming, which is usually destructive, pseudo-electroforming can be recovered when the electrical stimulation is removed. Furthermore, the time-dependent recovery process can be tuned by diverse voltage pulses applied in pseudo-electroforming; therefore, the device can be used as a time-delay switch in memristor-based neuromorphic networks. This "volatile" electroforming process can be attributed to the high oxygen vacancy concentration in the fluorine-doped tin oxide (FTO) bottom electrode, which acts as a non-blocking electrode in the resistive switching.

[Efficacy of tongfu mixture for treating post-ERCP pancreatitis: a clinical study].

OBJECTIVE: To observe the clinical efficacy of Tongfu Mixture (TM) for post-ERCP pancreatitis (PEP). METHODS: Totally 54 PEP patients were randomly assigned to the control group (treated by routine therapy, 26 cases) and the TM treatment group (treated by TM, 28 cases). Clinical indices including the alleviation time of abdominal pain/distention, gastrointestinal function recovery time, and the post-surgical length of stay were observed. Blood amylase (AMY), C-reactive protein (CRP), plasma endotoxin (PLS), TNF-alpha, and IL-6 were detected before surgery, 12 h, 48 h, and 96 h after surgery. RESULTS: The alleviation time of abdominal pain/distention, the gastrointestinal function recovery time, and the post-surgical length of stay were obviously shorter in the TM treatment group than those in the control group (P < 0.05). The recovery of AMY and CRP were better in the TM treatment group than in the control group at post-operative 48 h and 96 h (P < 0.05). The levels of LPS, TNF-alpha, and IL-6 were lower in the TM group than in the control group at post-operative 96 h (P < 0.05). CONCLUSION: TM showed better clinical efficacy and could significantly decrease the post-surgical length of stay. post-ERCP pancreatitis; integrative medicine; Tongfu Mixture

Stochastic neuro-fuzzy system implemented in memristor crossbar arrays.

Neuro-symbolic artificial intelligence has garnered considerable attention amid increasing industry demands for high-performance neural networks that are interpretable and adaptable to previously unknown problem domains with minimal reconfiguration. However, implementing neuro-symbolic hardware is challenging due to the complexity in symbolic knowledge representation and calculation. We experimentally demonstrated a memristor-based neuro-fuzzy hardware based on TiN/TaOx/HfOx/TiN chips that is superior to its silicon-based counterpart in terms of throughput and energy efficiency by using array topological structure for knowledge representation and physical laws for computing. Intrinsic memristor variability is fully exploited to increase robustness in knowledge representation. A hybrid in situ training strategy is proposed for error minimizing in training. The hardware adapts easier to a previously unknown environment, achieving ~6.6 times faster convergence and ~6 times lower error than deep learning. The hardware energy efficiency is over two orders of magnitude greater than field-programmable gate arrays. This research greatly extends the capability of memristor-based neuromorphic computing systems in artificial intelligence.

A memristive all-inclusive hypernetwork for parallel analog deployment of full search space architectures.

In recent years, there has been a significant advancement in memristor-based neural networks, positioning them as a pivotal processing-in-memory deployment architecture for a wide array of deep learning applications. Within this realm of progress, the emerging parallel analog memristive platforms are prominent for their ability to generate multiple feature maps in a single processing cycle. However, a notable limitation is that they are specifically tailored for neural networks with fixed structures. As an orthogonal direction, recent research reveals that neural architecture should be specialized for tasks and deployment platforms. Building upon this, the neural architecture search (NAS) methods effectively explore promising architectures in a large design space. However, these NAS-based architectures are generally heterogeneous and diversified, making it challenging for deployment on current single-prototype, customized, parallel analog memristive hardware circuits. Therefore, investigating memristive analog deployment that overrides the full search space is a promising and challenging problem. Inspired by this, and beginning with the DARTS search space, we study the memristive hardware design of primitive operations and propose the memristive all-inclusive hypernetwork that covers 2×1025 network architectures. Our computational simulation results on 3 representative architectures (DARTS-V1, DARTS-V2, PDARTS) show that our memristive all-inclusive hypernetwork achieves promising results on the CIFAR10 dataset (89.2% of PDARTS with 8-bit quantization precision), and is compatible with all architectures in the DARTS full-space. The hardware performance simulation indicates that the memristive all-inclusive hypernetwork costs slightly more resource consumption (nearly the same in power, 22%∼25% increase in Latency, 1.5× in Area) relative to the individual deployment, which is reasonable and may reach a tolerable trade-off deployment scheme for industrial scenarios.

ED-71 Ameliorates Bone Loss in Type 2 Diabetes Mellitus by Enhancing Osteogenesis Through Upregulation of the Circadian Rhythm Coregulator BMAL1.

Purpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms. Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3ß signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels. Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3ß activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3ß inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression. Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3ß signaling pathway is involved in the regulation of BMAL1.

Firing feature-driven neural circuits with scalable memristive neurons for robotic obstacle avoidance.

Neural circuits with specific structures and diverse neuronal firing features are the foundation for supporting intelligent tasks in biology and are regarded as the driver for catalyzing next-generation artificial intelligence. Emulating neural circuits in hardware underpins engineering highly efficient neuromorphic chips, however, implementing a firing features-driven functional neural circuit is still an open question. In this work, inspired by avoidance neural circuits of crickets, we construct a spiking feature-driven sensorimotor control neural circuit consisting of three memristive Hodgkin-Huxley neurons. The ascending neurons exhibit mixed tonic spiking and bursting features, which are used for encoding sensing input. Additionally, we innovatively introduce a selective communication scheme in biology to decode mixed firing features using two descending neurons. We proceed to integrate such a neural circuit with a robot for avoidance control and achieve lower latency than conventional platforms. These results provide a foundation for implementing real brain-like systems driven by firing features with memristive neurons and put constructing high-order intelligent machines on the agenda.

Reconstruction the feedback regulation of amino acid metabolism to develop a non-auxotrophic L-threonine producing Corynebacterium glutamicum.

L-Threonine is an important feed additive with the third largest market size among the amino acids produced by microbial fermentation. The GRAS (generally regarded as safe) industrial workhorse Corynebacterium glutamicum is an attractive chassis for L-threonine production. However, the present L-threonine production in C. glutamicum cannot meet the requirement of industrialization due to the relatively low production level of L-threonine and the accumulation of large amounts of by-products (such as L-lysine, L-isoleucine, and glycine). Herein, to enhance the L-threonine biosynthesis in C. glutamicum, releasing the aspartate kinase (LysC) and homoserine dehydrogenase (Hom) from feedback inhibition by L-lysine and L-threonine, respectively, and overexpressing four flux-control genes were performed. Next, to reduce the formation of by-products L-lysine and L-isoleucine without the cause of an auxotrophic phenotype, the feedback regulation of dihydrodipicolinate synthase (DapA) and threonine dehydratase (IlvA) was strengthened by replacing the native enzymes with heterologous analogues with more sensitive feedback inhibition by L-lysine and L-isoleucine, respectively. The resulting strain maintained the capability of synthesizing enough amounts of L-lysine and L-isoleucine for cell biomass formation but exhibited almost no extracellular accumulation of these two amino acids. To further enhance L-threonine production and reduce the by-product glycine, L-threonine exporter and homoserine kinase were overexpressed. Finally, the rationally engineered non-auxotrophic strain ZcglT9 produced 67.63 g/L (17.2% higher) L-threonine with a productivity of 1.20 g/L/h (108.0% higher) in fed-batch fermentation, along with significantly reduced by-product accumulation, representing the record for L-threonine production in C. glutamicum. In this study, we developed a strategy of reconstructing the feedback regulation of amino acid metabolism and successfully applied this strategy to de novo construct a non-auxotrophic L-threonine producing C. glutamicum. The main end by-products including L-lysine, L-isoleucine, and glycine were almost eliminated in fed-batch fermentation of the engineered C. glutamicum strain. This strategy can also be used for engineering producing strains for other amino acids and derivatives.

Effect of Annular Laser Metal Deposition (ALMD) Process Parameters on Track Geometry and Thermal History on Ti6Al4V Alloy Clad.

Annular laser metal deposition (ALMD) is a rising technology that fabricates near-net-shaped components. In this research, a single factor experiment with 18 groups was designed to study the influence of process parameters on the geometric characteristics (bead width, bead height, fusion depth, and fusion line) and thermal history of Ti6Al4V tracks. The results show that discontinuous and uneven tracks with pores or large-sized incomplete fusion defects were observed when the laser power was less than 800 W or the defocus distance was -5 mm. The laser power had a positive effect on the bead width and height, while the scanning speed had the opposite effect. The shape of the fusion line varied at different defocus distances, and the straight fusion line could be obtained with the appropriate process parameters. The scanning speed was the parameter that had the greatest effect on the molten pool lifetime and solidification time as well as the cooling rate. In addition, the microstructure and microhardness of the thin wall sample were also studied. Many clusters with various sizes in different zones were distributed within the crystal. The microhardness ranged from 330 HV to 370 HV.

Design and Numerical Analysis of an Inside-Beam Powder Feeding Nozzle for Wide-Band Laser Cladding.

Wide-band laser cladding technology has emerged as a solution to the limitations of traditional cladding techniques, which are small single-path dimensions and low processing efficiency. The existing wide-band cladding technology presents challenges related to the high precision required for the laser-powder coupling and the significant powder-divergence phenomenon. Based on the inside-beam powder-feeding technology, a wide-band powder-feeding nozzle was designed using the multi-channel powder flow shaping method. The size of the powder spot obtained at the processing location can reach 40 mm × 3 mm. A computational fluid dynamics analysis using the FLUENT software was conducted to investigate the impact of the nozzle's structural parameters on the powder distribution. It was determined that the optimal configuration was achieved when the powder-feeding channel was 8, and the transverse and longitudinal dimensions for the collimating gas outlet were 0.5 mm and 1 mm, respectively. Among the process parameters, an increase in the carrier gas flow rate was found to effectively enhance the stability of powder transportation. However, the powder feed rate had minimal impact on the powder concentration distribution, and the collimating gas flow rate appeared to have a minimal effect on the divergence angle of the powder stream. Wide-band laser cladding experiments were conducted using the designed powder-feeding nozzle, and a single-path cladding with a width of 39.96 mm was finally obtained.

Lineage-specific symbionts mediate differential coral responses to thermal stress.

BACKGROUND: Ocean warming is a leading cause of increasing episodes of coral bleaching, the dissociation between coral hosts and their dinoflagellate algal symbionts in the family Symbiodiniaceae. While the diversity and flexibility of Symbiodiniaceae is presumably responsible for variations in coral response to physical stressors such as elevated temperature, there is little data directly comparing physiological performance that accounts for symbiont identity associated with the same coral host species. Here, using Pocillopora damicornis harboring genotypically distinct Symbiodiniaceae strains, we examined the physiological responses of the coral holobiont and the dynamics of symbiont community change under thermal stress in a laboratory-controlled experiment. RESULTS: We found that P. damicornis dominated with symbionts of metahaplotype D1-D4-D6 in the genus Durusdinium (i.e., PdD holobiont) was more robust to thermal stress than its counterpart with symbionts of metahaplotype C42-C1-C1b-C1c in the genus Cladocopium (i.e., PdC holobiont). Under ambient temperature, however, the thermally sensitive Cladocopium spp. exhibited higher photosynthetic efficiency and translocated more fixed carbon to the host, likely facilitating faster coral growth and calcification. Moreover, we observed a thermally induced increase in Durusdinium proportion in the PdC holobiont; however, this "symbiont shuffling" in the background was overwhelmed by the overall Cladocopium dominance, which coincided with faster coral bleaching and reduced calcification. CONCLUSIONS: These findings support that lineage-specific symbiont dominance is a driver of distinct coral responses to thermal stress. In addition, we found that "symbiont shuffling" may begin with stress-forced, subtle changes in the rare biosphere to eventually trade off growth for increased resilience. Furthermore, the flexibility in corals' association with thermally tolerant symbiont lineages to adapt or acclimatize to future warming oceans should be viewed with conservative optimism as the current rate of environmental changes may outpace the evolutionary capabilities of corals. Video Abstract.