A high-fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN-MDSC differentiation.

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.

Abnormal condensation of water vapour at ambient temperature.

The homogeneous condensation of water vapor at ambient temperature is studied using molecular dynamics simulation. We reveal that there is a droplet size at the nanoscale where water droplets can be stabilized in the condensation process. Our simulations show that the growth of water droplets is dominated by collision and coagulation between small water droplets after nucleation. This process is found to be accompanied by exceptionally fast evaporation such that droplet growth is balanced by evaporation when water droplets grow to a critical size, approximately 12.5 Å in radius, reaching a stable size distribution. The extremely high evaporation rate is attributed to the curvature dependence of surface tension. Surface tension shows a significant decrease with decreasing droplet size below 20 Å, which causes the total free energy of nanoscaled water droplets to rise after collision and coagulation. Consequently, water droplets have to shrink via fast evaporation. The curvature dependence of surface tension is related to the dielectric ordering of water molecules near the surface of water droplets. Owing to fast evaporation, secondary condensation occurs, and many small water clusters form, ultimately exhibiting a bimodal distribution of water-droplet size.

Research progress on carotenoid production by Rhodosporidium toruloides.

Carotenoids are natural lipophilic pigments, which have been proven to provide significant health benefits to humans, relying on their capacity to efficiently scavenge singlet oxygen and peroxyl radicals as antioxidants. Strains belonging to the genus Rhodosporidium represent a heterogeneous group known for a number of phenotypic traits including accumulation of carotenoids and lipids and tolerance to heavy metals and oxidative stress. As a representative of these yeasts, Rhodosporidium toruloides naturally produces carotenoids with high antioxidant activity and grows on a wide variety of carbon sources. As a result, R. toruloides is a promising host for the efficient production of more value-added lipophilic compound carotenoids, e.g., torulene and torularhodin. This review provides a comprehensive summary of the research progress on carotenoid biosynthesis in R. toruloides, focusing on the understanding of biosynthetic pathways and the regulation of key enzymes and genes involved in the process. Moreover, the relationship between the accumulation of carotenoids and lipid biosynthesis, as well as the stress from diverse abiotic factors, has also been discussed for the first time. Finally, several feasible strategies have been proposed to promote carotenoid production by R. toruloides. It is possible that R. toruloides may become a critical strain in the production of carotenoids or high-value terpenoids by genetic technologies and optimal fermentation processes. KEY POINTS: • Biosynthetic pathway and its regulation of carotenoids in Rhodosporidium toruloides were concluded • Stimulation of abiotic factors for carotenoid biosynthesis in R. toruloides was summarized • Feasible strategies for increasing carotenoid production by R. toruloides were proposed.

Control of thermodynamic liquid-liquid phase transition in a fragility-tunable glassy model.

We propose a distinguishable-particle glassy model suitable for the molecular dynamics simulation of structural glasses. This model can sensitively tune the kinetic fragility of supercooled liquids in a wide range by simply changing the distribution of particle interactions. In the model liquid, we observe the occurrence of thermodynamic liquid-liquid phase transitions above glass transition. The phase transition is facilitated by lowering fragility. Prior to the liquid-liquid phase transition, our simulations verify the existence of a constant-volume heat capacity maximum varying with fragility. We reveal the characteristics of the equilibrium potential energy landscape in liquids with different fragility. Within the Gaussian excitation model, the liquid-liquid transition as well as the response to fragility is reasonably interpreted in configuration space.

New constraints on Ti diffusion in quartz and the priming of silicic volcanic eruptions.

Titanium diffusion profiles in quartz crystals are widely applied to constrain the duration of magmatic processes. However, experimentally determined Ti diffusion coefficients in quartz diverge by three orders of magnitude. To rectify this problem we derive Ti diffusion coefficients from natural quartz phenocrysts from the 1991 eruption at Mt. Pinatubo, by combining U-Th ages of small (15-40 µm long) zircon inclusions with Ti diffusion profiles measured at nearby growth zone contacts in the same quartz crystals. Application of the obtained data to quartz crystals with Ti-rich rims from thirteen silicic volcanic tuffs worldwide suggests that the magmas erupted years to thousands of years after magma chamber rejuvenation, with the priming time increasing with magma volume and decreasing temperature. Here we show that the time scales involved in the generation of silicic volcanic eruptions are much longer than originally thought.

Design, synthesis and biological evaluation of 3-substituted-2-thioxothiazolidin-4-one (rhodanine) derivatives as antitubercular agents against Mycobacterium tuberculosis protein tyrosine phosphatase B.

Mycobacterium tuberculosis infections still pose a serious threat to human health. Combination therapies are effective medical solutions to the problem. Mycobacterium tuberculosis is an intracellular pathogen that mainly depends on a virulence factor (Mycobacterium tuberculosis protein tyrosine phosphatase B, MptpB) for its survival in the host. Therefore, MptpB inhibitors are potential components of tuberculosis combination treatments. Herein, a new series of MptpB inhibitors bearing a rhodanine group were developed using a structure-based strategy based on the virtual screening hit. The new MptpB inhibitors displayed potent MptpB inhibitory activities and great improvements in cell membrane permeability. The optimal compounds reduced the bacterial burden in a dose-dependent manner in a macrophage infection model, especially, a combination of compound 20 and rifampicin led to a bacterial burden reduction of more than 95%, greater than the reductions achieved with compound 20 or rifampicin alone. This research provides new insights into the rational design of new MptpB inhibitors and verifies that the MptpB inhibitor has a promising potential as a component of tuberculosis treatment.

Identification of fecal microbiome signatures associated with familial longevity and candidate metabolites for healthy aging.

Gut microbiota associated with longevity plays an important role in the adaptation to damaging stimuli accumulated during the aging process. The mechanism by which the longevity-associated microbiota protects the senescent host remains unclear, while the metabolites of the gut bacteria are of particular interest. Here, an integrated analysis of untargeted metabolomics and 16S rRNA gene sequencing was used to characterize the metabolite and microbiota profiles of long-lived individuals (aged ≥90 years) in comparison to old-elderly (aged 75-89 years), young-elderly (aged 60-74 years), and young to middle-aged (aged ≤59 years) individuals. This novel study constructed both metabolite and microbiota trajectories across aging in populations from Jiaoling county (the seventh longevity town of the world) in China. We found that the long-lived group exhibited remarkably differential metabolomic signatures, highlighting the existence of metabolic heterogeneity with aging. Importantly, we also discovered that long-lived individuals from the familial longevity cohort harbored a microbiome distinguished from that of the general population. Specifically, we identified that the levels of a candidate metabolite, pinane thromboxane A2 (PTA2), which is positively associated with aging, were consistently higher in individuals with familial longevity and their younger descendants than in those of the general population. Furtherly, functional analysis revealed that PTA2 potentiated the efficiency of microglial phagocytosis of ß-amyloid 40 and enhanced an anti-inflammatory phenotype, indicating a protective role of PTA2 toward host health. Collectively, our results improve the understanding of the role of the gut microbiome in longevity and may facilitate the development of strategies for healthy aging.

Design of a Bistable Artificial Venus Flytrap Actuated by Low Pressure with Larger Capture Range and Faster Responsiveness.

The rapid closure of the Venus flytrap (Dionaea muscipula) can be completed within 0.1-0.5 s due to the bistability of hyperbolic leaves and the curvature change of midrib. Inspired by its bistable behavior, this paper presents a novel bioinspired pneumatic artificial Venus flytrap (AVFT), which can achieve a larger capture range and faster closure action at low working pressure and low energy consumption. Soft fiber-reinforced bending actuators are inflated to move artificial leaves and artificial midrib fabricated from bistable antisymmetric laminated carbon fiber-reinforced prepreg (CFRP) structures, and then the AVFT is rapidly closed. A two-parameter theoretical model is used to prove the bistability of the selected antisymmetric laminated CFRP structure, and analyze the factors affecting the curvature in the second stable state. Two physical quantities, critical trigger force and tip force, are introduced to associate the artificial leaf/midrib with the soft actuator. A dimension optimization framework for soft actuators is developed to reduce their working pressures. The results show that the closure range of the AVFT is extended to 180°, and the snap time is shortened to 52 ms by introducing the artificial midrib. The potential application of the AVFT for grasping objects is also shown. This research can provide a new paradigm for the study of biomimetic structures.

Vertical patterns of leaf physiology and biofilm characteristics for Hydrilla verticillata in both single and mixed communities.

Little is known about how community composition affects vertical patterns of leaf characteristics for submerged macrophytes in freshwater lakes. Here, after sampling Hydrilla verticillata in both single and mixed communities in shallow and deep areas in a shallow lake, we measured vertical patterns of leaf biofilm and physiology characteristics. Upper leaves of H. verticillata always had more attached abiotic biofilm matters, and all biofilm characteristics exhibited declining trends from top to bottom segments in deep areas. Moreover, the amount of attached biofilm matter in the mixed community was less than in the single community in shallow areas, but the reverse was true in deep areas. The vertical pattern of leaf physiology characteristics was obvious in the mixed community. In the shallow area, leaf pigment concentrations showed increasing trends with an increasing water depth, but the enzymatic specific activity of peroxidase (POD-ESA) was precisely the opposite. In the deep area, leaf chlorophyll concentrations were greatest in the leaves of bottom segments and lowest in top segments, while carotenoids and POD-ESA were greatest in the leaves of the middle segment-II. Light intensity and biofilm were found to play an important role in regulating the vertical patterns of photosynthetic pigments and POD-ESA. Our study highlighted the effect of community composition on the vertical pattern of leaf physiology and biofilm characteristics. HIGHLIGHTS: Biofilm characteristics always showed increasing trends with increasing water depth. Community composition changed the amount of attached biofilm matter. The vertical pattern of leaf physiology was more obvious in mixed communities. Light intensity and biofilm regulated the vertical pattern of leaf physiology.

Quantitative discrimination of algae multi-impacts on N2O emissions in eutrophic lakes: Implications for N2O budgets and mitigation.

It is generally accepted that eutrophic lakes significantly contribute to nitrous oxide (N2O) emissions. However, how these emissions are affected by the formation, disappearance, and mechanisms of algal blooms in these lakes has not been systematically investigated. This study examined and determined the relative contribution of spatiotemporal N2O production pathways in hypereutrophic Lake Taihu. Synchronously, the multi-impacts of algae on N2O production and release potential were measured in the field and in microcosms using isotope ratios of oxygen (δ18O) and bulk nitrogen (δ15N) to N2O and to intramolecular 15N site preference (SP). Results showed that N2O production in Lake Taihu was derived from microbial effects (nitrification and incomplete denitrification) and water air exchanges. N2O production was also affected by the N2O reduction process. The mean dissolved N2O concentrations in the water column during the pre-outbreak, outbreak, and decay stages of algae accumulation were almost the same (0.05 µmol·L-1), which was 2-10 times higher than in lake areas algae was not accumulating. However, except for the central lake area, all surveyed areas (with and without accumulated algae) displayed strong release potential and acted as the emission source because of dissolved N2O supersaturation in the water column. The mean N2O release fluxes during the pre-outbreak, outbreak, and decay stages of algae accumulation areas were 17.95, 26.36, and 79.32 µmol·m-2·d-1, respectively, which were 2.0-7.5 times higher than the values in the non-algae accumulation areas. In addition, the decay and decomposition of algae released large amounts of nutrients and changed the physiochemical properties of the water column. Additionally, the increased algae biomass promoted N2O release and improved the proportion of N2O produced via denitrification process to being 9.8-20.4% microbial-derived N2O. This proportion became higher when the N2O consumption during denitrification was considered as evidenced by isotopic data. However, when the algae biomass was excessive in hypereutrophic state, the algae decomposition also consumed a large amount of oxygen, thus limiting the N2O production due to complete denitrification as well as due to the limited substrate supply of nitrate by nitrification in hypoxic or anoxic conditions. Further, the excessive algae accumulation on the water surface reduced N2O release fluxes via hindering the migration of the dissolved N2O into the atmosphere. These findings provide a new perspective and understanding for accurately evaluating N2O release fluxes driven by algae processes in eutrophic lakes.

Rheological Performance of High-Temperature-Resistant, Salt-Resistant Fracturing Fluid Gel Based on Organic-Zirconium-Crosslinked HPAM.

Development of low-cost, high-temperature-resistant and salt-resistant fracturing fluids is a hot and difficult issue in reservoir fluids modification. In this study, an organic zirconium crosslinker that was synthesized and crosslinked with partially hydrolyzed polyacrylamide (HPAM) was employed as a cost-effective polymer thickener to synthesize a high-temperature-resistant and salt-resistant fracturing fluid. The rheological properties of HPAM in tap water solutions and 2 × 104 mg/L salt solutions were analyzed. The results demonstrated that addition of salt reduced viscosity and viscoelasticity of HPAM solutions. Molecular dynamics (MD) simulation results indicated that, due to electrostatic interaction, the carboxylate ions of HPAM formed an ionic bridge with metal cations, curling the conformation, decreasing the radius of rotation and thus decreasing viscosity. However, optimizing fracturing fluids formulation can mitigate the detrimental effects of salt on HPAM. The rheological characteristics of the HPAM fracturing fluid crosslinking process were analyzed and a crosslinking rheological kinetic equation was established under small-amplitude oscillatory shear (SAOS) test. The results of a large-amplitude oscillation shear (LAOS) test indicate that the heating effect on crosslinking is stronger than the shear effect on crosslinking. High-temperature-resistant and shear-resistant experiments demonstrated good performance of fracturing fluids of tap water and salt solution at 200 °C and 180 °C.

Cerebral arteriopathy and ischemic stroke in a pediatric MYH11 patient.

OBJECTIVES: Mutations in the MYH11 gene result in smooth muscle cell dysfunction and are associated with familial thoracic aortic aneurysms and dissection. We describe a pediatric patient with a stroke and a pathogenic MYH11 IVS32G>A mutation, and a phenotype similar to ACTA2. METHODS: A proband girl with an acute ischemic stroke underwent genetic analysis and 7T high-resolution MRI. RESULTS: A 12-year-old girl presented with a right middle cerebral artery occlusion. She received thrombolysis and underwent mechanical thrombectomy. An extensive stroke work-up was negative. A three-generation pedigree showed a splice site mutation of MYH11 IVS32G>A of the proband and three more family members. A 7T-MRI showed "broomstick-like" straightening of distal arterial segments, a V-shaped anterior corpus callosum and a post-stroke cystic area of encephalomalacia. This vascular appearance and parenchymal abnormalities typically present in patients with an ACTA2 phenotype. 7T-MRI also demonstrated thickening of the right middle cerebral arterial wall. DISCUSSION: This case suggests that MYH11 patients may have a similar angiographic and brain parenchymal phenotype to patients with ACTA2 mutations. This is the first report of arterial wall thickening in a MYH11 stroke patient using 7T-MRI. Patients with MYH11 mutations may display a focal cerebral steno-occlusive arteriopathy that may lead to stroke.

Extraordinary Solidification Mechanism of Liquid Alloys Under Acoustic Levitation State.

The acoustic levitation of various materials can be realized by highly intensive ultrasound, which provides a free surface and containerless state for materials processing under space simulation conditions. The nonlinear effects such as acoustic radiation pressure, acoustic streaming, and ultrasonic cavitation open up special access to modulate the fluid dynamics and solidification mechanisms of liquid materials. Here, the physical characteristics of liquid flow, undercooling capability, phase separation, and crystal nucleation and growth within acoustically levitated droplets are explored comprehensively to reveal the extraordinary solidification kinetics of liquid alloys. The sectorial shape oscillations of the 2nd to 10th order modes accompanying internal potential flow are observed for water droplets with modulated ultrasound amplitudes, while the enhanced ultrasound intensity promotes ice nucleation and thus reduces water undercooling. The migration of Sn-rich globules during phase separation of immiscible Al-Cu-Sn alloy is dominated by the droplet deformation and rotation related to acoustic levitation. The high undercooling states of liquid Ag-Cu-Ge and Ni-Sn alloys during acoustic levitation result in the refinement of (Ag) dendrites and the formation of anomalous (Ni+Ni3 Sn) eutectics. The ultrasound-liquid interaction also induces surface waves during the containerless solidification of Ag-Cu and Ni-Sn eutectic alloys.

A new anthraquinone from mangrove endophytic fungus Aspergillus sp. 16-5C.

A new anthraquinone, asperquinone A (1), and four known anthraquinone derivatives 2-5 were isolated from the mangrove endophytic fungus Aspergillus sp. 16-5C. These structures were elucidated by spectroscopic analysis and the absolute configuration of 1 was unambiguously determined by ECD calculation. Compounds 1-5 showed no significant inhibitory effect against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB).

Rotational dynamics of water associated with interfacial dielectric oscillation and its role in crystal growth of ice.

The rotational dynamics of water near the ice/water interface and its relation with the crystal growth of ice are investigated by using molecular dynamics simulations. We find that the dipole-moment profiles of water adjacent to interfaces display an oscillation behavior, which is in contrast to the monotonic decay near the free surface for water films. This dielectric oscillation phenomenon is associated with the strong response to hard solid/water interface. It significantly suppresses the dielectric relaxation and slows down the rotational diffusion near the interface compared to bulk water. We propose that the rotational diffusion determines the active degree of growth sites on interfaces, and its slowdown due to the interfacial dielectric oscillation contributes to reducing the growth rate of ice. With this idea, we predict the crystal growth rate of ice based on the modified Wilson-Frenkel model involving rotational dynamics. The theoretical result agrees well with the simulation.

Discovery of biphenyls bearing thiobarbiturate fragment by structure-based strategy as Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors.

Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) is an important virulence factor that blocks the host immune response and facilitates M. tuberculosis growth in host cells. MptpB inhibitors are potential components of tuberculosis combination treatment. Herein, we present the development of new biphenyls MptpB inhibitors with greatly improved MptpB inhibition based on our reported thiobarbiturate lead 6 by rational design with the structure-based strategy. The eight biphenyls bearing thiobarbiturate fragment target compounds showed more potent MptpB inhibition (IC50: 1.18-14.13 µM) than the lead compound 6. Further molecular docking studies showed that compounds 13, 26, 27 and 28 had multiple interactions with active sites. Among them, compound 13 exhibited dose-dependent increased antituberculosis activity in mouse macrophages. The results displayed that the strategy of modification utilizing biphenyl scaffold was efficient. Our study identifies biphenyls bearing thiobarbiturate fragment as new MptpB inhibitors and verifies the therapeutic potential of antimycobacterial agent targeting MptpB.

Giant impacts and the origin and evolution of continents.

Earth is the only planet known to have continents, although how they formed and evolved is unclear. Here using the oxygen isotope compositions of dated magmatic zircon, we show that the Pilbara Craton in Western Australia, Earth's best-preserved Archaean (4.0-2.5 billion years ago (Ga)) continental remnant, was built in three stages. Stage 1 zircons (3.6-3.4 Ga) form two age clusters with one-third recording submantle δ18O, indicating crystallization from evolved magmas derived from hydrothermally altered basaltic crust like that in modern-day Iceland1,2. Shallow melting is consistent with giant impacts that typified the first billion years of Earth history3-5. Giant impacts provide a mechanism for fracturing the crust and establishing prolonged hydrothermal alteration by interaction with the globally extensive ocean6-8. A giant impact at around 3.6 Ga, coeval with the oldest low-δ18O zircon, would have triggered massive mantle melting to produce a thick mafic-ultramafic nucleus9,10. A second low-δ18O zircon cluster at around 3.4 Ga is contemporaneous with spherule beds that provide the oldest material evidence for giant impacts on Earth11. Stage 2 (3.4-3.0 Ga) zircons mostly have mantle-like δ18O and crystallized from parental magmas formed near the base of the evolving continental nucleus12. Stage 3 (<3.0 Ga) zircons have above-mantle δ18O, indicating efficient recycling of supracrustal rocks. That the oldest felsic rocks formed at 3.9-3.5 Ga (ref. 13), towards the end of the so-called late heavy bombardment4, is not a coincidence.

Comparative genomics analysis of Bacillus velezensis LOH112 isolated from a nonagenarian provides insights into its biocontrol and probiotic traits.

Bacillus velezensis has recently received increasing attention as a biological fungicide and a potential probiotic agent because of its broad spectrum of antibacterial and antifungal activities. Here, we evaluated the beneficial traits of a newly isolated B. velezensis strain LOH112 using comprehensive bioinformatics and comparative genomic analyses and in vitro experimental approaches. Whole genome sequencing and assembly results showed that the genome of LOH112 consists of a circular chromosome and a circular plasmid, which encodes proteins involved in important biological processes such as sporulation, quorum sensing, and antibiotic synthesis. LOH112 contains 13 secondary metabolism gene clusters responsible for the production of antimicrobial compounds. In vitro experiments showed that LOH112 effectively inhibits several fungi and Gram-positive pathogenic bacteria, hydrolyzes protein and cellulose, and is capable of forming strong adhesive biofilms. Furthermore, comparative genomics revealed that LOH112 contains 34 strain-specific orthologous gene clusters, including two caseinolytic protease P (clpP) genes responsible for proteomic homeostasis. Selective pressure analysis indicated that the transmembrane transporter and ATP-dependent alanine/valine adenylase genes were strongly positively selected, which may endow LOH112 with better biocontrol ability and potential probiotic properties. Collectively, these results not only provide insights into a deeper understanding of the genomic characterization of LOH112 but also imply the potential application of LOH112 as biocontrol and probiotic agents.

Enhancing the dewaterability of waste activated sludge by the combined ascorbic acid and zero-valent iron/persulfate system.

In this work, a reducing/chelating agent, ascorbic acid (H2A) was introduced to the traditional zero-valent iron (Fe0)/persulfate (PS) process for waste activated sludge dewatering. The experimental data indicated that H2A-Fe0/PS process significantly enhanced the dewatering performance of sludge and enhanced the oxidation efficiency of Fe0-PS treatment. Under optimal conditions, the capillary suction time ratio before and after treatment (CST0/CST) of H2A-Fe0/PS treated sludge increased by 118% and 31.3% compared with untreated sludge and Fe0-PS treated sludge, respectively. The mechanism investigations revealed that the H2A-Fe0/PS induced excellent enhancement for sludge dewaterability could be credited to the reduction and chelating capacity of ascorbic acid. Free radicals including SO4•-, O2•- and •OH produced in the H2A-Fe0/PS process destroyed proteinaceous components and humic substances in sludge extracellular polymeric substances (EPS), thus reducing the negative charge and water holding capacity of sludge, improving the sludge rheological properties. As a result, the dewatering performance of sludge has been significantly improved.

New Global Insights on the Regulation of the Biphasic Life Cycle and Virulence Via ClpP-Dependent Proteolysis in Legionella pneumophila.

Legionella pneumophila, an environmental bacterium that parasitizes protozoa, causes Legionnaires' disease in humans that is characterized by severe pneumonia. This bacterium adopts a distinct biphasic life cycle consisting of a nonvirulent replicative phase and a virulent transmissive phase in response to different environmental conditions. Hence, the timely and fine-tuned expression of growth and virulence factors in a life cycle-dependent manner is crucial for survival and replication. Here, we report that the completion of the biphasic life cycle and bacterial pathogenesis is greatly dependent on the protein homeostasis regulated by caseinolytic protease P (ClpP)-dependent proteolysis. We characterized the ClpP-dependent dynamic profiles of the regulatory and substrate proteins during the biphasic life cycle of L. pneumophila using proteomic approaches and discovered that ClpP-dependent proteolysis specifically and conditionally degraded the substrate proteins, thereby directly playing a regulatory role or indirectly controlling cellular events via the regulatory proteins. We further observed that ClpP-dependent proteolysis is required to monitor the abundance of fatty acid biosynthesis-related protein Lpg0102/Lpg0361/Lpg0362 and SpoT for the normal regulation of L. pneumophila differentiation. We also found that the control of the biphasic life cycle and bacterial virulence is independent. Furthermore, the ClpP-dependent proteolysis of Dot/Icm (defect in organelle trafficking/intracellular multiplication) type IVB secretion system and effector proteins at a specific phase of the life cycle is essential for bacterial pathogenesis. Therefore, our findings provide novel insights on ClpP-dependent proteolysis, which spans a broad physiological spectrum involving key metabolic pathways that regulate the transition of the biphasic life cycle and bacterial virulence of L. pneumophila, facilitating adaptation to aquatic and intracellular niches.