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Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. The visceral fat is highly susceptible to the availability of external nutrients. Nutrient flux into the hexosamine biosynthetic pathway leads to protein posttranslational modification by O -linked β-N-acetylglucosamine ( O -GlcNAc) moieties. O -GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Here, we report that inducible deletion of adipose OGT causes a rapid visceral fat loss by specifically promoting lipolysis in visceral fat. Mechanistically, visceral fat maintains a high level of O -GlcNAcylation during fasting. Loss of OGT decreases O -GlcNAcylation of lipid droplet-associated perilipin 1 (PLIN1), which leads to elevated PLIN1 phosphorylation and enhanced lipolysis. Moreover, adipose OGT overexpression inhibits lipolysis and promotes diet-induced obesity. These findings establish an essential role for OGT in adipose tissue homeostasis and indicate a unique potential for targeting O -GlcNAc signaling in the treatment of obesity. Post-translational O-linked β-N acetylglucosamine (O-GlcNAc) modification acts as a nutrient-sensing mechanism. Here the authors report that O-GlcNAc transferase inhibits adipose tissue lipolysis via O-GlcNAcylation of the lipid droplet protein perilipin 1 and thus promotes diet-induced obesity.

Rational design of chimeric antigen receptor T (CAR-T) cells based on the recognition of antigenic epitopes capable of evoking the most potent CAR activation is an important objective in optimizing immune therapy. In solid tumors, the B7-H3 transmembrane protein is an emerging target that harbours two distinct epitope motifs, IgC and IgV, in its ectodomain. Here, we generate dromedary camel nanobodies targeting B7-H3 and demonstrate that CAR-T cells, based on the nanobodies recognizing the IgC but not IgV domain, had potent antitumour activity against large tumors in female mice. These CAR-T cells are characterized by highly activated T cell signaling and significant tumor infiltration. Single-cell transcriptome RNA sequencing coupled with functional T-cell proteomics analysis uncovers the top-upregulated genes that might be critical for the persistence of polyfunctional CAR-T cells in mice. Our results highlight the importance of the specific target antigen epitope in governing optimal CAR-T activity and provide a nanobody-based B7-H3 CAR-T product for use in solid tumor therapy. Chimeric antigen receptor T (CAR-T) cells represent an emerging form of immune therapy but success, especially in solid tumors, is limited by the scarcity of suitable target epitopes. Here authors show that a distinct epitope motif on the transmembrane protein B7-H3, recognized by a camel nanobody, triggers robust activation and anti-tumor function in cognate CAR-T cells.

Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we develop CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel V H H nanobody (D4)-based CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We find that a structurally rigid IgG4H and CD28TM domain brings the two D4 fragments in proximity, driving CAR dimerization and leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density in female mice. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR T cells reveals specific genes (e.g., HMGB1 ) associated with high T-cell polyfunctionality. This study demonstrates the potential of V H H-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes. Glypican-1 (GPC1) expression is elevated in pancreatic cancer and has been exploited as a therapeutic target. Here the authors report the development of V H H nanobody-based CAR-T cells targeting GPC1, showing anti-tumor activity in pancreatic cancer preclinical models.

In recent years, autonomous underwater vehicles (AUVs) have been increasingly employed for target surveillance and tracking. However, the limited performance and information-processing capability of a single AUV make it difficult to achieve high-precision tracking in practice. To address these challenges, this paper proposes an online-to-offline multi-agent reinforcement learning (MARL) framework that employs offline training on historical data to obtain the expert policy. Then, the optimal policy is generated by online fine-tuning technology, which enhances the training efficiency of reinforcement learning in new scenarios. To expand the surveillance range of AUV swarms, a distributed cooperative strategy based on area information entropy (AIE) is introduced. To reduce energy consumption in complex marine environments containing obstacles and vortices, ocean current and energy consumption models are introduced, together with an energy-efficiency optimization strategy. Furthermore, a long short-term memory (LSTM) network is integrated into the offline-to-online MARL framework to predict time-varying environmental states, thereby improving tracking accuracy and energy efficiency. Experimental results show that the proposed scheme is superior to the baseline schemes in terms of energy consumption, task success rate, and distance between AUVs. In addition, various performance indicators of the extended AUV swarm are also superior to the baseline schemes, demonstrating that the proposed scheme has excellent performance and scalability.

Cancer cells are known to adopt aerobic glycolysis in order to fuel tumor growth, but the molecular basis of this metabolic shift remains largely undefined. O-GlcNAcase (OGA) is an enzyme harboring O-linked β-N-acetylglucosamine (O-GlcNAc) hydrolase and cryptic lysine acetyltransferase activities. Here, we report that OGA is upregulated in a wide range of human cancers and drives aerobic glycolysis and tumor growth by inhibiting pyruvate kinase M2 (PKM2). PKM2 is dynamically O-GlcNAcylated in response to changes in glucose availability. Under high glucose conditions, PKM2 is a target of OGA-associated acetyltransferase activity, which facilitates O-GlcNAcylation of PKM2 by O-GlcNAc transferase (OGT). O-GlcNAcylation inhibits PKM2 catalytic activity and thereby promotes aerobic glycolysis and tumor growth. These studies define a causative role for OGA in tumor progression and reveal PKM2 O-GlcNAcylation as a metabolic rheostat that mediates exquisite control of aerobic glycolysis.

Endometriosis (EMs) is an estrogen-dependent chronic inflammatory disease. While apoptosis resistance (evidenced by Bcl-2 upregulation and Bax/caspase-3 downregulation) remains a hallmark of EMs, recent studies reveal a paradoxical coexistence of aberrant apoptotic activation (Fas/FADD/Caspase-8) and inflammatory PANoptosis in ectopic lesions, suggesting novel therapeutic targets for this complex disorder. GEO database mining revealed PANoptosis-related genes in EMs, which was experimentally validated through clinical and animal studies demonstrating the critical role of Fas/FADD/Caspase-8/RIPK1 signaling. Curcumol, the active component of Curcuma zedoaria rhizomes, exhibited strong binding affinity to Fas/RIPK1 in molecular docking and dynamics simulations, and effectively alleviated EMs progression by modulating this pathway, providing novel therapeutic insights for EMs management.

Membrane distillation technology, as a new membrane-based water treatment technology that combines the membrane technology and evaporation process, has the advantages of using low-grade heat, working at atmospheric pressure with simple configuration, etc. In this study, heat and mass transfer were coupled at the membrane surfaces through the user-defined function program. The effects of feed temperature, feed velocity and permeate velocity on temperature polarization were mainly investigated for a high-concentration NaCl solution. The temperature polarization was increased with the increase of feed temperature and the decrease of feed and permeate velocity. The effects of temperature, inlet velocity and solution concentration on the evaporation efficiency of the membrane module for co- and counter-current operations were investigated in detail. The counter-current operation performed better than co-current operation in most cases, except for the condition where the NaCl concentration was relatively low or the module length was long enough. In addition, the optimal membrane thickness for both PVDF and PTFE was studied. The optimal membrane thickness was found in the range of 10 to 20 μm, which corresponded to the highest permeate flux for the selected materials, pore size distribution, and operation conditions. Membrane material with lower thermal conductivity and larger porosity was prone to get higher permeate flux and had larger optimal membrane thickness. Increasing feed velocity or feed temperature could decrease the optimal membrane thickness.

Palatable foods (fat and sweet) induce hyperphagia, and facilitate the development of obesity. Whether and how overnutrition increases appetite through the adipose-to-brain axis is unclear. O -linked beta-D- N -acetylglucosamine (O-GlcNAc) transferase (OGT) couples nutrient cues to O-GlcNAcylation of intracellular proteins at serine/threonine residues. Chronic dysregulation of O-GlcNAc signaling contributes to metabolic diseases. Here we show that adipocyte OGT is essential for high fat diet-induced hyperphagia, but is dispensable for baseline food intake. Adipocyte OGT stimulates hyperphagia by transcriptional activation of de novo lipid desaturation and accumulation of N-arachidonyl ethanolamine (AEA), an endogenous appetite-inducing cannabinoid (CB). Pharmacological manipulation of peripheral CB1 signaling regulates hyperphagia in an adipocyte OGT-dependent manner. These findings define adipocyte OGT as a fat sensor that regulates peripheral lipid signals, and uncover an unexpected adipose-to-brain axis to induce hyperphagia and obesity. Endocannabinoid signaling regulates food intake and is a potential therapeutic target for obesity. Here the authors show that adipocyte O-GlcNAc transferase (OGT) is required for high fat diet-induced hyperphagia via transcriptional activation of de novo lipid desaturation and accumulation of an endogenous appetite-inducing cannabinoid.

To improve the adaptability of direct air-cooled power generating units to the variations of both meteorological condition and power load, a piping-main arrangement of air-cooled condensers was proposed. The heat and mass transfer models of the air-side were established for the air cooling system of 2 × 600 MW thermal power generating units. The coupled model for both flow resistance loss and condensate flow rate distributions of exhaust steam inside air-cooled condensers were developed based on the temperature fields through numerical simulation. Calculation results, including the condensate flow rate, back pressure, and coal consumption rate, were acquired under different ambient temperatures and wind velocities. The results show that the proposed piping-main arrangement can weaken the ambient wind impacts and reduce the backpressure significantly in summer by adjusting the number of air-cooled condenser cells in operation. The steam flow rate can be uniformed effectively by adjusting the number of operating air-cooled condenser cells during winter. It can also avoid the freezing accident in winter while cooling the exhaust steam of two turbines by part air-cooled condenser cells.

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease prominently featuring motor neuron (MN) loss and paralysis. A recent study using whole-cell patch clamp recording of MNs in acute spinal cord slices from symptomatic adult ALS mice showed that the fastest firing MNs are preferentially lost. To measure the in vivo effects of such loss, awake symptomatic-stage ALS mice performing self-initiated walking on a wheel were studied. Both single-unit extracellular recordings within spinal cord MN pools for lower leg flexor and extensor muscles and the electromyograms (EMGs) of the corresponding muscles were recorded. In the ALS mice, we observed absent or truncated high-frequency firing of MNs at the appropriate time in the step cycle and step-to-step variability of the EMG, as well as flexor-extensor coactivation. In turn, kinematic analysis of walking showed step-to-step variability of gait. At the MN level, the higher frequencies absent from recordings from mutant mice corresponded with the upper range of frequencies observed for fast-firing MNs in earlier slice measurements. These results suggest that, in SOD1-linked ALS mice, symptoms are a product of abnormal MN firing due at least in part to loss of neurons that fire at high frequency, associated with altered EMG patterns and hindlimb kinematics during gait.