Cytokine nanosponges suppressing overactive macrophages and dampening systematic cytokine storm for the treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction.Inspired by macrophage membranes harbor the receptors with special high affinity for proin-flammation cytokines,lipopolysaccharide(LPS)-stimulated macrophage membrane-coated nanoparticles(LMNP)were developed to show strong sponge ability to both IFN-γand IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo.Besides,LMNP also efficiently alleviated HLH-related symptoms including cytopenia,hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models.Furthermore,its sponge effect also worked well for five human HLH samples in vitro.Altogether,it’s firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation,which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.

LPS adsorption and inflammation alleviation by polymyxin B-modified liposomes for atherosclerosis treatment

Chronic inflammation is critical in the onset and progression of atherosclerosis(AS).The lipopolysaccharide(LPS)level in the circulation system is elevated in AS patients and animal models,which is correlated with the severity of AS.Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype,aggravate inflammation,and ultimately contribute to the exacerbation of AS,LPS in the circulation system was supposed to be the therapeutic target for AS treatment.In the present study,polymyxin(PMB)covalently conjugated to PEGylated liposomes(PLPs)were formulated to adsorb LPS through specific interactions between PMB and LPS.In vitro,the experiments demonstrated that PLPs could adsorb LPS,reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells.In vivo,the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines,decreased the proportion of M1-type macrophages in AS plaque,stabilized AS plaque,and downsized the plaque burdens in arteries,which eventually attenuated the progression of AS.Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.

The role of circadian clocks in cancer:Mechanisms and clinical implications

Circadian rhythm refers to the inherent 24-h cycle oscillation of biochemical,phys-iological and behavioral functions,which is almost universal in eukaryotes.At least 14 core clock genes have been reported to form multiple chain feedback loops that confer intrinsic circadian rhythmicity onto the molecular clock.Accumulating evidence has shown that the circadian gene dysfunction resulted from single nucleotide polymorphisms(SNPs),deletions,epigenetic modification,and deregulation is strongly associated with cancer risk.In the pre-sent review,we describe the composition of circadian rhythm system.We highlight the func-tion and mechanism of clock genes in cancer pathogenesis and progression.Moreover,their potential clinical implications as prognostic biomarkers and therapeutic targets have been ad-dressed.

PTEN-induced putative kinase 1 regulates mitochondrial quality control and is essential for the maturation of human induced pluripotent stem cell-derived cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)have attracted attention in the field of regenerative medicine due to their potential ability to repair damaged hearts.However,the immature phenotype of these cells limits their clinical application.Cardiomyocyte maturation is accompanied by changes in mitochondrial quality.PTEN-induced putative kinase 1(PINK1)has been linked to mitochondrial quality control.However,whether the changes in mitochondrial quality in hiPSC-CMs are associated with PINK1,and the impact of PINK1 on hiPSC-CMs development are not clear.In this study,we found that knockdown of PINK1 in hiPSC-CMs resulted in mitochondrial fragmentation and impaired mitochondrial functions such as mitophagy and mitochondrial biogenesis.PINK1 deletion also inhibited the maturation of hiPSC-CMs,reverting them to a naive structural and functional state.We found that restoring the mitochondrial structure did not completely rescue the mitochondrial dysfunction caused by PINK1 deletion,while activation of PINK1 kinase activity using kinetin promoted mitochondrial fusion,increased the mitochondrial membrane potential and ATP production,and maintained the development and maturation of hiPSC-CMs.In conclusion,PINK1 regulates the mitochondrial structure and function of hiPSC-CMs,and is essential for the maturation of hiPSC-CMs.

Searching Activity Tra jectories with Semantics

With the widespread use of smart phones and mobile Internet,social network users have generated massive geo-tagged tweets,photos and videos to form lots of informative trajectories which reveal not only their spatio-temporal dynamics,but also their activities in the physical world.Existing spatial trajectory query studies mainly focus on analyzing the spatio-temporal properties of the users'trajectories,while leaving the understanding of their activities largely untouched.In this paper,we incorporate the semantics of the activity information embedded in trajectories into query modelling and processing,with the aim of providing end users more informative and meaningful results.To this end,we propose a novel trajectory query that not only considers the spatio-temporal closeness but also,more importantly,leverages a proven technique in text mining field,probabilistic topic modelling,to capture the semantic relatedness of the activities between the data and query.To support efficient query processing,we design a hierarchical grid-based index by integrating the probabilistic topic distribution on the substructures of trajectories and their spatio-temporal extent at the corresponding level of the index hierarchy.This specialized structure enables a top-down search algorithm to traverse the index while pruning unqualified trajectories in spatial and topical dimensions simultaneously.The experimental results on real-world datasets demonstrate the good efficiency and scalability performance of the proposed indices and trajectory search methods.

Long-lasting photoluminescence quantum yield of cesium lead halide perovskite-type quantum dots

Cesium lead halide perovskite(CsPbX_(3),X=Cl,Br,I)quantum dots(QDs)and their partly Mn^(2+)-substituted QDs(CsPb1–xMnxX3)attract considerable attention owing to their unique photoluminescence(PL)efficiencies.The two types of QDs,having different PL decay dynamics,needed to be further investigated in a form of aggregates to understand their solid-state-induced exciton dynamics in conjunction with their behaviors upon degradation to achieve practical applications of those promising QDs.However,thus far,these QDs have not been sufficiently investigated to obtain deep insights related to the long-term stability of their PL properties as aggregated solid-states.Therefore,in this study,we comparatively examined CsPbX_(3)-and CsPb1–xMnxX_(3)-type QDs stocked for>50 d under dark ambient conditions by using excitation wavelength-dependent PL quantum yield and time-resolved PL spectroscopy.These investigations were performed with powder samples in addition to solutions to determine the influence of the inter-QD interaction of the aged QD aggregates on their radiative decays.It turns out that the Mn^(2+)-substituted QDs exhibited long-lasting PL quantum efficiencies,while the unsubstituted CsPbX_(3)-type QDs exhibited a drastic reduction of their PL efficiencies.And the obtained PL traces were clearly sensitive to the sample status.This is discussed with the possible interaction depending on the size and distance of the QD aggregates.

Nanoplateletsomes for rapid hemostasis performance

Uncontrollable hemorrhage remains staple trouble in surgical procedures and a leading cause after major trauma.The bleeding issue may trigger various pathologic scenarios that can lead to tissue morbidities and mortalities,and currently available on-site hemostatic agents are confined to a narrow therapeutic index and may carry the risk of immunogenicity.Inspired by the crucial role of platelets in the process of thrombus,a platelet-mimetic plateletsome with wound targeting and blood coagulation properties is developed for hemorrhage control.Plateletsome is formulated by integrating platelet membranes with functionalized synthetic liposomes and exhibits superior wound targeting and effective hemostasis properties.It presents less blood loss and shorter hemostasis time than the platelet membrane vehicles or the conventional liposomes in the mouse tail transection model.The strong homing of the biomimetic plateletsome to the thrombus was also confirmed,demonstrating the potential of this engineered cell membrane vesicle as a biomimetic hemostat for bleeding treatment.

Operating pesticide use reduction within the boundary of food security in peri-urban settings

Pesticide use in peri-urban areas afects the urban enviroment and public health,and reducing the use may present food security isues for urban dwellers.In this study,we explore how a muiallyadopted goal of a 20%reduetion in pesticide use could be achieved,along with local food security and environmental implica-tions,for Shanghai located in the densely populated East China.A regional Shanghai Agricultural Sector Model inorporating district-and technology-varying crop budgets,was developed to simulate the efects of pesticide reduction policy.Here we find that achieving the reduction goal had the largest implications in districts with high pesticide use totals and intensities,potentially reducing pesticide non point source pollution in the Yangtze River Estuary and Dianshan Lake;the production levels of rice and leafy vegetables would be most afected;and adopting machinery that allows more precise pesticide application modulates these results.Moreover,imposing the requlrements at the district-level caused more severe local food security concerns,and less environmental benefits.Furthermore,a closed Shanghai's agricultural economy would subtantally enlarge the regional het-erogeneity in the above-mentioaned outcomes.Exploring the ffects of a quantity control policy on current-use pesticides at diferent aggregation levels has important implications for regulating the use of agrochemicals.