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Chemotherapy drugs can cause pyroptotic cell death by activating caspase-3 to cleave gasdermin E, potentially contributing to their toxicity and adverse effects. Chemotherapy-induced cell death The negative side effects of chemotherapy are well documented but the mechanisms behind them are not always known. Feng Shao and colleagues show that chemotherapy drug treatment of gasdermin-E-expressing tumour cells results in a caspase-3-dependent switch from apoptotic to pyroptotic cell death. The majority of human tumours tested appeared to have lost expression of gasdermin E, whereas normal tissues express it. This observation has potential implications for the treatment of gasdermin-E-expressing tumours, and for chemotherapy-induced tissue damage. Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide 1 , 2 , 3 . The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity 4 , 5 , 6 , 7 , 8 , 9 . GSDMD belongs to a gasdermin family that shares the pore-forming domain 4 , 6 , 10 . The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5) 11 , can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme −/− (also known as Dfna5 −/− ) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.

Pyrin, encoded by the MEFV gene, is best known for its gain-of-function mutations causing familial Mediterranean fever (FMF), an autoinflammatory disease. Pyrin forms a caspase-1–activating inflammasome in response to inactivating modifications of Rho GTPases by various bacterial toxins or effectors. Pyrin-mediated innate immunity is unique in that it senses bacterial virulence rather than microbial molecules, but its mechanism of activation is unknown. Here we show that Pyrin was phosphorylated in bone marrow-derived macrophages and dendritic cells. We identified Ser-205 and Ser-241 in mouse Pyrin whose phosphorylation resulted in inhibitory binding by cellular 14-3-3 proteins. The two serines underwent dephosphorylation upon toxin stimulation or bacterial infection, triggering 14-3-3 dissociation, which correlated with Pyrin inflammasome activation. We developed antibodies specific for phosphorylated Ser-205 and Ser-241, which confirmed the stimuli-induced dephosphorylation of endogenous Pyrin. Mutational analyses indicated that both phosphorylation and signal-induced dephosphorylation of Ser-205/241 are important for Pyrin activation. Moreover, microtubule drugs, including colchicine, commonly used to treat FMF, effectively blocked activation of the Pyrin inflammasome. These drugs did not affect Pyrin dephosphorylation and 14-3-3 dissociation but inhibited Pyrin-mediated apoptosis-associated Speck-like protein containing CARD (ASC) aggregation. Our study reveals that site-specific (de)phosphorylation and microtubule dynamics critically control Pyrin inflammasome activation, illustrating a fine and complex mechanism in cytosolic immunity.

Background As a perennial crop, oil-Camellia possesses a long domestication history and produces high-quality seed oil that is beneficial to human health. Camellia oleifera Abel. is a sister species to the tea plant, which is extensively cultivated for edible oil production. However, the molecular mechanism of the domestication of oil-Camellia is still limited due to the lack of sufficient genomic information. Results To elucidate the genetic and genomic basis of evolution and domestication, here we report a chromosome-scale reference genome of wild oil-Camellia (2.95 Gb), together with transcriptome sequencing data of 221 cultivars. The oil-Camellia genome, assembled by an integrative approach of multiple sequencing technologies, consists of a large proportion of repetitive elements (76.1%) and high heterozygosity (2.52%). We construct a genetic map of high-density corrected markers by sequencing the controlled-pollination hybrids. Genome-wide association studies reveal a subset of artificially selected genes that are involved in the oil biosynthesis and phytohormone pathways. Particularly, we identify the elite alleles of genes encoding sugar-dependent triacylglycerol lipase 1 , β-ketoacyl-acyl carrier protein synthase III , and stearoyl-acyl carrier protein desaturases ; these alleles play important roles in enhancing the yield and quality of seed oil during oil-Camellia domestication. Conclusions We generate a chromosome-scale reference genome for oil-Camellia plants and demonstrate that the artificial selection of elite alleles of genes involved in oil biosynthesis contributes to oil-Camellia domestication.

Tillering and panicle branching are important determinants of plant architecture and yield potential in rice (Oryza sativa). IDEAL PLANT ARCHITECTURE1 (IPA1) encodesSQUAMOSA PROMOTER BINDING PROTEIN-LIKE14, which acts as a key transcription factor regulating tiller outgrowth and panicle branching by directly activating the expression of O. sativa TEOSINTE BRANCHED1 (OsTB1) and O. sativa DENSE AND ERECT PANICLE1 (OsDEP1), thereby influencing grain yield in rice. Here, we report the identification of a rice mutant named shi1 that is characterized by dramatically reduced tiller number, enhanced culm strength, and increased panicle branch number. Map-based cloning revealed that O. sativa SHORT INTERNODES1 (OsSHI1) encodes a plant-specific transcription factor of the SHI family with a characteristic family-specific IGGH domain and a conserved zinc-finger DNA binding domain. Consistent with the mutant phenotype, OsSHI1 is predominantly expressed in axillary buds and young panicle, and its encoded protein is exclusively targeted to the nucleus. We show that OsSHI1 physically interacts with IPA1 both in vitro and in vivo. Moreover, OsSHI1 could bind directly to the promoter regions of both OsTB1 and OsDEP1 through a previously unrecognized cis-element (T/GCTCTAC motif). OsSHI1 repressed the transcriptional activation activity of IPA1 by affecting its DNA binding activity toward the promoters of both OsTB1 and OsDEP1, resulting in increased tiller number and diminished panicle size. Taken together, our results demonstrate that OsSHI1 regulates plant architecture through modulating the transcriptional activity of IPA1 and provide insight into the establishment of plant architecture in rice.

Ionic thermoelectric (i-TE) liquid cells offer an environmentally friendly, cost effective, and easy-operation route to low-grade heat recovery. However, the lowest temperature is limited by the freezing temperature of the aqueous electrolyte. Applying a eutectic solvent strategy, we fabricate a high-performance cryo-temperature i-TE liquid cell. Formamide is used as a chaotic organic solvent that destroys the hydrogen bond network between water molecules, forming a deep eutectic solvent that enables the cell to operate near cryo temperatures (down to –35 °C). After synergistic optimization of the electrode and cell structure, the as-fabricated liquid i-TE cell with cold (–35 °C) and hot (70 °C) ends achieve a high power density (17.5 W m −2 ) and a large two-hour energy density (27 kJ m −2 ). In a prototype 25-cell module, the open-circuit voltage and short-circuit current are 6.9 V and 68 mA, respectively, and the maximum power is 131 mW. The anti-freezing ability and high output performance of the as-fabricated i-TE liquid cell system are requisites for applications in frigid regions. The authors make an ionic thermoelectric cell with a eutectic solvent of formamide that can operate at temperatures as low as −35 °C by applying hydrophilic and gold coated treatments to the electrode and introducing a thermal separator.

Population decline is leading to a shrinking city size in industrialized countries. In some developing countries, because majority of the population is concentrated in big cities, the population in undeveloped cities has begun to decline. Japan experienced rapid urban expansion surrounding industrial districts, including steeply sloped areas, between the 1950s and 1970s. In the past forty years, Japan’s population has decreased, and the average age of the population is increasing. The reduction in the size of cities, following population decreases is becoming an important issue, and the study of sustainable, concentrated urban planning to cope with shrinking city size is, therefore, necessary. We have conducted a case study using Yahatahigashi-ku to determine its redevelopment potential, based on a combination of urban geographic data. This paper (1) presents a typical case study using Geographic Information System (GIS) data to evaluate an aging and shrinking society; (2) explores the GIS design approaches configured for an aging society; and (3) evaluates the optimization of environmental performance for an urban regeneration plan. The primary factors related to this urban design case study included, a declining population, mixed urban land use, and the placement of public facilities. We developed a method involving the slope degree to evaluate land-use to model the importance of informational evaluation in the urban planning process. This method could contribute to the urban regeneration for an aging society and could also be applied to other aging and shrinking cities, in mountainous regions.

In humans, odors are detected by ~400 functional olfactory receptor (OR) genes. The superfamily of functional OR genes can be further divided into tens of families. In large part, the OR genes have experienced extensive tandem duplications, which have led to gene gains and losses. However, whether different OR gene families have experienced distinct modes of gene duplication has yet to be reported. We conducted comparative genomic and evolutionary analyses for human functional OR genes. Based on analysis of human-mouse 1-1 orthologs, we found that human functional OR genes show higher-than-average evolutionary rates, and there are significant differences among families of functional OR genes. Via comparison with seven vertebrate outgroups, families of human functional OR genes show different extents of gene synteny conservation. Although the superfamily of human functional OR genes is enriched in tandem and proximal duplications, there are particular families which are enriched in segmental duplications. These findings suggest that human functional OR genes may be governed by different evolutionary mechanisms and that large-scale gene duplications have contributed to the early evolution of human functional OR genes.

Background Tissue inhibitor matrix metalloproteinase 1 (TIMP1) plays a vital role in carcinogenesis, yet its precise functional roles and regulation remain unclear. In this study, we aim to investigate its biological function and clinical significance in human colon cancer. Methods We analyzed the expression of TIMP1 in both public database (Oncomine and TCGA) and 94 cases of primary colon cancer and matched normal colon tissue specimens. The underlying mechanisms of altered TIMP1 expression on cell tumorigenesis, proliferation, and metastasis were explored in vitro and in vivo. Results TIMP1 was overexpressed in colon tumorous tissues and lymph node metastasis specimens than in normal tissues. The aberrant expression of TIMP1 was significantly associated with the regional lymph node metastasis ( p  = 0.033), distant metastasis ( p  = 0.039), vascular invasion ( p  = 0.024) and the American Joint Committee on Cancer (AJCC) stage ( p  = 0.026). Cox proportional hazards model showed that TIMP1 was an independent prognostic indicator of disease-free survival (HR = 2.603, 95 % CI: 1.115–6.077, p  = 0.027) and overall survival (HR = 2.907, 95 % CI: 1.254–6.737, p  = 0.013) for patients with colon cancer. Consistent with this, our findings highlight that suppression of TIMP1 expression decreased proliferation, and metastasis but increased apoptosis by inducing TIMP1 specific regulated FAK-PI3K/AKT and MAPK pathway. Conclusion TIMP1 might play an important role in promoting tumorigenesis and metastasis of human colon cancer and function as a potential prognostic indicator for colon cancer.

Developing nanozymes with effective reactive oxygen species (ROS) scavenging ability is a promising approach for osteoarthritis (OA) treatment. Nonetheless, numerous nanozymes lie in their relatively low antioxidant activity. In certain circumstances, some of these nanozymes may even instigate ROS production to cause side effects. To address these challenges, a copper‐based metal–organic framework (Cu MOF) nanozyme is designed and applied for OA treatment. Cu MOF exhibits comprehensive and powerful activities (i.e., SOD‐like, CAT‐like, and •OH scavenging activities) while negligible pro‐oxidant activities (POD‐ and OXD‐like activities). Collectively, Cu MOF nanozyme is more effective at scavenging various types of ROS than other Cu‐based antioxidants, such as commercial CuO and Cu single‐atom nanozyme. Density functional theory calculations also confirm the origin of its outstanding enzyme‐like activities. In vitro and in vivo results demonstrate that Cu MOF nanozyme exhibits an excellent ability to decrease intracellular ROS levels and relieve hypoxic microenvironment of synovial macrophages. As a result, Cu MOF nanozyme can modulate the polarization of macrophages from pro‐inflammatory M1 to anti‐inflammatory M2 subtype, and inhibit the degradation of cartilage matrix for efficient OA treatment. The excellent biocompatibility and protective properties of Cu MOF nanozyme make it a valuable asset in treating ROS‐related ailments beyond OA. A Cu‐based metal–organic framework (Cu MOF) nanozyme fabricated through a simple self‐assembly strategy exhibits comprehensive and powerful antioxidant activities while minimal pro‐oxidant activities. The Cu MOF nanozyme shows excellent scavenging capabilities against various types of ROS and relieves the hypoxic microenvironment of synovial macrophages, resulting in efficient and safe treatment of osteoarthritis (OA).

Non-conventional yeasts are ideal hosts for next-generation organic acid production because of their stress tolerance and broad substrate spectrum.Recent advances in sequencing, omics, and in silico modeling analysis have provided genomic information and genetic toolkits to design and construct robust organic acid producers.Selecting a microbial host that is well suited to the desired product is an important point for the industrial production of organic acids and can enhance overall process efficiency.Organic acid production at low pH using acid-tolerant yeasts is financially viable and environmentally beneficial, but this process has not yet been implemented industrially. Microbial production of organic acids has been hindered by the poor acid tolerance of microorganisms and the high costs of waste salt reprocessing. The robustness of non-conventional microorganisms in an acidic environment makes it possible to produce organic acids at low pH and greatly simplifies downstream processing. In this review we discuss the environmental adaptability features of non-conventional yeasts, as well as the latest developments in genomic engineering strategies that have facilitated metabolic engineering of these strains. We also use selected examples of three-carbon (C3), C4, and C6 organic acids to illustrate the ongoing efforts and challenges of using non-conventional yeasts for organic acid production. This review provides theoretical guidance for the construction of highly robust organic acid producers. Microbial production of organic acids has been hindered by the poor acid tolerance of microorganisms and the high costs of waste salt reprocessing. The robustness of non-conventional microorganisms in an acidic environment makes it possible to produce organic acids at low pH and greatly simplifies downstream processing. In this review we discuss the environmental adaptability features of non-conventional yeasts, as well as the latest developments in genomic engineering strategies that have facilitated metabolic engineering of these strains. We also use selected examples of three-carbon (C3), C4, and C6 organic acids to illustrate the ongoing efforts and challenges of using non-conventional yeasts for organic acid production. This review provides theoretical guidance for the construction of highly robust organic acid producers.