As the basic unit of life, cells are compartmentalized microreactors with molecularly crowded microenvironments. The quest to understand the cell origin inspires the design of synthetic analogs to mimic their functionality and structural complexity. In this work, we integrate membraneless coacervate microdroplets, a prototype of artificial organelles, into a proteinosome to build hierarchical protocells that may serve as a more realistic model of cellular organization. The protocell subcompartments can sense extracellular signals, take actions in response to these stimuli, and adapt their physicochemical behaviors. The tiered protocells are also capable of enriching biomolecular reactants within the confined organelles, thereby accelerating enzymatic reactions. The ability of signal processing inside protocells allows us to design the Boolean logic gates (NOR and NAND) using biochemical inputs. Our results highlight possible exploration of protocell-community signaling and render a flexible synthetic platform to study complex metabolic reaction networks and embodied chemical computation.

Liver and kidney cancers are notorious for drug resistance. Due to the complexity, redundancy and interpatient heterogeneity of resistance mechanisms, most efforts targeting a single pathway were unsuccessful. Novel personalized therapies targeting multiple essential drug resistance pathways in parallel hold a promise for future cancer treatment. Exploiting the multitarget characteristic of microRNAs (miRNAs), we developed a new therapeutic strategy by the combinational use of miRNA and anticancer drugs to increase drug response. By a systems approach, we identified that miR-27b, a miRNA deleted in liver and kidney cancers, sensitizes cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo. Functionally, miR-27b enhances drug response by activating p53-dependent apoptosis and reducing CYP1B1-mediated drug detoxification. Notably, miR-27b promotes drug response specifically in patients carrying p53-wild-type or CYP1B1-high signature. Together, we propose that miR-27b synergizes with anticancer drugs in a defined subgroup of liver and kidney cancer patients.

Dual-specificity phosphatases (DUSPs) are a family of protein phosphatases that dephosphorylate both phosphotyrosine and phosphoserine/ phosphothreonine residues. DUSPs are de-regulated in many human diseases, including cancers. However, the function of DUSPs in tumorigenesis remains largely unknown. Here, using short hairpin RNA-based gene knockdown, we found that several members of the DUSP family play critical roles in regulating cell proliferation. In particular, we showed that DUSP16 ablation leads to a G 1 /S transition arrest, reduced incorporation of 5-bromodeoxyuridine, enhanced senescence-associated b-galactosidase activity, and formation of senescence-associated heterochromatic foci. Mechanistically, DUSP16 silencing causes cellular senescence by activating the tumor suppressors p53 and Rb. The phosphatase activity of DUSP16 is necessary for antagonizing cellular senescence. Importantly, the expression levels of DUSP16 are up-regulated in human liver cancers, and are positively correlated with tumor cell proliferation. Taken together, our findings indicate that DUSP16 plays a role in tumorigenesis by protecting cancer cells from senescence.

As the preliminary synthetic analogs of living cells, protocells with life-like features serve as a versatile platform to explore the origin of life. Although protocells constructed from multiple components have been developed, the transition of primitive cellular compartments toward structural complexity and advanced function remains a scientific challenge. Herein, a programmable pathway is established to exploit a simple chemistry to construct structural transition of protocell models from emulsion droplets, nanocapsules to molecularly crowded droplets. The transitional process toward distinct cell-like compartments is driven by interfacial self-assembly of simple components and regulated by physicochemical cues (e.g., mechanical force, solvent evaporation, acid/base equilibrium) triggered dynamic covalent chemistry. These protocell models are further studied by comparing their compartmentalization behavior, sequestration efficiency, and the ability to enrich biomolecules (e.g., enzyme and substrate) toward catalytic reaction or biological activity within the compartments. The results showcase physiochemical cues-driven programmable transition of life-like compartments toward functionalization, and offer a new step toward the design of living soft materials.

No abstract

A photoactive membraneless protocell from cooperative coacervation of J-aggregates and polyelectrolytes via liquid–liquid phase separation offers an efficient energy transduction pathway to confine photocatalytic reactions within compartments.

ObjectivesThe purpose of this study was systematically and quantitatively to assess the value of the neutrophil-to-lymphocyte ratio (NLR) for the diagnosis of neonatal sepsis by systematic review and meta-analysis.DesignSystematic review and meta-analysis.MethodsEight major databases, including The Cochrane, PubMed, Embase, Web of Science, CNKI, Wanfang, China Biomedical Literature Database and VIP Database, were systematically searched for NLR diagnoses of neonatal sepsis from inception to June 2022. Two investigators independently conducted the literature search, screening, data extraction and quality evaluation with the Quality Assessment of Diagnostic Accuracy Studies-2 checklist. Statistical analysis was performed using Review Manager V.5.3, Stata V.16.0, R (V.3.6.0) and Meta-DISC V.1.4.ResultsA total of 14 studies comprising 1499 newborns were included in this meta-analysis. With a cut-off value ranging from 0.1 to 9.4, the pooled sensitivity of the NLR in the diagnosis of neonatal sepsis was 0.74 (95% CI: 0.61 to 0.83), the pooled specificity was 0.88 (95% CI: 0.73 to 0.95), the positive likelihood ratio (LR+) was 6.35 (95% CI: 2.6 to 15.47), the negative likelihood ratio (LR−) was 0.30 (95% CI: 0.19 to 0.46), the diagnostic OR (DOR) was 12.88 (95% CI: 4.47 to 37.08), area under the curve (AUC) was 0.87 (95% CI: 0.84 to 0.89). In the subgroup analysis of early-onset neonatal sepsis, the pooled sensitivity was 0.75 (95% CI: 0.47 to 0.91), the pooled specificity was 0.99 (95% CI: 0.88 to 1.00), the LR+was 63.3 (95% CI: 5.7 to 696.8), the LR−was 0.26 (95% CI: 0.10 to 0.63), the DOR was 247 (95% CI: 16 to 3785) and the AUC was 0.97 (95% CI: 0.95 to 0.98).ConclusionsOur findings suggest that the NLR is a helpful indicator for the diagnosis of early neonatal sepsis, but it still needs to be combined with other laboratory tests and specific clinical manifestations.

Living systems create complex structures and functions by mastering self-organization in a variety of equilibrium and non-equilibrium states. Mimicking the dynamical phenomena with synthetic cell-like entities (protocells) under non-equilibrium conditions offers an important step toward the representation of minimum life. Here, the cell-sized coacervate microdroplets assembled from associative metallosurfactant coacervation via liquid-liquid phase separation (LLPS) that exhibits non-equilibrium behaviors are reported. The compartmentalized protocell coacervates display collective dynamics that synchronize into system oscillations, showing autonomous death/regeneration and contraction/expansion cycles with external redox stress. The collective oscillation of abiotic metallosurfactant microdroplets can sustain both in solution and at the colloidal interface, allowing for dynamic sequestration, mass transport, and passing through nanosized channels, reminiscent of red blood cells that can deform and squeeze through narrow capillaries. The design of self-oscillating cell-sized constructs will shed a light on the creation of life-like soft materials with autonomous motion driven by complex chemical stimuli, which can be further used as nonbiological models for dynamic aggregates and intercellular communication.