Gene therapy corrects the neurological deficits of mice with sialidosis.

Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the neuraminidase 1 (NEU1) gene. Currently, there is no treatment for sialidosis. In this study, we developed an adeno-associated virus (AAV)-mediated gene therapy for a Neu1 knockout (Neu1-/-) mouse model of sialidosis. The vector, AAV9-P3-NP, included the human NEU1 promoter, NEU1 cDNA, IRES, and CTSA cDNA. Untreated Neu1-/- mice showed astrogliosis and microglial LAMP1 accumulation in the nervous system, including brain, spinal cord, and dorsal root ganglion, together with impaired motor function. Coexpression of NEU1 and protective protein/cathepsin A (PPCA) in neonatal Neu1-/- mice by intracerebroventricular injection, and less effective by facial vein injection, decreased astrogliosis and LAMP1 accumulation in the nervous system and improved rotarod performance of the treated mice. Facial vein injection also improved the grip strength and survival of Neu1-/- mice. Therefore, cerebrospinal fluid delivery of AAV9-P3-NP, which corrects the neurological deficits of mice with sialidosis, could be a suitable treatment for patients with sialidosis type I. After intracerebroventricular or facial vein injection of AAV vectors, NEU1 and PPCA are expressed together. PPCA-protected NEU1 is then sent to lysosomes, where ß-Gal binds to this complex to form a multienzyme complex in order to execute its function.

Engineering a Rolling-Circle Strand Displacement Amplification Mediated Label-Free Ultrasensitive Electrochemical Biosensing Platform.

In this work, an original rolling-circle strand displacement amplification (RC-SDA) was developed by introducing a circle DNA with two recognition domains as a template instead of the limited liner DNA template in traditional strand displacement amplification (SDA), which displayed much shorter reaction time down to 30 min and quite higher conversion efficiency of more than 1.77 × 108 compared with those of traditional strand displacement amplification (SDA) and could be applied to construct a label-free biosensor for ultrasensitive detection of an HIV DNA fragment. Once the target HIV DNA fragment interacts with the template circle DNA, the RC-SDA could be activated to dramatically output amounts of mimic target DNA with the assistance of the Phi29 DNA polymerase and Nb.BbvCI enzyme. In application, while the output products were captured by the DNA tetrahedral nanoprobe (DTNP) modified electrode, the electrochemical tag silver nanoclusters (AgNCs) on DTNP would be released from the electrode surface, accompanied with an obviously decreased electrochemical signal. This way, the developed signal-off biosensor was successfully applied to realize the rapid and ultrasensitive detection of target HIV DNA fragment with a detection limit down to 0.21 fM, which exploits the new generation of a universal strategy beyond the traditional ones for applications in biosensing assay, clinic diagnosis, and DNA nanobiotechnology.

Critical Role of Simultaneous Reduction of Atmospheric Odd Oxygen for Winter Haze Mitigation.

The lockdown due to COVID-19 created a rare opportunity to examine the nonlinear responses of secondary aerosols, which are formed through atmospheric oxidation of gaseous precursors, to intensive precursor emission reductions. Based on unique observational data sets from six supersites in eastern China during 2019-2021, we found that the lockdown caused considerable decreases (32-61%) in different secondary aerosol components in the study region because of similar-degree precursor reductions. However, due to insufficient combustion-related volatile organic compound (VOC) reduction, odd oxygen (Ox = O3 + NO2) concentration, an indicator of the extent of photochemical processing, showed little change and did not promote more decreases in secondary aerosols. We also found that the Chinese provinces and international cities that experienced reduced Ox during the lockdown usually gained a greater simultaneous PM2.5 decrease than other provinces and cities with an increased Ox. Therefore, we argue that strict VOC control in winter, which has been largely ignored so far, is critical in future policies to mitigate winter haze more efficiently by reducing Ox simultaneously.

Synthetic Immunogenic Cell Death Mediated by Intracellular Delivery of STING Agonist Nanoshells Enhances Anticancer Chemo-immunotherapy.

Many favorable anticancer treatments owe their success to the induction immunogenic cell death (ICD) in cancer cells, which results in the release of endogenous danger signals along with tumor antigens for effective priming of anticancer immunity. We describe a strategy to artificially induce ICD by delivering the agonist of stimulator of interferon genes (STING) into tumor cells using hollow polymeric nanoshells. Following intracellular delivery of exogenous adjuvant, subsequent cytotoxic treatment creates immunogenic cellular debris that spatiotemporally coordinate tumor antigens and STING agonist in a process herein termed synthetic immunogenic cell death (sICD). sICD is indiscriminate to the type of chemotherapeutics and enables colocalization of exogenously administered immunologic adjuvants and tumor antigens for enhanced antigen presentation and anticancer adaptive response. In three mouse tumor models, sICD enhances therapeutic efficacy and restrains tumor progression. The study highlights the benefit of delivering STING agonists to cancer cells, paving ways to new chemo-immunotherapeutic designs.

Viromimetic STING Agonist-Loaded Hollow Polymeric Nanoparticles for Safe and Effective Vaccination against Middle East Respiratory Syndrome Coronavirus.

The continued threat of emerging, highly lethal infectious pathogens such as Middle East respiratory syndrome coronavirus (MERS-CoV) calls for the development of novel vaccine technology that offers safe and effective prophylactic measures. Here, a novel nanoparticle vaccine is developed to deliver subunit viral antigens and STING agonists in a virus-like fashion. STING agonists are first encapsulated into capsid-like hollow polymeric nanoparticles, which show multiple favorable attributes, including a pH-responsive release profile, prominent local immune activation, and reduced systemic reactogenicity. Upon subsequent antigen conjugation, the nanoparticles carry morphological semblance to native virions and facilitate codelivery of antigens and STING agonists to draining lymph nodes and immune cells for immune potentiation. Nanoparticle vaccine effectiveness is supported by the elicitation of potent neutralization antibody and antigen-specific T cell responses in mice immunized with a MERS-CoV nanoparticle vaccine candidate. Using a MERS-CoV-permissive transgenic mouse model, it is shown that mice immunized with this nanoparticle-based MERS-CoV vaccine are protected against a lethal challenge of MERS-CoV without triggering undesirable eosinophilic immunopathology. Together, the biocompatible hollow nanoparticle described herein provides an excellent strategy for delivering both subunit vaccine candidates and novel adjuvants, enabling accelerated development of effective and safe vaccines against emerging viral pathogens.

Follicular B Cells Promote Atherosclerosis via T Cell-Mediated Differentiation Into Plasma Cells and Secreting Pathogenic Immunoglobulin G.

OBJECTIVE: B cells promote or protect development of atherosclerosis. In this study, we examined the role of MHCII (major histocompatibility II), CD40 (cluster of differentiation 40), and Blimp-1 (B-lymphocyte-induced maturation protein) expression by follicular B (FO B) cells in development of atherosclerosis together with the effects of IgG purified from atherosclerotic mice. APPROACH AND RESULTS: Using mixed chimeric Ldlr-/- mice whose B cells are deficient in MHCII or CD40, we demonstrate that these molecules are critical for the proatherogenic actions of FO B cells. During development of atherosclerosis, these deficiencies affected T-B cell interactions, germinal center B cells, plasma cells, and IgG. As FO B cells differentiating into plasma cells require Blimp-1, we also assessed its role in the development of atherosclerosis. Blimp-1-deficient B cells greatly attenuated atherosclerosis and immunoglobulin-including IgG production, preventing IgG accumulation in atherosclerotic lesions; Blimp-1 deletion also attenuated lesion proinflammatory cytokines, apoptotic cell numbers, and necrotic core. To determine the importance of IgG for atherosclerosis, we purified IgG from atherosclerotic mice. Their transfer but not IgG from nonatherosclerotic mice into Ldlr-/- mice whose B cells are Blimp-1-deficient increased atherosclerosis; transfer was associated with IgG accumulating in atherosclerotic lesions, increased lesion inflammatory cytokines, apoptotic cell numbers, and necrotic core size. CONCLUSIONS: The mechanism by which FO B cells promote atherosclerosis is highly dependent on their expression of MHCII, CD40, and Blimp-1. FO B cell differentiation into IgG-producing plasma cells also is critical for their proatherogenic actions. Targeting B-T cell interactions and pathogenic IgG may provide novel therapeutic strategies to prevent atherosclerosis and its adverse cardiovascular complications.

Interaction of heat shock protein 60 (HSP60) with microRNA in Chinese mitten crab during Spiroplasma eriocheiris infection.

Heat shock protein 60 from the Chinese mitten crab Eriocheir sinensis (EsHSP60) was previously identified in relation to Spiroplasma eriocheiris infection by isobaric tags for relative and absolute quantitation labelling followed by liquid chromatography-tandem mass spectrometry. In the present study, to validate the immune function of this protein, the cDNA of the EsHSP60 gene was cloned. Various crab tissues were assessed using real-time PCR, which showed that EsHSP60 transcription occurred in all tissues examined. The expression profiles of EsHSP60 in haemolymph at transcription and protein levels when infected with S. eriocheiris were investigated by real-time PCR and Western blot analysis, respectively. A significant increase of EsHSP60 transcription and protein expression appeared post-injection in response to S. eriocheiris infection when compared to the control group. The double-luciferase reporter gene assay showed that the microRNA PC-533-3p interacted with the 3'-untranslated region of EsHSP60 and inhibited the translation of EsHSP60. The expression profiles of PC-533-3p during S. eriocheiris infection were also investigated by real-time PCR. However, the change tendency of PC-533-3p was opposite to that of the EsHSP60 after S. eriocheiris challenge. These data indicate that the EsHSP60 proteins may play an important role in mediating the immune responses of E. sinensis to an S. eriocheiris challenge.

Alleviation of Ultraviolet B-Induced Photodamage by Coffea arabica Extract in Human Skin Fibroblasts and Hairless Mouse Skin.

Coffea arabica extract (CAE) containing 48.3 ± 0.4 mg/g of chlorogenic acid and a trace amount of caffeic acid was found to alleviate photoaging activity in human skin fibroblasts. In this study, polyphenol-rich CAE was investigated for its antioxidant and antiinflammatory properties, as well as for its capability to alleviate ultraviolet B (UVB)-induced photodamage in BALB/c hairless mice. The results indicated that 500 µg/mL of CAE exhibited a reducing power of 94.7%, ferrous ion chelating activity of 46.4%, and hydroxyl radical scavenging activity of 20.3%. The CAE dose dependently reduced UVB-induced reactive oxygen species (ROS) generation in fibroblasts. Furthermore, CAE inhibited the UVB-induced expression of cyclooxygenase-2 and p-inhibitor κB, and the translocation of nuclear factor-kappa B (NF-κB) to the nucleus of fibroblasts. In addition, CAE alleviated UVB-induced photoaging and photodamage in BALB/c hairless mice by restoring the collagen content and reduced UVB-induced epidermal hyperplasia. CAE also inhibited UVB-induced NF-κB, interleukin-6, and matrix metalloproteinase-1 expression in the hairless mouse skin. The results indicated that CAE exhibits antiphotodamage activity by inhibiting UV-induced oxidative stress and inflammation. Therefore, CAE is a candidate for use in antioxidant, antiinflammatory, and antiphotodamage products.

In vitro activity of SecA inhibitors in combination with carbapenems against carbapenem-hydrolysing class D ß-lactamase-producing Acinetobacter baumannii.

OBJECTIVES: According to our previous study, OXA-58 translocates to the periplasm via the Sec pathway in carbapenem-resistant Acinetobacter baumannii (CRAb). In the present study, carbapenem-hydrolysing class D ß-lactamases (CHDLs) belonging to the OXA-23, OXA-40 and OXA-51 families were examined to determine whether they are also Sec-dependent. Additionally, the effects of SecA inhibitors combined with carbapenems against CHDL-producing CRAb were examined. METHODS: Cell fractionation and western blot analyses were performed to detect periplasmic His-tagged CHDLs. A chequerboard analysis with pairwise combinations of carbapenems (imipenem or meropenem) and SecA inhibitors (rose bengal, sodium azide or erythrosin B) was performed using six clinical CRAb isolates harbouring different CHDL genes. The fractional inhibitory concentration (FIC) index was determined. The combination with the lowest FIC index was subjected to a time-kill analysis to examine synergistic effects. RESULTS: In an in silico analysis, the CHDLs OXA-23, OXA-40 and OXA-51 were preferentially translocated via the Sec system. The SecA inhibitor rose bengal decreased periplasmic translocation of His-tagged OXA-23 and OXA-83 (belonging to the OXA-51 family), but not OXA-72 (belonging to the OXA-40 family) from ATCC 15151 transformants. Imipenem or meropenem with rose bengal showed synergistic effects (FIC index, ≤0.5) for six and four clinical isolates, respectively. Imipenem or meropenem with sodium azide showed no interactions (FIC index, 0.5-4) against all clinical isolates. Imipenem and rose bengal had the lowest FIC index and showed synergy at 24 h in the time-kill assay. CONCLUSIONS: Combinations of SecA inhibitors and carbapenems have synergistic effects against CHDL-producing CRAb.

Human amniotic epithelial cells suppress relapse of corticosteroid-remitted experimental autoimmune disease.

BACKGROUND AIMS: Multiple sclerosis (MS) is considered to be a T-cell-mediated disease. Although MS remits with corticosteroid treatment, the disease relapses on discontinuation of therapy. Human amniotic epithelial cells (hAEC) from the placenta are readily accessible in large quantities and have anti-inflammatory properties. Previously we reported that hAEC given near disease onset ameliorated clinical signs and decreased myelin oligodendrocyte glycoprotein (MOG)-specific immune responses in MOG-induced experimental autoimmune encephalomyelitis (EAE), an experimental MS model. METHODS: To examine the therapeutic effect of hAEC in a clinically relevant setting, we first treated MOG peptide-induced EAE mice with a corticosteroid, prednisolone, in drinking water to induce remission. hAEC were then infused intravenously into the remitted mice. Anti-MOG antibodies in serum were detected by enzyme-linked immunoassay. Splenocyte proliferation was assessed by (3)H-thymidine incorporation. Immune cell subpopulations in spleens and lymph nodes and secreted cytokines in splenocyte culture were quantified by flow cytometry. Central nervous system histology was examined with the use of hematoxylin and eosin, Luxol fast blue and immunostaining. RESULTS: With cessation of prednisolone treatment, hAEC delayed EAE relapse for 7 days, and, after another 7 days, largely remitted disease in six of eight responder mice. Splenocyte proliferation was suppressed, anti-MOG35-55 antibodies in serum were decreased and interleukin-2 and interleukin-5 production by splenocytes were elevated after hAEC treatment. In the central nervous system, hAEC-treated mice had decreased demyelination and fewer macrophages in the inflammatory infiltrates. hAEC treatment also increased CD4(+)CD25(+)FoxP3(+) regulatory T cells in inguinal lymph nodes. CONCLUSIONS: These data demonstrate that the therapeutic effects of hAEC after corticosteroid treatment in an MS model probably are the consequence of peripheral immunoregulation. We suggest that hAEC may have potential as a cell therapy for remitted MS.

Application of three-dimensional material CZIF-8/CS-MS as adsorbents for the determination of plant growth regulators in Schisandra chinensis.

In this study, we employed a melamine sponge (MS) as the skeleton material and utilized carbonized ZIF-8 (CZIF-8) and chitosan (CS) as the raw materials to prepare CZIF-8/CS-MS, a novel material featuring a three-dimensional interconnected porous network. The resulting CZIF-8/CS-MS material possesses a unique porous structure, significant specific surface area and abundant active sites. These characteristics make CZIF-8/CS-MS a promising absorbent for selective purification of plant growth regulators (PGRs) including 1-naphthlcetic acid (NAA), naphthoxyacetic acid (NOA), 4-chlorophenoxyacetic acid (4-CPA), 2,4-dichlorophenoxyacetic acid (2,4-D). After optimizing the extraction conditions, excellent linearity (r > 0.9994) was observed within a wide linear range of 1-100 ng/mL using ultra high performance liquid chromatography-tandem quadrupole mass spectrometry. The detection limits (LODs) and limits of quantification (LOQs) were found to be in the range of 0.013-0.154 ng/mL and 0.044-0.515 ng/mL, respectively. Additionally, the relative recovery of Schisandra chinensis fruit samples was determined to be 89.7-99.4 %, with a relative standard deviation (RSDs) of ≤ 8.4 % (n = 3). Compared to other methods, this approach offers a multitude of benefits, which include but are not limited to exceptional sensitivity, reduced sample volume requirements, low LODs, a comparable linear range, and high reproducibility. The findings of this study pave the way for exploring novel functionalized sponge columns, which leverage the integration of nano-sorbent materials and coating agents, for the purpose of analyzing PGRs within intricate matrix samples.

Effects of mindful breathing training combined with diary-based rehabilitation guidance in lung cancer patients undergoing surgery: A randomized controlled trial.

BACKGROUND AND PURPOSE: Lung cancer surgery patients experience severe physical and mental symptoms, which seriously affect their quality of life and prognosis. Mindful breathing training is a promising strategy to improve their symptoms, but its effectiveness is affected by training compliance, and diary-based rehabilitation instruction has been shown to help improve training compliance. Therefore, the aim of this study was to evaluate the effects of mindful breathing training combined with diary-based rehabilitation guidance on improving perioperative outcomes in lung cancer surgery patients. MATERIALS AND METHODS: This single-center, assessor-blinded, prospective, three-arm randomized controlled trial was conducted from November 1, 2021 to November 1, 2022. Patients diagnosed with primary non-small cell lung cancer and scheduled for thoracoscopic surgery were randomly allocated to the combined intervention group, the mindful breathing group or the control group, with 34 patients in each group. The control group received routine care, while the mindful breathing group received mindful breathing training and routine care. The combined intervention group received both mindful breathing training and diary-based rehabilitation guidance, along with routine care. RESULTS: The per-protocol analysis revealed that patients in the mindful breathing group experienced statistically significant improvements in dyspnea, fatigue and anxiety. Patients in the combined intervention group had statistically significant improvements in dyspnea, fatigue, anxiety, depression, exercise self-efficacy and training compliance. CONCLUSION: This study provides evidence that mindful breathing training combined with diary-based rehabilitation guidance can be effective in improving perioperative outcomes in lung cancer patients. It can be applied in clinical practice in the future.

Rapid plasma membrane isolation via intracellular polymerization-mediated biomolecular confinement.

Plasma membrane isolation is a foundational process in membrane proteomic research, cellular vesicle studies, and biomimetic nanocarrier development, yet separation processes for this outermost layer are cumbersome and susceptible to impurities and low yield. Herein, we demonstrate that cellular cytosol can be chemically polymerized for decoupling and isolation of plasma membrane within minutes. A rapid, non-disruptive in situ polymerization technique is developed with cell membrane-permeable polyethyleneglycol-diacrylate (PEG-DA) and a blue-light-sensitive photoinitiator, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP). The photopolymerization chemistry allows for precise control of intracellular polymerization and tunable confinement of cytosolic molecules. Upon cytosol solidification, plasma membrane proteins and vesicles are rapidly derived and purified as nucleic acids and intracellular proteins as small as 15 kDa are stably entrapped for removal. The polymerization chemistry and membrane derivation technique are broadly applicable to primary and fragile cell types, enabling facile membrane vesicle extraction from shorted-lived neutrophils and human primary CD8 T cells. The study demonstrates tunable intracellular polymerization via optimized live cell chemistry, offers a robust membrane isolation methodology with broad biomedical utility, and reveals insights on molecular crowding and confinement in polymerized cells. STATEMENT OF SIGNIFICANCE: Isolating the minute fraction of plasma membrane proteins and vesicles requires extended density gradient ultracentrifugation processes, which are susceptible to low yield and impurities. The present work demonstrates that the membrane isolation process can be vastly accelerated via a rapid, non-disruptive intracellular polymerization approach that decouples cellular cytosols from the plasma membrane. Following intracellular polymerization, high-yield plasma membrane proteins and vesicles can be derived from lysis buffer and sonication treatment, respectively. And the intracellular content entrapped within the polymerized hydrogel is readily removed within minutes. The technique has broad utility in membrane proteomic research, cellular vesicle studies, and biomimetic materials development, and the work offers insights on intracellular hydrogel-mediated molecular confinement.

Apoptosis of Ascogregarina taiwanensis (Apicomplexa: Lecudinidae), which failed to migrate within its natural host.

Sexual reproduction of Ascogregarina taiwanensis (Apicomplexa: Lecudinidae), a parasite specific to the mosquito Aedes albopictus, in Malpighian tubules is initiated by the entry of the trophotozoites developed in the midgut shortly after pupation (usually <5 h). However, only a low proportion of trophozoites are able to migrate; others end up dying. In this study, we demonstrated that those trophozoites that failed to migrate eventually died of apoptosis. Morphological changes such as shrinkage, chromatin aggregations and formation of blunt ridges on the surface were seen in moribund trophozoites. In addition, DNA fragmentation of trophozoites isolated from the midgut of pupae was demonstrated by the presence of DNA ladders, Annexin V staining and TUNEL assays. Detection of caspase-like activity suggests that apoptosis of those trophozoites may have occurred through a mechanism of an intrinsic or mitochondrial-mediated pathway. Although apoptosis has been observed in various protozoan species, it is not clear how apoptosis in single-celled organisms might result from evolution by natural selection. However, we speculate that apoptosis may regulate the parasite load of A. taiwanensis within its natural mosquito host, leading to an optimized state of the survival rate for both parasite and host.

Engineering ß-ketoamine covalent organic frameworks for photocatalytic overall water splitting.

Covalent organic frameworks (COFs) are an emerging type of crystalline and porous photocatalysts for hydrogen evolution, however, the overall water splitting activity of COFs is rarely known. In this work, we firstly realized overall water splitting activity of ß-ketoamine COFs by systematically engineering N-sites, architecture, and morphology. By in situ incorporating sub-nanometer platinum (Pt) nanoparticles co-catalyst into the pores of COFs nanosheets, both Pt@TpBpy-NS and Pt@TpBpy-2-NS show visible-light-driven overall water splitting activity, with the optimal H2 and O2 evolution activities of 9.9 and 4.8 µmol in 5 h for Pt@TpBpy-NS, respectively, and a maximum solar-to-hydrogen efficiency of 0.23%. The crucial factors affecting the activity including N-sites position, nano morphology, and co-catalyst distribution were systematically explored. Further mechanism investigation reveals the tiny diversity of N sites in COFs that induces great differences in electron transfer as well as reaction potential barriers.

Loss of Flot2 expression in deep cerebellar nuclei neurons of mice with Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is caused by a deficiency of the NPC1 or NPC2 gene, leading to storages of unesterified cholesterol and sphingolipids. Cerebellar ataxia is a main symptom of NPC and the deep cerebellar nuclei (DCN) is the sole signal output of the cerebellum. In this study, we explored the pathological changes in DCN neurons of Npc1 knockout mice (Npc1-). We first demonstrated that DCN neurons of Npc1- mice had prominent ganglioside GM2 accumulation in the late endosomes but not in the lysosomes. More importantly, Flot2 expression, a marker for the lipid rafts, was lost. Single-nucleus RNA sequencing analysis revealed a generalized reduction in gene expression in DCN neurons, though Camk1d, encoding one of the Ca2+/calmodulin-dependent protein kinases (CaMKs), increased in expression. We treated Npc1- mice with CaMK inhibitor KN-93, but CaMK1D expression increased further. We also fed Npc1- mice with two medications for NPC. We found that miglustat, a sphingolipid synthesis inhibitor, increased the expression of Flot2. Moreover, N-acetyl l-leucine (NALL), an experimental medicine for NPC, recovered Flot2 expression. Therefore, our data suggest that in Npc1- mice, GM2 sequestration and the loss of lipid rafts lead to cell dysfunction and symptoms of NPC.

Constructing tightly integrated conductive metal-organic framework/covalent triazine framework heterostructure by coordination bonds for photocatalytic hydrogen evolution.

The construction of tightly integrated heterostructures with metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) has been confirmed to be an effective way for improved hydrogen evolution. However, the reported tightly integrated MOF/COF hybrids were usually limited to the covalent connection of COFs with aldehyde groups and NH2-MOF via Schiff base reaction, restricting the development of MOF/COF hybrids. Herein, a covalent triazine framework (CTF-1), a subtype of crystalline COFs, was integrated with a conductive two-dimensional (2D) MOF (Ni-CAT-1) by a novel coordinating connection mode for significantly enhanced visible-light-driven hydrogen evolution. The terminal amidine groups in the CTF-1 layers offer dual N sites for the coordination of metal ions, which provides the potential of coordinating connection between CTF-1 and Ni-CAT-1. The conductive 2D Ni-CAT-1 in Ni-CAT-1/CTF-1 hybrids effectively facilitates the separation of photogenerated carriers of CTF-1 component, and the resultant hybrid materials show significantly enhanced photocatalytic hydrogen evolution activity. In particular, the Ni-CAT-1/CTF-1 (1:19) sample exhibits the maximum hydrogen evolution rate of 8.03 mmol g-1h-1, which is about four times higher than that of the parent CTF-1 (1.96 mmol g-1h-1). The enhanced photocatalytic activity of Ni-CAT-1/CTF-1 is mainly attributed to the incorporation of conductive MOF which leads to the formation of a Z-Scheme heterostructure, promoting the electron transfer in hybrid materials. The coordinating combination mode of Ni-CAT-1 and CTF-1 in this work provides a novel strategy for constructing tightly integrated MOF/COF hybrid materials.

Engineering Cyborg Bacteria Through Intracellular Hydrogelation.

Natural and artificial cells are two common chassis in synthetic biology. Natural cells can perform complex tasks through synthetic genetic constructs, but their autonomous replication often causes safety concerns for biomedical applications. In contrast, artificial cells based on nonreplicating materials, albeit possessing reduced biochemical complexity, provide more defined and controllable functions. Here, for the first time, the authors create hybrid material-cell entities termed Cyborg Cells. To create Cyborg Cells, a synthetic polymer network is assembled inside each bacterium, rendering them incapable of dividing. Cyborg Cells preserve essential functions, including cellular metabolism, motility, protein synthesis, and compatibility with genetic circuits. Cyborg Cells also acquire new abilities to resist stressors that otherwise kill natural cells. Finally, the authors demonstrate the therapeutic potential by showing invasion into cancer cells. This work establishes a new paradigm in cellular bioengineering by exploiting a combination of intracellular man-made polymers and their interaction with the protein networks of living cells.

Lymph Node Follicle-Targeting STING Agonist Nanoshells Enable Single-Shot M2e Vaccination for Broad and Durable Influenza Protection.

The highly conserved matrix protein 2 ectodomain (M2e) of influenza viruses presents a compelling vaccine antigen candidate for stemming the pandemic threat of the mutation-prone pathogen, yet the low immunogenicity of the diminutive M2e peptide renders vaccine development challenging. A highly potent M2e nanoshell vaccine that confers broad and durable influenza protectivity under a single vaccination is shown. Prepared via asymmetric ionic stabilization for nanoscopic curvature formation, polymeric nanoshells co-encapsulating high densities of M2e peptides and stimulator of interferon genes (STING) agonists are prepared. Robust and long-lasting protectivity against heterotypic influenza viruses is achieved with a single administration of the M2e nanoshells in mice. Mechanistically, molecular adjuvancy by the STING agonist and nanoshell-mediated prolongation of M2e antigen exposure in the lymph node follicles synergistically contribute to the heightened anti-M2e humoral responses. STING agonist-triggered T cell helper functions and extended residence of M2e peptides in the follicular dendritic cell network provide a favorable microenvironment that induces Th1-biased antibody production against the diminutive antigen. These findings highlight a versatile nanoparticulate design that leverages innate immune pathways for enhancing the immunogenicity of weak immunogens. The single-shot nanovaccine further provides a translationally viable platform for pandemic preparedness.

Curcuma Longa Induces the Transcription Factor FOXP3 to Downregulate Human Chemokine CCR5 Expression and Inhibit HIV-1 Infection.

HIV mutations occur frequently despite the substantial success of combination antiretroviral therapy, which significantly impairs HIV progression. Failure to develop specific vaccines, the occurrence of drug-resistant strains, and the high incidence of adverse effects due to combination antiviral therapy regimens call for novel and safer antivirals. Natural products are an important source of new anti-infective agents. For instance, curcumin inhibits HIV and inflammation in cell culture assays. Curcumin, the principal constituent of the dried rhizomes of Curcuma longa L. (turmeric), is known as a strong anti-oxidant and anti-inflammatory agent with different pharmacological effects. This work aims to assess curcumin's inhibitory effects on HIV in vitro and to explore the underpinning mechanism, focusing on CCR5 and the transcription factor forkhead box protein P3 (FOXP3). First, curcumin and the RT inhibitor zidovudine (AZT) were evaluated for their inhibitory properties. HIV-1 pseudovirus infectivity was determined by green fluorescence and luciferase activity measurements in HEK293T cells. AZT was used as a positive control that inhibited HIV-1 pseudoviruses dose-dependently, with IC50 values in the nanomolar range. Then, a molecular docking analysis was carried out to assess the binding affinities of curcumin for CCR5 and HIV-1 RNase H/RT. The anti-HIV activity assay showed that curcumin inhibited HIV-1 infection, and the molecular docking analysis revealed equilibrium dissociation constants of [Formula: see text]9.8[Formula: see text]kcal/mol and [Formula: see text]9.3[Formula: see text]kcal/mol between curcumin and CCR5 and HIV-1 RNase H/RT, respectively. To examine curcumin's anti-HIV effect and its mechanism in vitro, cell cytotoxicity, transcriptome sequencing, and CCR5 and FOXP3 amounts were assessed at different concentrations of curcumin. In addition, human CCR5 promoter deletion constructs and the FOXP3 expression plasmid pRP-FOXP3 (with an EGFP tag) were generated. Whether FOXP3 DNA binding to the CCR5 promoter was blunted by curcumin was examined using transfection assays employing truncated CCR5 gene promoter constructs, a luciferase reporter assay, and a chromatin immunoprecipitation (ChIP) assay. Furthermore, micromolar concentrations of curcumin inactivated the nuclear transcription factor FOXP3, which resulted in decreased expression of CCR5 in Jurkat cells. Moreover, curcumin inhibited PI3K-AKT activation and its downstream target FOXP3. These findings provide mechanistic evidence encouraging further assessment of curcumin as a dietary agent used to reduce the virulence of CCR5-tropic HIV-1. Curcumin-mediated FOXP3 degradation was also reflected in its functions, namely, CCR5 promoter transactivation and HIV-1 virion production. Furthermore, curcumin inhibition of CCR5 and HIV-1 might constitute a potential therapeutic strategy for reducing HIV progression.