A Synthetic Multivalent Lipopeptide Derived from Pam3CSK4 with Irreversible Influenza Inhibition and Immuno-Stimulating Effects.

The activation of the host adaptive immune system is crucial for eliminating viruses. However, influenza infection often suppresses the innate immune response that precedes adaptive immunity, and the adaptive immune responses are typically delayed. Dendritic cells, serving as professional antigen-presenting cells, have a vital role in initiating the adaptive immune response. In this study, an immuno-stimulating antiviral system (ISAS) is introduced, which is composed of the immuno-stimulating adjuvant lipopeptide Pam3CSK4 that acts as a scaffold onto which it is covalently bound 3 to 4 influenza-inhibiting peptides. The multivalent display of peptides on the scaffold leads to a potent inhibition against H1N1 (EC50  = 20 nM). Importantly, the resulting lipopeptide, Pam3FDA, shows an irreversible inhibition mechanism. The chemical modification of peptides on the scaffold maintains Pam3CSK4's ability to stimulate dendritic cell maturation, thereby rendering Pam3FDA a unique antiviral. This is attributed to its immune activation capability, which also acts in synergy to expedite viral elimination.

A Benzil- and BODIPY-Based Turn-On Fluorescent Probe for Detection of Hydrogen Peroxide.

Faced with rising threats of terrorism, environmental and health risks, achieving sensitive and selective detection of peroxide-based explosives (PEs) has become a global focus. In this study, a turn-on fluorescent probe (BOD) based on benzil (H2O2-recognition element) and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) derivative (fluorophore) was developed to sensitively and specifically detect hydrogen peroxide (H2O2). The synthesized BOD had a very weak fluorescence due to intramolecular donor-excited photo-induced electron transfer (d-PET) effect; however, it could emit a strong fluorescence since H2O2 selectively oxidized the benzil moiety and released free BODIPY fluorophore (BOD-COOH). As a result, the proposed BOD detected H2O2 in linear detection ranged from 25 to 125 µM with a detection limit of 4.41 µM. Meanwhile, the proposed BOD showed good selectivity toward H2O2, which is not affected by other common reactive oxygen species (ROS) and ions from explosive residues. In addition, a blue shift from 508 to 498 nm was observed in the absorption spectra upon addition of H2O2. More importantly, the BOD was successfully applied for rapid detection of H2O2 vapor with good sensitivity (down to 7 ppb), which holds great potential for practical use in public safety, forensic analysis and environmental monitoring.

A model to predict unstable carotid plaques in population with high risk of stroke.

BACKGROUND: Several models have been developed to predict asymptomatic carotid stenosis (ACS), however these models did not pay much attention to people with lower level of stenosis (<50% or carotid plaques, especially instable carotid plaques) who might benefit from early interventions. Here, we developed a new model to predict unstable carotid plaques through systematic screening in population with high risk of stroke. METHODS: Community residents who participated the China National Stroke Screening and Prevention Project (CNSSPP) were screened for their stroke risks. A total of 2841 individuals with high risk of stroke were enrolled in this study, 266 (9.4%) of them were found unstable carotid plaques. A total of 19 risk factors were included in this study. Subjects were randomly distributed into Derivation Set group or Validation Set group. According to their carotid ultrasonography records, subjects in derivation set group were further categorized into unstable plaque group or stable plaque group. RESULTS: 174 cases and 1720 cases from Derivation Set group were categorized into unstable plaque group and stable plaque group respectively. The independent risk factors for carotid unstable plaque were: male (OR 1.966, 95%CI 1.406-2.749), older age (50-59, OR 6.012, 95%CI 1.410-25.629; 60-69, OR 13.915, 95%CI 3.381-57.267;≥70, OR 31.267, 95%CI 7.472-130.83), married(OR 1.780, 95%CI 1.186-2.672), LDL-C(OR 2.015, 95%CI 1.443-2.814), and HDL-C(OR 2.130, 95%CI 1.360-3.338). A predictive scoring system was generated, ranging from 0 to 10. The cut-off value of this predictive scoring system is 6.5. The AUC value for derivation and validation set group were 0.738 and 0.737 respectively. CONCLUSIONS: For those individuals with high risk of stroke, we developed a new model which could identify those who have a higher chance to have unstable carotid plaques. When an individual's predictive model score exceeds 6.5, the probability of having carotid unstable plaques is high, and carotid ultrasonography should be conducted accordingly. This model could be helpful in the primary prevention of stroke.

Detection of renal brush border membrane enzymes for evaluation of renal injury in neonatal scleredema.

OBJECTIVE: To evaluate renal brush border membrane enzymes in urine as an indicator for renal injury in neonatal scleredema (NS). METHODS: Sixty nine NS patients in our hospital were enrolled and divided into mild group and moderate/severe group. Patients were further randomly divided into therapy and control subgroups for 7 days ligustrazine administration. Urine samples were collected to detect renal brush border membrane enzymes (RBBME) by ELISA and ß2-microglobulin (ß2-MG) by radioimmunoassay (RIA). The results were compared with those of 30 normal neonates. Data were statistically analyzed using SPSS13.0 software. RESULTS: Both RBBME and ß2-MG were found to be higher in urine in NS patients than normal controls (P < 0.01). Level of RBBME increased with the severity of NS (P <0.05), while urinary ß2-MG did not (P >0.05). After being treated with ligustrazine, a medicine for renal function recovery, both RBBME and ß2-MG were similarly significantly decreased comparing to untreated groups (P < 0.05). 79.7% of NS patients showed abnormal RBBME while only 52.2% had an abnormal urinary ß2-MG (χ (2)=11.65，P < 0.01). CONCLUSION: RBBME was more sensitive than ß2-MG in reflecting the renal injury in NS. Examination of RBBME effectively reflected the recovery of renal injury after treatment with ligustrazine.

Design of ProCAs (protein-based Gd(3+) MRI contrast agents) with high dose efficiency and capability for molecular imaging of cancer biomarkers.

Magnetic resonance imaging (MRI) is the leading imaging technique for disease diagnostics, providing high resolution, three-dimensional images noninvasively. MRI contrast agents are designed to improve the contrast and sensitivity of MRI. However, current clinically used MRI contrast agents have relaxivities far below the theoretical upper limit, which largely prevent advancing molecular imaging of biomarkers with desired sensitivity and specificity. This review describes current progress in the development of a new class of protein-based MRI contrast agents (ProCAs) with high relaxivity using protein design to optimize the parameters that govern relaxivity. Further, engineering with targeting moiety allows these contrast agents to be applicable for molecular imaging of prostate cancer biomarkers by MRI. The developed protein-based contrast agents also exhibit additional in vitro and in vivo advantages for molecular imaging of disease biomarkers, such as high metal-binding stability and selectivity, reduced toxicity, proper blood circulation time, and higher permeability in tumor tissue in addition to improved relaxivities.

The association between blood pressure variability and renal damage in patients with primary aldosteronism.

This research examines the association between blood pressure variability (BPV) and renal damage in a cohort of 129 primary aldosteronism (PA) patients, employing ambulatory blood pressure monitoring (ABPM) for comparative analysis with individuals diagnosed with essential hypertension (EH). The study reveals that PA patients exhibited significantly elevated levels of cystatin C and urine microalbumin/creatinine ratio (UACR). Additionally, a higher prevalence of non-dipping blood pressure patterns in PA patients suggests an increased risk of circadian blood pressure regulation disturbances. Notably, while most BPV indices were comparable between the two groups, the standard deviation of 24-h weighted diastolic blood pressure was markedly lower in the PA cohort, distinguishing it as a unique variable. Through multiple linear regression analysis, the duration of hypertension, angiotensin II concentrations, and daytime systolic blood pressure standard deviation emerged as significant determinants of estimated glomerular filtration rate (eGFR) in PA patients. Furthermore, UACR was significantly influenced by variables including the 24-h weighted standard deviation (wSD) of systolic BP, glycosylated hemoglobin levels, nocturnal systolic BP peaks, aldosterone-renin ratio (ARR), and total cholesterol, with the most pronounced association observed with the 24-h wSD of systolic BP (ß = 0.383).The study also found significant correlations between the 24-h wSD of systolic BP, ARR, HbA1c, serum potassium levels, and 24-h urinary microalbumin, underscoring the critical role of the 24-h wSD of systolic BP (ß = 0.267). These findings underscore the imperative of an integrated management strategy for PA, addressing the intricate interconnections among metabolic abnormalities, blood pressure variability, and renal health outcomes.

Benzene with Alkyl Chains Is a Universal Scaffold for Multivalent Virucidal Antivirals.

Most viruses start their invasion by binding to glycoproteins' moieties on the cell surface (heparan sulfate proteoglycans [HSPG] or sialic acid [SA]). Antivirals mimicking these moieties multivalently are known as broad-spectrum multivalent entry inhibitors (MEI). Due to their reversible mechanism, efficacy is lost when concentrations fall below an inhibitory threshold. To overcome this limitation, we modify MEIs with hydrophobic arms rendering the inhibitory mechanism irreversible, i.e., preventing the efficacy loss upon dilution. However, all our HSPG-mimicking MEIs only showed reversible inhibition against HSPG-binding SARS-CoV-2. Here, we present a systematic investigation of a series of small molecules, all containing a core and multiple hydrophobic arms terminated with HSPG-mimicking moieties. We identify the ones that have irreversible inhibition against all viruses including SARS-CoV-2 and discuss their design principles. We show efficacy in vivo against SARS-CoV-2 in a Syrian hamster model through both intranasal instillation and aerosol inhalation in a therapeutic setting (12 h postinfection). We also show the utility of the presented design rules in producing SA-mimicking MEIs with irreversible inhibition against SA-binding influenza viruses.

How China's digital technology development affects the environmental costs related to global value chains? Evidence from regional manufacturing sectors.

China needs to address the environmental costs to participate in global value chains (GVCs) more sustainably. Digitalization presents a potential solution to overcome information barriers and improve energy efficiency in global production networks. However, the impact of digital technology on GVC-related carbon intensity has not been systematically studied. This paper utilizes embedded multi-regional input-output (EMRIO) tables to analyze the relationship between digital technology and GVC-related carbon intensity in China's 28 regions and 11 manufacturing sectors. The study calculates three indexes: digital technology development, the openness degree of digital technology, and the carbon intensity related to GVCs for the years 2002, 2007, 2010, and 2012. Through a fixed-effect model, the paper examines how digital technology can reduce domestic embodied carbon intensity related to GVCs in China. The findings indicate that: (1) digital technology development has a negative impact on GVC-related domestic embodied carbon intensity; (2) digital technology development indirectly reduces domestic embodied carbon intensity by decreasing energy consumption intensity and increasing foreign services' input intensity; (3) enhancing the openness of digital technology in China can strengthen the reduction effect of digital technology development on the environmental cost related to GVCs.

Exploring heterogeneity of tumor immune cells and adrenal cells in aldosterone-producing adenomas using single-cell RNA-seq and investigating differences by sex.

The mechanism behind the higher incidence of aldosterone-producing adenoma (APA) in women compared to men is not yet understood. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to investigate the immune cell infiltration and adrenal cell characteristics in APA. Our findings revealed a high presence of immune cells in the tumor microenvironment, with macrophages and T lymphocytes being the most prevalent. Comparison of infiltrating cells between males and females showed that female CD8+T cells had stronger cytotoxic and inflammation-related functions, while female myeloid cells had more enrichment in inflammatory pathways. Additionally, we found that female adrenal cells had greater upregulation of immune-related and antigen presentation pathways. Furthermore, our analysis revealed that zona glomerulosa (ZG) cells had a higher capability for aldosterone synthesis. These results provide a deeper understanding of the APA microenvironment in patients of different sexes and offer new insights into the onset of APA.

Temporal changes of blood mercury concentrations in Chinese newborns and the general public from 1980s to 2020s.

Mercury (Hg) is a global pollutant that threatens the environment and human health. As a major producer, emitter and consumer of Hg, China is currently taking different measures to curb mercury pollution in accordance with the requirements of the Minamata Convention on Mercury. Blood Hg can reflect the human body's recent exposure to Hg. This review summarized the temporal changes in blood Hg concentrations in newborns and the general public in China from 1980 s to 2020 s. It was shown that the blood Hg concentrations of newborns showed the downward trend, although it was not significant. The general public Hg concentrations showed a trend of first increase and then decrease trend. Most of the cord blood Hg and venous blood Hg concentrations in China were lower than the USEPA reference concentration of 5.8 µg/L. Since low-dose prenatal Hg exposure can affect fetal and neonatal development, continuous attention needs to be paid to reduce maternal and neonatal Hg exposure. The information provided in this review may lay a basis for the effectiveness evaluation on the implementation of Minamata Convention on Mercury.

Peptide-Grafted Nontoxic Cyclodextrins and Nanoparticles against Bacteriophage Infections.

One of the biggest threats for bacteria-based bioreactors in the biotechnology industry is infections caused by bacterial viruses called bacteriophages. More than 70% of companies admitted to encountering this problem. Despite phage infections being such a dangerous and widespread risk, to date, there are no effective methods to avoid them. Here we present a peptide-grafted compounds that irreversibly deactivate bacteriophages and remain safe for bacteria and mammalian cells. The active compounds consist of a core (cyclodextrin or gold nanoparticle) coated with a hydrophobic chain terminated with a peptide selective for bacteriophages. Such peptides were selected via a phage display technique. This approach enables irreversible deactivation of the wide range of T-like phages (including the most dangerous in phage infections, phage T1) at 37 °C in 1 h. We show that our compounds can be used directly inside the environment of the bioreactor, but they are also a safe additive to stocks of antibiotics and expression inducers (such as isopropyl ß-d-1-thiogalactopyranoside, i.e., IPTG) that cannot be autoclaved and are a common source of phage infections.

Redox-Responsive Polycondensate Neoepitope for Enhanced Personalized Cancer Vaccine.

A versatile and highly effective platform remains a major challenge in the development of personalized cancer vaccines. Here, we devised a redox-responsive polycondensate neoepitope (PNE) through a reversible polycondensation reaction of peptide neoantigens and adjuvants together with a tracelessly responsive linker-monomer. Peptide-based neoantigens with diverse sequences and structures could be copolymerized with molecular adjuvants to form PNEs of high loading capacity for vaccine delivery without adding any carriers. The redox-responsive PNEs with controlled molecular weights and sizes efficiently targeted and accumulated in draining lymph nodes and greatly promoted the antigen capture and cross-presentation by professional antigen presenting cells. Mice immunized with PNEs showed markedly enhanced antigen-specific T cell response and the protective immunity against the tumor cell challenge.

Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells.

Interleukin-2 (IL-2) is a potent T-cell mitogen that can adjuvant anti-cancer adoptive T-cell transfer (ACT) immunotherapy by promoting T-cell engraftment. However, the clinical applications of IL-2 in combination with ACT are greatly hindered by the severe adverse effects such as vascular leak syndrome (VLS). Here, we developed a synthetic delivery strategy for IL-2 via backpacking redox-responsive IL-2/Fc nanogels (NGs) to the plasma membrane of adoptively transferred T-cells. The NGs prepared by traceless chemical cross-linking of cytokine proteins selectively released the cargos in response to T-cell receptor activation upon antigen recognition in tumors. We found that IL-2/Fc delivered by T-cell surface-bound NGs expanded transferred tumor-reactive T-cells 80-fold more than the free IL-2/Fc of an equivalent dose administered systemically and showed no effects on tumor-infiltrating regulatory T-cell expansion. Intriguingly, IL-2/Fc NG backpacks that facilitated a sustained and slow release of IL-2/Fc also promoted the CD8+ memory precursor differentiation and induced less T-cell exhaustion in vitro compared to free IL-2/Fc. The controlled responsive delivery of IL-2/Fc enabled the safe administration of repeated doses of the stimulant cytokine with no overt toxicity and improved efficacy against melanoma metastases in a mice model.

Rational design of protein-based MRI contrast agents.

We describe the rational design of a novel class of magnetic resonance imaging (MRI) contrast agents with engineered proteins (CAi.CD2, i = 1, 2,..., 9) chelated with gadolinium. The design of protein-based contrast agents involves creating high-coordination Gd(3+) binding sites in a stable host protein using amino acid residues and water molecules as metal coordinating ligands. Designed proteins show strong selectivity for Gd(3+) over physiological metal ions such as Ca(2+), Zn(2+), and Mg(2+). These agents exhibit a 20-fold increase in longitudinal and transverse relaxation rate values over the conventional small-molecule contrast agents, e.g., Gd-DTPA (diethylene triamine pentaacetic acid), used clinically. Furthermore, they exhibit much stronger contrast enhancement and much longer blood retention time than Gd-DTPA in mice. With good biocompatibility and potential functionalities, these protein contrast agents may be used as molecular imaging probes to target disease markers, thereby extending applications of MRI.

Immunoengineering with biomaterials for enhanced cancer immunotherapy.

Cancer immunotherapy has recently shown dramatic clinical success inducing durable response in patients of a wide variety of malignancies. Further improvement of the clinical outcome with immune related cancer treatment requests more exquisite manipulation of a patient's immune system with increased immunity against diseases while mitigating the toxicities. To meet this challenge, biomaterials applied to immunoengineering are being developed to achieve tissue- and/or cell-specific immunomodulation and thus could potentially enhance both the efficacy and safety of current cancer immunotherapies. Here, we review the recent advancement in the field of immunoengineering using biomaterials and their applications in promoting different modalities of cancer immunotherapies, with focus on cell-, antibody-, immunomodulator-, and gene-based immune related treatments and their combinations with conventional therapies. Challenges and opportunities are discussed in applying biomaterials engineering strategies in the development of future cancer immunotherapies. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanomaterials and Implants.

Study on combustion of gasoline/MTBE in laminar flame with synchrotron radiation.

Synchrotron radiation offers important advantages with the use of tunable vacuum ultraviolet (VUV) lasers for molecular beam sampling mass spectrometry (MBMS). These advantages include superior signal-to-noise, soft ionization, and access to photon energies outside the limited tuning ranges of current VUV laser sources. Combining MBMS with tunable synchrotron radiation photoionization, two similar types of fuels, gasoline/oxygen and gasoline/MTBE/oxygen in low-pressure premixed laminar flame were investigated. Photoionization efficiency (PIE) measurements were used to identify the intermediates isomers within flame. The two combustion processes are discussed by comparing the intermediates and their spatial profiles within the two kinds of flame mentioned above.

Effects of hyperbaric oxygen and nerve growth factor on the long-term neural behavior of neonatal rats with hypoxic ischemic brain damage.

PURPOSE:: To evaluate the effects of HBO (Hyperbaric oxygen) and NGF (Nerve growth factor) on the long-term neural behavior of neonatal rats with HIBD (Neonatal hypoxic ischemic brain damage). METHODS:: The HIBD model was produced by ligating the right common carotid artery of 7 days old SD (Sprague-Dawley) rats followed by 8% O2 + 92% N2 for 2h. Totally 40 rats were randomly divided into 5 groups including sham-operated group, HIBD control group, HBO treated group, NGF treated group and NGF + HBO treated group. The learning and memory ability of these rats was evaluated by Morris water maze at 30 days after birth, and sensory motor function was assessed by experiments of foot error and limb placement at 42 days after birth. RESULTS:: The escape latency of HBO treated group, NGF treated group and NGF + HBO treated group was shorter than that of HIBD control group (p<0.01) and longer than that of sham-operated group. The piercing indexes of 3 treated groups were higher than that of HIBD control group (p<0.01). CONCLUSION:: Hyperbaric oxygen and nerve growth factor treatments may improve learning and memory ability and sensory motor function in neonatal rats after hypoxic ischemic brain damage.

Selection of Lung Cancer-Specific Landscape Phage for Targeted Drug Delivery.

Cancer cell-specific diagnostic or therapeutic tools are commonly believed to significantly increase the success rate of cancer diagnosis and targeted therapies. To extend the repertoire of available cancer cell-specific phage fusion proteins and study their efficacy as navigating moieties, we used two landscape phage display libraries f8/8 and f8/9 displaying an 8- or 9-mer random peptide fusion to identify a panel of novel peptide families that are specific to Calu-3 cells. Using a phage capture assay, we showed that two of the selected phage clones, ANGRPSMT and VNGRAEAP (phage and their recombinant proteins are named by the sequence of the fusion peptide), are selective for the Calu-3 cell line in comparison to phenotypically normal lung epithelial cells and distribute into unique subcellular fractions.

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy.

Ovarian cancer is a leading gynecological malignancy associated with high mortality. The development of acquired drug resistance is the primary cause of chemotherapy failure in the treatment of ovarian cancer. To examine the mechanism underlying paclitaxel resistance in ovarian cancer and attempt to reverse it, the present study induced a TAX-resistant ovarian cancer cell line, SKOV3/TAX. Cathepsin L (CTSL) has been found to be overexpressed in ovarian cancer. The aim of the present study was to investigate the possible involvement of CTSL in the development of TAX resistance in ovarian cancer. CTSL expression was knocked down in SKOV3 ovarian cancer cells and their phenotypic changes were analyzed. The effects of silenced CTSL on the resistant cell line were investigated by proliferation and apoptosis analysis compared with control SKOV3 cells. CTSL was more highly expressed in SKOV3/TAX cells compared with SKOV3 cells. Paclitaxel treatment downregulated the expression of CTSL in SKOV-3 but not in the paclitaxel-resistant SKOV3/TAX cells. CTSL small hairpin RNA (shRNA) knockdown significantly potentiated apoptosis induced by paclitaxel compared with SKOV3/TAX cells transfected with control shRNA, suggesting that CTSL contributes to paclitaxel resistance in ovarian cancer cells and that CTSL silencing can enhance paclitaxel-mediated cell apoptosis. Thus, CTSL should be explored as a candidate of therapeutic target for modulating paclitaxel sensitivity in ovarian cancer.

The impact of Tegillarca granosa extract haishengsu on HL-60 cell.

Haishengsu (Hss) is a purified protein from Tegillarca granosa that has been used as a traditional Chinese medicine to treat cancer for more than a century. In this study, we observed the impact of Haishengsu (Hss) on the proliferation and differentiation of HL-60 cells in the leukemic cell line by taking tretinoin and AS2O3 as a positive control and making a comparative analysis between the effect of Hss and tretinoin and AS2O3. We found that Hss could significantly inhibit the proliferation of HL-60 cells and caused most of the cells to stay in the G0/G1 phase. Its effect was much stronger than that of tretinoin and AS2O3, and the ability of Hss to induce differentiation was close to tretinoin. Hss functions probably by inhibiting the expression of the Bcl-2 and MPO genes and further promoting the expression of the Bax gene. Hss has a significant effect on both inhibiting the proliferation and inducing the differentiation of HL-60 cells. It is possible that Hss may be a new kind of clinical differentiation inducer.