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Weight loss by increasing energy consumption of thermogenic adipocytes to overcome obesity remains a challenge. Herein, we established a transdermal device that was based on the local and temporarily controlled delivery of succinate (SC), a tricarboxylic acid cycle metabolic intermediate to stimulate the thermogenesis pathway of uncoupling protein 1 (UCP1) and accelerate energy dissipation of brown adipose tissue (BAT) under the dorsal interscapular skin, further initiating the consumption of fatty acids by systemic metabolism. SC microneedle patches significantly suppressed weight gain and fat accumulation of remote organs, including liver and peripheral white adipose tissue (WAT) in high-fat diet-induced obese mice. mRNA expression levels of

A major challenge in the use of chemotherapy and immunotherapy is hypoxia-induced progression of tumor cells. We aim to curb hypoxia using metal-based O

Background Inappropriate management of medications is a major threat to homebound patients with chronic conditions. Despite many efforts in improving medication reconciliation in ambulatory and inpatient settings, little research has focused on home care settings. In 2016, Taiwan initiated the Integrated Home Health Care programme, which was intended to reduce potentially inappropriate medication management and risks of uncontrolled polypharmacy through the integration of different medication sources for chronic conditions among homebound patients. This study investigated factors associated with having home care physicians as an integrated source of medications for chronic conditions among homebound patients. Method This retrospective cohort study enrolled 3142 community-dwelling homebound patients from Taipei City Hospital. Homebound patients’ adherence to using home care physicians as an integrated source of chronic condition medications was defined as having all prescriptions for their chronic conditions prescribed by a single home care physician for at least 6 months. Both patient and home care physician characteristics were analysed. Multivariable logistic regression was applied. Results Of the 3142 patients with chronic conditions, 1002 (31.9%) had consistently obtained all medications for their chronic illnesses from their home care physicians for 6 months and 2140 (68.1%) had not. The most common chronic diseases among homebound patients were hypertension, diabetes mellitus, dementia, cerebrovascular disease and constipation. Oldest-old patients with poor functional status, fewer daily medications, no co-payment exemption and no recent inpatient experience were more likely to adhere to this medication integration system. In addition, patients whose outpatient physicians were also their home care physicians were more likely to adhere to the system. Conclusions The finding suggests that building trust and enhancing communication among homebound patients, caregivers and home care physicians are critical. Patient and provider variations highlight the need for further improvement and policy modification for medication reconciliation and management in home care settings. The improvement in medication management and care integration in home care settings may reduce misuse and polypharmacy and improve homebound patients’ safety.

In living systems, non‐equilibrium states that control the assembly‐disassembly of cellular components underlie the gradual complexification of life, whereas in nonliving systems, most molecules follow the laws of thermodynamic equilibrium to sustain dynamic consistency. Little is known about the roles of non‐equilibrium states of interactions between supramolecules in living systems. Here, a non‐equilibrium state of interaction between supramolecular lipopolysaccharide (LPS) and Aβ42, an aggregate‐prone protein that causes Alzheimer's disease (AD), was identified. Structurally, Aβ42 presents a specific groove that is recognized by the amphiphilicity of LPS bait in a non‐equilibrium manner. Functionally, the transient complex elicits a cellular response to clear extracellular Aβ42 deposits in neuronal cells. Since the impaired clearance of toxic Aβ42 deposits correlates with AD pathology, the non‐equilibrium LPS and Aβ42 could represent a useful target for developing AD therapeutics., Here, a non‐equilibrium state of interaction between supramolecular lipopolysaccharide (LPS) and Aβ42, an aggregate‐prone protein that causes Alzheimer's disease (AD), was identified. Oscillation of the non‐equilibrium state for co‐assembly and clearance of Aβ42 is triggered through the use of a supramolecular bait. Since the impaired clearance of toxic Aβ42 deposits correlates with AD pathology, the LPS and Aβ42 non‐equilibrium could represent a useful target for developing AD therapeutics.

Background/Purpose Reactivation of herpes viruses poses threat to corneal graft survival. This study evaluated the presence of herpes simplex virus type 1 (HSV-1), HSV type 2 (HSV-2), and cytomegalovirus (CMV) DNA in recipient corneas and the aqueous humor of patients undergoing penetrating keratoplasty (PKP), and the impact on graft survival. Methods This retrospective study reviewed 90 eyes of 71 patients underwent PKP between 2008 and 2016. Cornea and aqueous humor samples were sent for polymerase chain reaction (PCR) testing for viral DNA. The main outcomes were PCR results and graft survival. Results Recipient corneas tested positive for HSV-1 in 47 eyes (52.2%), for HSV-2 in 24 eyes (26.7%), and for CMV in seven eyes (7.8%). Aqueous humor tested positive for HSV-1 in 44 eyes (48.9%), for HSV-2 in 25 eyes (27.8%), and for CMV in eight eyes (8.9%). The presence of aqueous HSV-1 DNA was associated with higher risk of graft failure (p = 0.005), whereas corneal HSV-1 DNA was not. The presence of HSV-2 DNA had no significant impact on graft survival. Aqueous CMV DNA was associated with higher risk of graft failure in univariate model, but not in multivariate model. Conclusion There were high positive rates of HSV-1, HSV-2, and CMV DNA in recipient corneas and aqueous humor at the time of PKP, even among patients not suspected of latent viral infection. The presence of aqueous HSV-1 DNA was associated with higher risk of graft failure.

Background Gold nanoparticles with high biocompatibility and immunomodulatory properties have potential applications in the development of new diagnostic and therapeutic strategies for nanomedicine. Nanoparticles targeting macrophages can manipulate or control immunological diseases. This study assessed the activity of dendrimer-encapsulated gold nanodots (AuNDs) with three surface modifications [ie, outfacing groups with primary amine (AuNDs-NH2), hydroxyl (AuNDs-OH), and quaternary ammonium ions (AuNDs-CH3)] regulated macrophage function and antioxidant response through Nrf2-dependent pathway. Methods AuNDs were prepared and characterized. Intracellular distribution of AuNDs in human macrophages was observed through confocal microscopy. The activity of AuNDs was evaluated using macrophage functions and antioxidant response in the human macrophage cell line THP-1. Results AuNDs-NH2 and AuNDs-CH3, but not AuNDs-OH, drove the obvious Nrf2-antioxidant response element pathway in THP-1 cells. Of the three, AuNDs-NH2 considerably increased mRNA levels and antioxidant activities of heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 in THP-1 cells. IL-6 mRNA and protein expression was mediated through Nrf2 activation in AuNDs-NH2-treated macrophages. Furthermore, Nrf2 activation by AuNDs-NH2 increased the phagocytic ability of THP-1 macrophages. Conclusion AuNDs-NH2 had immunomodulatory activities in macrophages. The findings of the present work suggested that AuNDs have potential effects against chronic inflammatory diseases via the Nrf2 pathway.

Bioimaging in the near-infrared window is of great importance to study the dynamic processes in vivo with deep penetration, high spatiotemporal resolution, and minimal tissue absorption, scattering...

Background: Poultry vaccine has limited choices of adjuvants and is facing severe threat of infectious diseases due to ineffective of widely used commercial vaccines. Thus, development of novel adjuvant that offers safe and effective immunity is of urgent need. Materials and Methods: The present research engineers a novel chicken adjuvant with potent immune-potentiating capability by incorporating avian tolli»?-like receptor 21 (TLR21) agonist CpG ODN 2007 with a poly(lactic-co-glycolic acid) (PLGA)-based hollow nanoparticle platform (CpG-NP), which subsequently assessed ex vivo and in vivo. Results: CpG-NPs with an average diameter of 164 nm capable of sustained release of CpG for up to 96 hours were successfully prepared. With the ex vivo model of chicken bone marrowi»?-derived dendritic cells (chBMDCs), CpG-NP was engulfed effectively and found to induce DC maturation, promoting dendrite formation and upregulation of CD40, CD80 and CCR7. In addition to enhanced expression of IL-1s, IL-6, IL-12 and IFN-I³, 53/84 immunei»?-related genes were found to be stimulated in CpG-NP-treated chBMDCs, whereas only 39 of such genes were stimulated in free CpG-treated cells. These upregulated genes suggest immune skewing toward T helper cell 1 bias and evidence of improved mucosal immunity upon vaccination with the CpG-NP. The CpG-NP-treated chBMDCs showed protective effects to DF-1 cells against avian influenza virus H6N1 infection. Upon subsequent coupling with infectious bronchitis virus subunit antigen administration, chickens were immunostimulated to acquire higher humoral immune response and protective response against viral challenge. Conclustion: This work presents a novel hollow CpG-NP formulation, demonstrating effective and long-lasting immunostimulatory ability ex vivo and in vivo for chickens, as systemically compared to free CpG. This enhanced immune stimulation benefits from high stability and controlled release of internal component of nanoparticles that improve cellular delivery, lymphoid organ targeting and sustainable DC activation. CpG-NP has broad application potential in antiviral and vaccine development.

Bioimaging in the near-infrared window is of great importance to study the dynamic processes

Pseudostellaria wuyishanensis, a new species from the Wuyishan National Park, Fujian, China, is described and illustrated. Morphologically, Pseudostellaria wuyishanensis resembles P. heterantha. However, the new species can be distinguished by presence of stolons, 1 line of hairs on the stem, smaller leaf blades, shorter pedicels, and ovary with 2 styles.

Mask usage is an effective measure to prevent severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, however, mask reuse is not recommended. Studies examining the factors associated with mask reuse during the coronavirus disease (COVID-19) pandemic are limited. This nationwide survey aimed to determine the prevalence and factors associated with mask reuse among Taiwanese citizens during the pandemic. From 18 May through 31 May 2020, a computer-assisted telephone interview system was used to randomly select Taiwanese citizens for interview regarding COVID-19-preventive behaviors and knowledge on mask usage. For a total of 1075 participants, the overall mean age was 57.4 years, and 82.2% of participants reported mask reuse during the COVID-19 pandemic. After controlling for other covariates, participants who had a greater knowledge of mask usage or had a high supply of masks were less likely to reuse masks during the pandemic. Moreover, generalized estimating equations (GEE) analysis showed that, compared with the participants’ mask-wearing behaviors before the COVID-19 pandemic, they were more likely to reuse masks during the pandemic. Thus, it is imperative to educate people on the correct usage of masks. Furthermore, the government should provide sufficient masks to the general population to reduce mask reuse.

Knee osteoarthritis is a common form of joint disease found in humans and one of the leading causes of disability globally. Knee osteoarthritis (KOA) is responsible for a higher number of disabilities than any other medical condition affecting activities of daily living (ADL). To date no definitive, conventional medical protocol is available to deal with KOA.The study intended to clinically investigate whether the benefits of acupuncture in the treatment of KOA) could be augmented by the addition of Chinese herbal fumigation steam therapy (CHFST) to the treatment protocol and to what degree it had benefits.The research team designed a three-armed, randomized, controlled trial. The sample size was determined by analysis of power; for a sample size of 42, the power was 83.5%; the effect size was 0.5; and the α was 0.05.The setting was the traumatology department in the Chinese Medicine Branch of Taipei City Joint Hospital in Kun Ming, Taiwan.Participants were 45 males and females between the ages of 35 and 75, who were patients in the traumatology department and who were suffering from bilateral knee osteoarthritis. Three participants were lost to follow-up.Participants were randomly assigned to one of three groups, each with 15 participants; (1) the control group, who received acupuncture only; (2) the normal CHFST group, an intervention group who received acupuncture plus a normal dose of CHFST; and (3) the one-sixteenth CHFST group, an intervention group who received acupuncture plus one-sixteenth of a normal dose of CHFST. Participants underwent biweekly treatments for four consecutive weeks.The primary outcome measures included a visual analog scale (VAS) to assess variations in pain intensity and a goniometer measure for range of motion (ROM).The addition of CHFST to acupuncture in the treatment of KOA significantly reduced pain (P = .0017) for the normal CHFST group compared to the control group and the one-sixteenth CHFST group. Chinese medical interventions overall for all groups showed a decrease in pain and increases in ROM, and health related quality of life (HrQoL).CHFST, in conjunction with acupuncture, showed promise in the treatment of KOA in reducing pain, increasing ROM, and improving quality of life (QoL).

We aimed to examine the differences between female and male surgeons in urology, general surgery, and gynecology by analyzing a nationwide, population-based database in Taiwan. We identified surgeons with a clinical experience of 6 − 13 years, between 1995 to 2013, from the National Health Insurance Research Database. We collected patient volume and revenue per month in outpatient and inpatient services, as well as surgical volumes per month of female and male surgeons for analysis. Student’s t-test was used to compare the differences between female and male surgeons. Female urologists and general surgeons had a significantly higher ratio of female patients. Female urologists had comparable patient numbers, revenues, and surgical volumes as male urologists. In contrast, female general surgeons had significantly lesser involvement in outpatient and inpatient care and had lower monthly revenues than males; however, female general surgeons performed more oncological surgeries per month. Female gynecologists had similar outpatient services and outpatient revenue but significantly lesser inpatient services and surgical volume per month. A gender-based gap exists among surgeons in Taiwan; this gap is narrower in urology than in general surgery and gynecology. Gender stereotypes should be reduced to ensure that patients receive the best care regardless of surgeons’ gender.

Summary Infectious bronchitis virus (IBV) causes respiratory diseases in chickens and poses an economic threat to the poultry industry worldwide. Despite vaccine use, there have been field outbreaks of IBV in Taiwan. This study aimed to characterize the emerging IBV variants circulating in Taiwan. The analysis of the structural protein genes showed that these variants emerged through frequent recombination events among Taiwan strains, China strains, Japan strains and vaccine strains. Cross‐neutralization tests revealed that two of the variants exhibited novel serotypes. Clinicopathological assessment showed that two of the variants caused high fatality rates of 67% and 20% in one‐day‐old SPF chicks, and all the variants possessed multiorgan tropisms, including trachea, proventriculus and urogenital tissues. Furthermore, the commercial live‐attenuated Mass‐type vaccine conferred poor protection against these variants. This study identified novel genotypes, serotypes and pathotypes of emerging IBV variants circulating in Taiwan. There is an urgent need for effective countermeasures against these variant strains.

Summary Objective We sought to determine the outcomes of office-based autologous fat injection laryngoplasty in the treatment of patients under 50 years old with glottic insufficiency but without neurological problems or acquired organic lesions in the vocal fold. Methods We conducted a retrospective chart review of consecutive patients under 50 years of age who underwent office-based autologous fat injection laryngoplasty for glottic insufficiency. None of the patients presented neurological problems or acquired organic lesions in the vocal fold. Videolaryngostroboscopic data, objective voice assessment, perceptual measurements of vocal quality, and subjective ratings of voice quality were evaluated before and after treatment. Results The 23 patients (7 men and 16 women) in this study presented significant improvements in phonatory function in terms of maximum phonation time, jitter, grade, asthenia, and Voice Handicap Index-10 (VHI-10) values at 3 months. Significant improvements in terms of jitter, noise-to-harmonic ratio, grade, roughness, breathiness, asthenia, and the VHI-10 values were also observed at 6 months. Conclusions Glottic insufficiency in younger patients without neurological problems or acquired organic lesions in the vocal fold can be treated effectively using office-based autologous fat injection laryngoplasty. Significant improvements in phonatory function were observed even 6 months after surgery.

Semiconducting polymer dots (Pdots) have recently emerged as a new type of ultrabright fluorescent probe that has been proved to be very useful for biomedical imaging. However, Pdots often suffer from serious fluorescence aggregation-caused quenching (ACQ) especially for near-infrared (NIR) fluorescent Pdots. This article compared two strategies to overcome the ACQ effect in near-infrared emissive Pdot systems: aggregation-induced emission (AIE) and anti-aggregation-caused quenching (anti-ACQ). The results show that the anti-ACQ platform outperforms the AIE system. The fluorescence quantum yield of anti-ACQ-based Pdots can be over 50% and the average per-particle brightness of the Pdots is about 5 times higher than that of the commercially available quantum dots. To help understand why the monomer conformations could greatly affect the optical properties of Pdots, molecular dynamics simulations were performed for the first time in such complicated Pdot systems. To demonstrate applications for in vivo fluorescence imaging, both microangiography imaging on living zebrafish embryos and specific tumor targeting on mice were performed. We anticipate that these studies will pave the way for the design of new highly fluorescent Pdot systems.

Delayed double-J ureteric stent (DJ) removal may cause severe morbidity. We aimed to identify high-risk patients for forgotten DJs to prevent iatrogenic injury and improve safety. Data of patients with DJs placed after ureterorenoscopic lithotripsy (URSL) between 2000 and 2013 from the National Health Insurance Database in Taiwan were included. Forgotten DJs were defined as indwelling DJs for > 6 months after URSL, which is approximately two times longer than the expiratory duration. Age at stenting, sex, socioeconomic status, specialty of stenting physician, comorbidities, postoperative emergency room visiting and abdominal plain x-ray filming frequencies, and alpha blocker use for > 7 days after stenting were analysed. Of 13,058 patients, 12,969 (99.31%) had timely removed DJs while 89 (0.68%) had forgotten DJs. Per a univariate analysis, patients with forgotten DJs were older, female, and of low socioeconomic status, and the use of more than one DJ for one URSL, placement by non-urologists, and less frequent postoperative abdominal plain x-ray filming and postoperative alpha blocker use were risk factors. Per a multivariate analysis, elderly patients (Odds ratio [OR] = 3.37, 95% confidence interval (CI) 1.36–8.32, p = 0.0085), DJ placement by non-urologists (OR = 9.63, 95% CI 6.09–15.24, p

The inverse association between obesity and education level has been demonstrated in many developed countries; however, few studies have investigated obesity in geriatric populations. This cross-sectional analysis explored the association between geriatric obesity and education level, along with other demographic characteristics in Taipei, Taiwan between 2013 and 2015. Taipei citizens ≥ 65 years (aborigines ≥ 55 years) were recruited to participate in the elderly health examination programme. Logistic regression was applied to analyse the relationship between obesity (defined as body mass index ≥ 27 kg/m2 in Taiwan) and education level among men and women after controlling for age, race, income status, and smoking status. A total of 28,092 men and 31,835 women were included in the final analysis. Compared to those with education years ≥ 16, older men and women with education years ≤ 12 had higher odds of being obese. The odds ratios increase as years of education decrease, and the trend is more pronounced among women. Aborigines had much higher chances of being obese among men and women, while there were no differences by income status. The results clarified the factors related to obesity in the elderly, and will be useful for authorities working to improve health outcomes among this population.

H6 avian influenza viruses (AIVs) have a worldwide distribution, and they pose a potential concern for public health. In Taiwan, H6 AIVs have circulated in domestic chickens for more than 40 years, and certain strains have crossed the species barrier to infect mammals. With the goal of containing the disease, there is a pressing need to develop a safe and effective vaccine for pandemic preparedness. In this study, we prepared a virus-like particle (VLP) that consisted of the hemagglutinin (HA) and matrix protein 1 (M1) derived from a H6 AIV as a vaccine antigen, and we examined the immunogenicity and protective efficacy when combined with an adjuvant in a chicken model. Full-length HA and M1 protein genes were cloned and expressed using a baculovirus expression system, and VLPs were purified from the supernatant of insect cell cultures. We performed nanoparticle-tracking analysis and transmission electron microscopy to validate that the particle structure and properties resembled the native virions. In animal experiments, specific-pathogen-free chickens that received the H6 VLPs in combination with an adjuvant showed superior H6N1 virus-specific serum IgG and hemagglutination-inhibition antibody responses, which lasted more than 112 days. Following the H6N1 viral challenge, the vaccinated chickens showed reduced viral replication in the lungs, kidneys and conjunctival/cloacal shedding. The antibodies induced in the chickens by the vaccine were able to cross-react with the H6N1 human isolate and drifted avian H6N1 isolates. In summary, the H6 VLP vaccine elicited superb immunogenicity in vivo, and the use of an adjuvant further enhanced the antiviral protective efficacy. This vaccine formulation could potentially be used to manage H6 influenza virus infections in chickens.

Nonviral vectors used in gene delivery, such as cationic polymers and dendrimers, exhibit problems of inherent toxicity and inefficient cytosolic access that must be overcome. In this work, a simple co-caging strategy focused on overcoming the two limitations of dendrimers for siRNA transfection is reported. By embedding gold nanoclusters within a dendrimer, the structure of the dendrimer becomes compact and allows an irreversible backfolding of exterior primary amines from the branch to the core, which dramatically eliminates dendrimer toxicity and enhances safety. Gold nanoclusters with strong emissions can confer a trackable function to dendrimers acting as a transfection vector (TV) for siRNA transfection. In order to maximize efficiency of complexing with siRNA, the TV further incorporated caged methyl motifs, transforming the partially tertiary amines into quaternary ammonium ions to form a methylated TV (MTV). The cellular responses to the MTV were similar to those of the TV, but the responses to the MTV can also enhance cytosolic access to better deliver siRNA for mRNA knockdown. This finding offers a novel perspective to facilitate the use of various cationic polymers for detoxification in biological applications through a co-caging strategy without further chemical modifications.

When gold nanoparticles (AuNPs) become extremely small (2 nm in diameter) as gold nanoclusters (AuNCs), an intriguing issue is whether the interactions of free radicals with AuNCs would be essentially different at sufficiently small size. Herein, we report for the first time that the fluorescence of a polyamidoamine (PAMAM) dendrimer-entrapped Au

A nucleus penetrating vehicle is indispensible when seeking to deliver plasmid DNA for gene transfection. In this study, dendrimers with terminal thymine groups were synthesized to meet this objective. Through modifications of the hydrophilic and neutral thymine moieties on hyperbranched peripheries, these dendrimers can achieve biosafety, efficient endosomal escape ability, cytosolic accessibility, and eventually, nuclear entry for the purposes of gene transfection. After optimization of the thymine coverages, better gene expression can only be achieved while replacing ∼50% of the amine groups of a dendrimer with thymine moieties. Presumably, a specific dendrimer comprising thymine and primary amines might possess a synergistic effect to promote pDNA condensation via the cooperation of electrostatic interaction and hydrogen bonding. In comparison, a dendrimer entirely capped by thymine can lose external amines, decreasing pDNA complexity and stability, which would cause poor gene transfection. The utility of specific thymine-capped dendrimers in vivo level was demonstrated to successfully and efficiently deliver plasmid DNA at a low complex ratio into mouse muscle by intramuscular injection. Upon the easy accessibility of intramuscular administration, the capability of thymine-capped dendrimers might be potentially used in immunotherapeutic gene transfection in the future.

The progress of wound regeneration relies on inflammation management, while neovascular angiogenesis is a critical aspect of wound healing. In this study, the bioactive core and corona synergism of quantized gold (QG) were developed to simultaneously address these complicated issues, combining the abilities to eliminate endotoxins and provide oxygen. The QG was constructed from ultrasmall nanogold and a loosely packed amine-based corona via a simple process, but it could nonetheless eliminate endotoxins (a vital factor in inflammation also called lipopolysaccharides) and provide oxygen in situ for the remodeling of wound sites. Even while capturing endotoxins through electrostatic interactions, the catalytic active sites inside the nanogold could maintain its surface accessibility to automatically transform the overexpressed hydrogen peroxide in hypoxic wound regions into oxygen. Since the inflammatory stage is an essential stage of wound healing, the provision of endotoxin clearance by the outer organic corona of the QG could slow inflammation in a way that subsequently promoted two other important stages of wound bed healing, namely proliferation and remodeling. Relatedly, the efficacy of two forms of the QG, a liquid form and a dressing form, was demonstrated at wound sites in this study, with both forms promoting the development of granulation, including angiogenesis and collagen deposition. Thus, the simply fabricated dual function nanocomposite presented herein not only offers reduced batch-to-batch variation but also increased options for homecare treatments.

The dual-targeted immunogene therapy that inhibits PD-L1 and provides IL-2 can enhance the therapeutic efficacy of cancer vaccine., While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)–cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2–encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

Periodontitis is a frequently cited extraintestinal manifestation of Crohn’s disease (CD). Despite a plethora of investigations and a recent meta-analysis linking CD and periodontitis, no study has estimated the risk of periodontitis among CD patients with respect to a comparison group nor has any investigation analyzed the effect of CD-specific medications on the risk of periodontitis. The present cohort study compared CD patients and matched subjects without a history of inflammatory bowel disease (IBD) to estimate the effect of CD and CD-specific pharmaceutical prescriptions on the risk of developing periodontitis by leveraging a population-based dataset in Taiwan. We sourced 6657 CD patients and 26,628 comparison subjects without a history of IBD from the Taiwan National Health Insurance Database. Cox proportional hazards regressions were used to estimate the risk of subsequent periodontitis by CD status and pharmaceutical prescription during the follow-up period. After adjusting for socioeconomic status (SES), urbanicity, selected medical co-morbidities, and CD-specific pharmaceutical prescriptions, the hazard ratio (HR) for subsequent periodontitis among patients with CD was 1.36 (95% CI = 1.25–1.48) that of comparison subjects. There was not a significant difference in risk between genders or across ages. Steroids (95% CI = 0.66–0.77) appeared to confer a protective effect and Aspirin, Plavix, and Licodin were marginally protective (95% CI = 0.76–0.95). This is the first study to report an increased HR for subsequent periodontitis among CD patients when compared to matched comparison subjects without IBD. The protective effect of some pharmaceuticals may suggest that treatment of CD protects against periodontitis.

Dye-loaded, fluorescent nanoparticles (FNPs) have been extensively studied as promising imaging or probing agents for therapeutic and biomedical applications, because of improved photostability and reduced cytotoxicity (compared with free dyes). The synthesis of FNPs often involves entrapment of fluorescent dye molecules into nanostructures, which, however, would encounter a problem associated with the formation of molecular aggregates within the confined matrix space. The formation of nonfluorescent aggregates seems unavoidable for some conventional fluorescent dyes, thereby leading to fluorescent quenching. The problem is well-recognized, but frequently ignored; and FNPs are usually applied as prepared without addressing it either during or after the synthesis of FNPs. The ignorance may be due to the difficulty in altering post-synthetically the intraparticulate molecular arrangements and interactions. Herein, we describe how light-responsive S-nitrosothiol (SNO) can be engineered into fluorophore-loaded silica nanoparticles for efficient dye-loading and post-synthesis fluorescence augmentation. Silica nanoparticles loaded with various fluorescent molecules were prepared using one-pot, simultaneous, acid-catalyzed sol–gel condensation and nitrosation of a single mercaptosilane source, 3-mercaptopropyl trimethoxysilane (MPTMS), followed by nanoprecipitation. We first show how doxorubicin-loaded silica NPs respond to stepwise visible-light exposure and exhibit ON/OFF fluorescent response. We then demonstrate that rhodamine 6G (R6G) can be stably incorporated into SNO-enriched silica nanostructure with negligible payload leakage (

Heparin-binding hemagglutinin (HBHA) is a 199 amino acid virulence factor at the envelope of Mycobacterium tuberculosis that contributes to latent tuberculosis. The binding of HBHA to respiratory epithelial cells, which leads to extrapulmonary dissemination of the pathogen, is mediated by cell-surface heparan sulfate (HS). We report the structural characterization of the HBHA/HS complex by NMR spectroscopy. To develop a model for the molecular recognition, the first chemically synthesized uniformly 13 C- and 15 N-labeled HS octasaccharide and a uniformly 13 C- and 15 N-labeled form of HBHA were prepared. Residues 180-195 at the C-terminal region of HBHA show large chemical shift perturbation upon association with the octasaccharide. Molecular dynamics simulations conforming to the multidimensional NMR data revealed key electrostatic and even hydrophobic interactions between the binding partners that may aid in the development of agents targeting the binding event.

This article describes the design and synthesis of donor-bridge-acceptor-based semiconducting polymer dots (Pdots) that exhibit narrow-band emissions, ultrahigh brightness, and large Stokes shifts in the near-infrared (NIR) region. We systematically investigated the effect of π-bridges on the fluorescence quantum yields of the donor-bridge-acceptor-based Pdots. The Pdots could be excited by a 488 or 532 nm laser and have a high fluorescence quantum yield of 33% with a Stokes shift of more than 200 nm. The emission full width at half-maximum of the Pdots can be as narrow as 29 nm, about 2.5 times narrower than that of inorganic quantum dots at the same emission wavelength region. The average per-particle brightness of the Pdots is at least 3 times larger than that of the commercially available quantum dots. The excellent biocompatibility of these Pdots was demonstrated in vivo, and their specific cellular labeling capability was also approved by different cell lines. By taking advantage of the durable brightness and remarkable stability of these NIR fluorescent Pdots, we performed in vivo microangiography imaging on living zebrafish embryos and long-term tumor monitoring on mice. We anticipate these donor-bridge-acceptor-based NIR-fluorescent Pdots with narrow-band emissions to find broad use in a variety of multiplexed biological applications.

A strong interaction between colistin, a last‐resort antibiotic of the polymyxin family, and free lipopolysaccharide (LPS, also referred to as endotoxin), released from the Gram‐negative bacterial (GNB) outer membrane (OM), has been identified that can decrease the antibacterial efficacy of colistin, potentially increasing the dose of this antibiotic required for treatment. The competition between LPS in the GNB OM and free LPS for the interaction with colistin was prevented by using a supramolecular trap to capture free LPS. The supramolecular trap, fabricated from a subnanometer gold nanosheet with methyl motifs (SAuM), blocks lipid A, preventing the interaction between lipid A and colistin. This can minimize endotoxemia and maximize the antibacterial efficacy of colistin, enabling colistin to be used at lower doses. Thus, the potential crisis of colistin resistance could be avoided., Caught in a trap: The antibiotic colistin targets lipopolysaccharide (LPS) in the Gram‐negative bacterial (GNB) membrane. This interaction is disrupted by free LPS released during infection (path a). A methylated gold nanosheet (SAuM) binds to free LPS, preventing free LPS from binding colistin and reducing endotoxemia (path b). This increases the antibacterial efficacy of colistin, decreasing both the required dose and the risk of resistance.

The ongoing battle against current and rising viral infectious threats has prompted increasing effort in the development of vaccine technology. A major thrust in vaccine research focuses on developing formulations with virus-like features towards enhancing antigen presentation and immune processing. Herein, a facile approach to formulate synthetic virus-like particles (sVLPs) is demonstrated by exploiting the phenomenon of protein corona formation induced by the high-energy surfaces of synthetic nanoparticles. Using an avian coronavirus spike protein as a model antigen, sVLPs were prepared by incubating 100 nm gold nanoparticles in a solution containing an optimized concentration of viral proteins. Following removal of free proteins, antigen-laden particles were recovered and showed morphological semblance to natural viral particles under nanoparticle tracking analysis and transmission electron microscopy. As compared to inoculation with free proteins, vaccination with the sVLPs showed enhanced lymphatic antigen delivery, stronger antibody titers, increased splenic T-cell response, and reduced infection-associated symptoms in an avian model of coronavirus infection. Comparison to a commercial whole inactivated virus vaccine also showed evidence of superior antiviral protection by the sVLPs. The study demonstrates a simple yet robust method in bridging viral antigens with synthetic nanoparticles for improved vaccine application; it has practical implications in the management of human viral infections as well as in animal agriculture., Graphical abstract

Despite nanoparticulate platinum (nano-Pt) has been validated to be acting as a platinum-based prodrug for anticancer therapy, the key factor in controlling its cytotoxicity remains to be clarified. In this study, it is found that the corrosion susceptibility of nano-Pt can be triggered by inducing the oxidization of superficial Pt atoms, which can kill both cisplatin-sensitive/resistance cancer cells. Direct evidence in the oxidization of superficial Pt atoms is validated to observe the formation of platinum oxides by X-ray absorption spectroscopy. The cytotoxicity is originated from the dissolution of nano-Pt followed by the release of highly toxic Pt ions during the corrosion process. Additionally, the limiting autophagy induction by nano-Pt might prevent cancer cells from acquiring autophagy-related drug resistance. With such advantages, the possibility of further autophagy-related drug resistance could be substantially reduced or even eliminated in cancer cells treated with nano-Pt. Moreover, nano-Pt is demonstrated to kill cisplatin-resistant cancer cells not only by inducing apoptosis but also by inducing necrosis for pro-inflammatory/inflammatory responses. Thus, nano-Pt treatment might bring additional therapeutic benefits by regulating immunological responses in tumor microenvironment. These findings support the idea that utilizing nano-Pt for its cytotoxic effects might potentially benefit patients with cisplatin resistance in clinical chemotherapy.

The cytotoxicity of nanozymes has drawn much attention recently because their peroxidase-like activity can decompose hydrogen peroxide (H2 O2 ) to produce highly toxic hydroxyl radicals (•OH) under acidic conditions. Although catalytic activities of nanozymes are highly associated with their surface properties, little is known about the mechanism underlying the surface coating-mediated enzyme-like activities. Herein, it is reported for the first time that amine-terminated PAMAM dendrimer-entrapped gold nanoclusters (AuNCs-NH2 ) unexpectedly lose their peroxidase-like activity while still retaining their catalase-like activity in physiological conditions. Surprisingly, the methylated form of AuNCs-NH2 (i.e., MAuNCs-N(+) R3 , where R = H or CH3 ) results in a dramatic recovery of the intrinsic peroxidase-like activity while blocking most primary and tertiary amines (1°- and 3°-amines) of dendrimers to form quaternary ammonium ions (4°-amines). However, the hidden peroxidase-like activity is also found in hydroxyl-terminated dendrimer-encapsulated AuNCs (AuNCs-OH, inside backbone with 3°-amines), indicating that 3°-amines are dominant in mediating the peroxidase-like activity. The possible mechanism is further confirmed that the enrichment of polymeric 3°-amines on the surface of dendrimer-encapsulated AuNCs provides sufficient suppression of the critical mediator •OH for the peroxidase-like activity. Finally, it is demonstrated that AuNCs-NH2 with diminished cytotoxicity have great potential for use in primary neuronal protection against oxidative damage.

Introduction: Multidrug-resistant Acinetobacter baumannii (MDRAB) pneumonia with severe sepsis in a patient with rheumatoid arthritis (RA), who is predisposed after treatment with tumor necrosis factor inhibitor (TNFI), is a rare severe infection and can be successfully treated with prompt antibiotics. Case presentation: A 75-year-old woman was diagnosed with RA >30 years previously. After inadequate treatment responses to conventional disease-modifying antirheumatic drugs (DMARDs), she developed progressive RA, including swollen joints in both hands, and had a high disease activity score of 4.96 when presenting at our rheumatology clinic. She had started taking the TNFI, golimumab (50 mg/month), 3 years before and developed a productive cough 4 weeks before this admission. One week after admission, she developed fever, dyspnea, hypoxemia, tachycardia, and increased serum C-reactive protein level. Diagnosis: Chest plain film (CxR) and computed tomography of the chest showed hospital-acquired pneumonia; microbial examination of the sputum showed the presence of MDRAB. Therapeutics: She was prescribed a full course of antibiotics with cefoperazone sulbactam. Outcomes: CxR showed complete remission of pneumonia. Conclusion: Biological DMARDs, such as TNFI, act as a double-edged sword: these drugs are used to treat autoimmune diseases, but they increase the risk of infection. The trend toward antibiotic resistance and persistent environmental survival of MDRAB is an emerging problem in countries with high rates of antibiotic abuse. TNFI may affect intestinal immunity by inducing dysbiosis, which affects T helper 17–mediated mucosal immunity and can contribute to A baumannii colonization and the development of MDRAB in frequently hospitalized patients.