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BACKGROUND: In 2022-2023, 15- and 20-valent pneumococcal conjugate vaccines (PCV15/PCV20) were recommended for infants. We aimed to estimate the incidence of outpatient visits and antibiotic prescriptions in US children (≤17 years) from 2016-2019 for acute otitis media, pneumonia, and sinusitis associated with PCV15- and PCV20-additional (non-PCV13) serotypes to quantify PCV15/20 potential impacts. METHODS: We estimated the incidence of PCV15/20-additional serotype-attributable visits and antibiotic prescriptions as the product of all-cause incidence rates, derived from national health care surveys and MarketScan databases, and PCV15/20-additional serotype-attributable fractions. We estimated serotype-specific attributable fractions using modified vaccine-probe approaches incorporating incidence changes post-PCV13 and ratios of PCV13 versus PCV15/20 serotype frequencies, estimated through meta-analyses. RESULTS: Per 1000 children annually, PCV15-additional serotypes accounted for an estimated 2.7 (95% confidence interval, 1.8-3.9) visits and 2.4 (95% CI, 1.6-3.4) antibiotic prescriptions. PCV20-additional serotypes resulted in 15.0 (95% CI, 11.2-20.4) visits and 13.2 (95% CI, 9.9-18.0) antibiotic prescriptions annually per 1000 children. PCV15/20-additional serotypes account for 0.4% (95% CI, 0.2%-0.6%) and 2.1% (95% CI, 1.5%-3.0%) of pediatric outpatient antibiotic use. CONCLUSIONS: Compared with PCV15-additional serotypes, PCV20-additional serotypes account for > 5 times the burden of visits and antibiotic prescriptions. Higher-valency PCVs, especially PCV20, may contribute to preventing pediatric pneumococcal respiratory infections and antibiotic use.

Practical Application This study aims to obtain sunnhemp protein isolate (SHPI) and dextran conjugates by dry heating method of Maillard conjugation. The effects of different incubation time (0, 1, 3, 5, 7, and 9 days) on the molecular flexibility, available lysine content, antioxidant properties, molecular structure, and thermal and micro‐structural properties of conjugates were compared with SHPI (no conjugation) at 60°C and 79% relative humidity. The results indicated the formation of SHPI–dextran conjugates as confirmed by the change in molecular flexibility, lysine content, antioxidant activities, color, and water activity values. The molecular structure revealed the confirmation of covalent bonding between SHPI and dextran. Differential scanning calorimetry and thermo‐gravimetric analysis results exhibited improvement in the thermal stability of SHPI when conjugated with dextran. The microstructural characterization showed that Maillard conjugation changed the surface structure of SHPI. The analysis of amino acid composition displayed that lysine, arginine, and phenylalanine were the dominant Maillard reaction sites of SHPI and dextran. Among all the conjugated samples, 5 days of incubation time was selected as an optimum condition for the development of SHPI–dextran conjugates on the basis of the aforementioned characterization. Overall, it was concluded that Maillard conjugation of sunnhemp protein with dextran via dry‐heating technique could modify and improve its various attributes.The conjugation of plant proteins with polysaccharide through the Maillard reaction under dry heating conditions represents a natural and green technique for improving the techno‐functional properties of proteins. The study has the potential to establish framework for the utilization of Sunnhemp protein isolate‐dextran conjugates. This approach offers the potential for cost‐effective production of emulsifiers and development of effective encapsulating matrices. The investigation expands on an underutilized plant protein source facilitating an alternative to animal‐based proteins and contributing to the development of a sustainable circular bioeconomy. [ABSTRACT FROM AUTHOR]

Dimethylcurcumin (DMC) is a synthetic curcuminoid which can enhance androgen receptor (AR) degradation to suppress AR-associated cancers. However, the poor water solubility and low bioavailability of DMC limit its biomedical applications. In our study, a water-soluble methoxypolyethylene glycol-dimethylcurcumin conjugate (cDMC-mPEG) was synthesized and further used for preparation of DMC loaded nanoparticles for effective DMC delivery. cDMC-mPEG was synthesized and characterized by proton nuclear magnetic resonance, fourier transform infrared spectroscopy, ultraviolet–visible spectroscopy, thermogravimetric analysis and differential scanning calorimetry. cDMC-mPEG self-assemble into nanoparticles in aqueous solution and can be used to encapsulate free DMC to form DMC-loaded cDMC-mPEG nanoparticles with small sizes and spherical morphology. The in vitro drug release study shows that DMC@cDMC-mPEG (15.3%) nanoparticles exhibit pH-triggered DMC release behaviors. The cellular uptake study shows that cDMC-mPEG and DMC@cDMC-mPEG (15.3%) nanoparticles exhibit enhanced cellular uptake as compared to free DMC, and DMC@cDMC-mPEG (15.3%) nanoparticles exhibit the highest cellular uptake amount. As a result, DMC@cDMC-mPEG (15.3%) nanoparticles exhibit enhanced cytotoxicity against 22Rv1 cells as compared to cDMC-mPEG and free DMC in in vitro antitumor effect study. The DMC@cDMC-mPEG (15.3%) nanoparticles developed in this work provide an effective nano-formulation for anti-prostate cancer DMC delivery. [ABSTRACT FROM AUTHOR]

BACKGROUND: Whey protein isolate (WPI) generally represents poor functional properties such as thermal stability, emulsifying activity and antioxidant activity near its isoelectric point or high temperatures, which limit its application in the food industry. The preparation of WPI–polysaccharide covalent conjugates based on Maillard reaction is a promising method to improve the physical and chemical stability and functional properties of WPI. In this research, WPI–inulin conjugates were prepared through wet heating method and ultrasound method and their structural and functional properties were examined. RESULTS: In conjugates, the free amino acid content was reduced, the high molecular bands were emerged at sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE), new C–N bonds were formed in Fourier‐transform infrared (FTIR) spectroscopy, and fluorescence intensity was reduced compared with WPI. Furthermore, the result of circular dichroism (CD) spectroscopy also showed that the secondary structure of conjugates was changed. Conjugates with ultrasound treatment had better structural properties compared with those prepared by wet heating treatment. The functional properties such as thermal stability, emulsifying activity index (EAI), emulsion stability (ES) and antioxidant activity of conjugates with wet heating treatment were significantly improved compared with WPI. The EAI and ES of conjugates with ultrasound treatment were the highest, but the thermal stability and antioxidant activity were only close to that of the conjugates with wet heating treatment for 2 h. CONCLUSION: This study revealed that WPI–inulin conjugates prepared with ultrasound or wet heating method not only changed the structural characteristics of WPI but also could promote its functional properties including thermal stability, EAI, ES and antioxidant activity. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

BACKGROUND: Plant proteins are being increasingly utilized as functional ingredients in foods because of their potential health, sustainability, and environmental benefits. However, their functionality is often worse than the synthetic or animal‐derived ingredients they are meant to replace. The functional performance of plant proteins can be improved by conjugating them with polyphenols. In this study, the formation and stability of oil‐in‐water emulsions prepared using faba bean protein–grape leaf polyphenol (FP‐GLP) conjugates as emulsifiers. Initially, FP‐GLP conjugates were formed using an ultrasound‐assisted alkali treatment. Then, corn oil‐in‐water emulsions were prepared using high‐intensity sonication (60% amplitude, 10 min) and the impacts of conjugate concentration, pH, ionic strength, freezing–thawing, and heating on their physicochemical properties and stability were determined. RESULTS: Microscopy and light scattering analysis showed that oil‐in‐water emulsions containing small oil droplets could be formed at conjugate concentrations of 2% and higher. The addition of salt reduced the electrostatic repulsion between the droplets, which increased their susceptibility to aggregation. Indeed, appreciable droplet aggregation was observed at ≥ 50 mmol/L sodium chloride. The freeze–thaw stability of emulsions prepared with protein–polyphenol conjugates was better than those prepared using the proteins alone. In addition, the emulsions stabilized by the conjugates had a higher viscosity than those prepared by proteins alone. CONCLUSION: This study showed that FP‐GLP conjugates are effective plant‐based emulsifiers for forming and stabilizing oil‐in‐water emulsions. Indeed, emulsions formed using these conjugates showed improved resistance to pH changes, heating, freezing, and salt addition. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Photocatalysis is one of the most effective ways to solve environmental problems by solving pollutants. This article designed and prepared a conjugated system of 2,4,6-triaminopyrimidine-g-C3N4 (TAP-CN) to modify ZnO NWs. We systematically studied the photocatalytic performance of ZnO NWs modified with different ratios of TAP-CN. The results showed that 9 wt% TAP-CN-30/ZnO NWs had the best degradation effect on Rhodamine B dye. The degradation rate was 99.36% in 80 min. The excellent degradation performance was attributed to the TAP-CN conjugated system promoting photo-generated charge transfer. This work provided guidance for designing efficient composite catalysts for application in other renewable energy fields. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a noncommunicable disease caused by cholesterol plaque, can cause chronic diseases. The antiplatelet medicines used in its treatment can cause complications. Marine collagen peptides can be used as a natural atherosclerosis remedy. The present study investigated the preparation and characterization of hydrolyzed collagen (HC) from jellyfish and its conjugation with black jelly mushroom extract (BJME). Their cytotoxicity and ability to prevent cholesterol-induced endothelial cell injury were also examined. HC was prepared using Alcalase or papain hydrolysis (0.2–0.4 units/g of dry matter (DM)). Higher yield, degree of hydrolysis, and antioxidant activities (AAs) were found in the HC obtained from Alcalase, especially at 0.4 units/g DM (A-0.4), compared to other processes (p < 0.05). Thus, A-0.4 was further conjugated with BJME (1–4%, w/w of HC). The HC-2%BJME conjugate showed the highest surface hydrophobicity and AAs compared to other samples. The FTIR spectra and size distribution also confirmed the conjugation between HC and BJME. When EA.hy926 endothelial cells were treated with HC or HC-2%BJME (25–1000 µg/mL), HC-2%BJME had no cytotoxicity, whereas HC at 1000 µg/mL induced cytotoxicity (p < 0.05). Both samples also exhibited protective ability against cholesterol-induced apoptosis and VE-cadherin downregulation of cells. Therefore, HC and conjugate could be natural agents for preventing atherosclerosis. [ABSTRACT FROM AUTHOR]

Organic pollutants were one of the main sources of environmental pollutants. The degradation of organic pollutants through photocatalytic technology was one of the effective solutions. By preparing zinc oxide(ZnO) nanowires modified with sodium-doped conjugated 2,4,6-triaminopyrimidin-g-C3N4 (NaTCN) heterojunction (ZnO/NaTCN), the photocatalytic performance of NaTCN modified with different ratios of ZnO was systematically studied. The photocatalytic performance was studied through the degradation performance of methyl blue (MB) dye. The results showed that 22.5 wt% ZnO/NaTCN had the best degradation effect on MB dye. The degradation rate of MB reached 98.54% in 70 min. After three cycles, it shows good cycling stability (degradation rate is 96.99%) for dye degradation. It was found that there are two types of active species: ·OH and h+, of which h+ is the main active species produced by photocatalytic degradation of dyes. The excellent degradation performance was attributed to the fact that ZnO facilitated the extraction and transport of photogenerated carriers. The doping of sodium facilitated charge transfer. The NaTCN conjugated system promoted the extraction and transfer of photogenerated carriers. It provided guidance for designing efficient composite catalysts for use in other renewable energy fields. [ABSTRACT FROM AUTHOR]

Ipidacrine conjugates were synthesized by alkylation of 4-hydroxycoumarin, dihydrofuro[3,4-c]pyridine, bipyridine, and azolo[1,5-a]pyrimidines with 2-chloro-N-(hexahydrocyclopenta[b]quinolin-9-yl)acetamide. Their isomeric structure was determined by NMR spectroscopy. Heterocycles containing ambident N,O-nucleophilic centers underwent alkylation at the oxygen atom, while in the presence of alternative carboxy and hydroxy functions, the alkylation occurred with the formation of an ester derivative. The study of the esterase profile, inhibitory effect on β-amyloid self-aggregation, as well as antioxidant activity of the conjugates, showed that coumarin derivatives are promising for the development of butyrylcholinesterase inhibitors, whereas conjugates of azolo[1,5-a]-pyrimidines are promising in the search for β-amyloid self-aggregation inhibitors. [ABSTRACT FROM AUTHOR]

Carbohydrates are commonly found in conjunction with lipids or proteins, resulting in the formation of glycoconjugates such as glycoproteins, glycolipids, and proteoglycans. These glycoconjugates are essential in various biological activities, including inflammation, cell-cell recognition, bacterial infections, and immune response. Nonetheless, the isolation of naturally occurring glycoconjugates presents challenges due to their typically heterogeneous nature, resulting in variations between batches in structure and function, impeding a comprehensive understanding of their mechanisms of action. Consequently, there is a strong need for the efficient synthesis of artificial glycoconjugates with precisely described compositions and consistent biological properties. The chemical and enzymatic approaches discussed in this paper present numerous research opportunities to develop customised glycoconjugate vaccines.

BackgroundInteractions of Streptococcus pneumoniae with viruses feature in the pathogenesis of numerous respiratory illnesses.MethodsWe undertook a case-control study among adults at Kaiser Permanente Southern California between 2015 and 2019. Case patients had diagnoses of lower respiratory tract infection (LRTI; including pneumonia or nonpneumonia LRTI diagnoses), with viral infections detected by multiplex polymerase chain reaction testing. Controls without LRTI diagnoses were matched to case patients by demographic and clinical attributes. We measured vaccine effectiveness (VE) for 13-valent (PCV13) against virus-associated LRTI by determining the adjusted odds ratio for PCV13 receipt, comparing case patients and controls.ResultsPrimary analyses included 13 856 case patients with virus-associated LRTI and 227 887 matched controls. Receipt of PCV13 was associated with a VE of 24.9% (95% confidence interval, 18.4%-30.9%) against virus-associated pneumonia and 21.5% (10.9%-30.9%) against other (nonpneumonia) virus-associated LRTIs. We estimated VEs of 26.8% (95% confidence interval, 19.9%-33.1%) and 18.6% (9.3%-27.0%) against all virus-associated LRTI episodes diagnosed in inpatient and outpatient settings, respectively. We identified statistically significant protection against LRTI episodes associated with influenza A and B viruses, endemic human coronaviruses, parainfluenza viruses, human metapneumovirus, and enteroviruses but not respiratory syncytial virus or adenoviruses.ConclusionsAmong adults, PCV13 conferred moderate protection against virus-associated LRTI. The impacts of pneumococcal conjugate vaccines may be mediated, in part, by effects on polymicrobial interactions between pneumococci and respiratory viruses.

Their unique physicochemical properties and multi-enzymatic activity make CeO2 nanoparticles (CeO2 NPs) the most promising active component of the next generation of theranostic drugs. When doped with gadolinium ions, CeO2 NPs constitute a new type of contrast agent for magnetic resonance imaging, possessing improved biocatalytic properties and a high level of biocompatibility. The present study is focused on an in-depth analysis of the enzyme-like properties of gadolinium-doped CeO2 NPs (CeO2:Gd NPs) and their antioxidant activity against superoxide anion radicals, hydrogen peroxide, and alkylperoxyl radicals. Using an anion-exchange method, CeO2:Gd NPs (~5 nm) with various Gd-doping levels (10 mol.% or 20 mol.%) were synthesized. The radical-scavenging properties and biomimetic activities (namely SOD- and peroxidase-like activities) of CeO2:Gd NPs were assessed using a chemiluminescent method with selective chemical probes: luminol, lucigenin, and L-012 (a highly sensitive luminol analogue). In particular, gadolinium doping has been shown to enhance the radical-scavenging properties of CeO2 NPs. Unexpectedly, both bare CeO2 NPs and CeO2:Gd NPs did not exhibit SOD-like activity, acting as pro-oxidants and contributing to the generation of reactive oxygen species. Gadolinium doping caused an increase in the pro-oxidant properties of nanoscale CeO2. At the same time, CeO2:Gd NPs did not significantly inhibit the intrinsic activity of the natural enzyme superoxide dismutase, and CeO2:Gd NPs conjugated with SOD demonstrated SOD-like activity. In contrast to SOD-like properties, peroxidase-like activity was observed for both bare CeO2 NPs and CeO2:Gd NPs. This type of enzyme-like activity was found to be pH-dependent. In a neutral medium (pH = 7.4), nanoscale CeO2 acted as a prooxidant enzyme (peroxidase), while in an alkaline medium (pH = 8.6), it lost its catalytic properties; thus, it cannot be regarded as a nanozyme. Both gadolinium doping and conjugation with a natural enzyme were shown to modulate the interaction of CeO2 NPs with the key components of redox homeostasis. [ABSTRACT FROM AUTHOR]

Shigellosis is a severe gastrointestinal disease that annually affects approximately 270 million individuals globally. It has particularly high morbidity and mortality in low-income regions; however, it is not confined to these regions and occurs in high-income nations when conditions allow. The ill effects of shigellosis are at their highest in children ages 2 to 5, with survivors often exhibiting impaired growth due to infection-induced malnutrition. The escalating threat of antibiotic resistance further amplifies shigellosis as a serious public health concern. This review explores Shigella pathology, with a primary focus on the status of Shigella vaccine candidates. These candidates include killed whole-cells, live attenuated organisms, LPS-based, and subunit vaccines. The strengths and weaknesses of each vaccination strategy are considered. The discussion includes potential Shigella immunogens, such as LPS, conserved T3SS proteins, outer membrane proteins, diverse animal models used in Shigella vaccine research, and innovative vaccine development approaches. Additionally, this review addresses ongoing challenges that necessitate action toward advancing effective Shigella prevention and control measures. [ABSTRACT FROM AUTHOR]

We characterize algebraic integers which are differences of two Pisot numbers. Each such number α must be real and its conjugates over Q must all lie in the union of the disc | z | < 2 and the strip | ℑ (z) | < 1 . In particular, we prove that every real algebraic integer α whose conjugates over Q , except possibly for α itself, all lie in the disc | z | < 2 can always be written as a difference of two Pisot numbers. We also show that a real quadratic algebraic integer α with conjugate α ′ over Q is always expressible as a difference of two Pisot numbers except for the cases α < α ′ < - 2 or 2 < α ′ < α when α cannot be expressed in that form. A similar complete characterization of all algebraic integers α expressible as a difference of two Pisot numbers in terms of the location of their conjugates is given in the case when the degree d of α is a prime number. [ABSTRACT FROM AUTHOR]

Introduction: A 20-valent pneumococcal conjugate vaccine (PCV20) was recently recommended for use among US children. We evaluated the cost-effectiveness of PCV20 among children aged 6 years with chronic medical conditions (CMC+) and children aged 6 years with immunocompromising conditions (IC) versus one and two doses of 23-valent pneumococcal polysaccharide vaccine (PPSV23), respectively. Methods: A probabilistic model was employed to depict 10-year risk of clinical outcomes and economic costs of pneumococcal disease, reduction in life years from premature death, and expected impact of vaccination among one cohort of children with CMC+ and IC aged 6 years. Vaccine uptake was assumed to be 20% for both PCV20 and PPSV23. Cost per quality-adjusted life year (QALY) gained was evaluated from the US societal and healthcare system perspectives; deterministic and probabilistic sensitivity analyses (DSA/PSA) were also conducted. Results: Among the 226,817 children with CMC+ aged 6 years in the US, use of PCV20 (in lieu of PPSV23) was projected to reduce the number cases of pneumococcal disease by 5203 cases, medical costs by US$8.7 million, and nonmedical costs by US$6.2 million. PCV20 was the dominant strategy versus PPSV23 from both the healthcare and societal perspectives. In the PSA, 99.9% of the 1000 simulations yielded a finding of dominance for PCV20. Findings in analyses of children with IC aged 6 years in the USA were comparable (i.e., PCV20 was the dominant vaccination strategy). Scenario analyses showed that increasing PCV20 uptake to 100% could potentially prevent > 22,000 additional cases of pneumococcal disease and further reduce medical and nonmedical costs by US$70.0 million among children with CMC+ and IC. Conclusions: Use of PCV20 among young children with CMC+ and IC in the USA would reduce the clinical burden of pneumococcal disease and yield overall cost savings from both the US healthcare system and societal perspectives. Higher PCV20 uptake could further reduce the number of pneumococcal disease cases in this population. [ABSTRACT FROM AUTHOR]

Previously, the Vi-typhoid conjugate vaccine (Vi-TT) was found to be highly efficacious in Nepalese children under 16 years of age. We assessed the immunogenicity of Vi-TT at 9 and 12 months of age and response to a booster dose at 15 months of age. Infants were recruited at Patan Hospital, Kathmandu and received an initial dose of Vi-TT at 9 or 12 months of age with a booster dose at 15 months of age. Blood was taken at four timepoints, and antibody titres were measured using a commercial ELISA kit. The primary study outcome was seroconversion (4-fold rise in antibody titre) of IgG one month after both the doses. Fifty children were recruited to each study group.Some visits were disrupted by the COVID19 pandemic and occurred out of protocol windows. Both the study groups attained 100 % IgG seroconversion after the initial dose. IgG seroconversion in the 9-month group was significantly higher than in the 12-month group (68.42 % vs 25.8 %, p < 0.001). Among individuals who attended visits per protocol, IgG seroconversion after the first dose occurred in 100 % of individuals (n = 27/27 in 9-month and n = 32/32 in 12-month group). However, seroconversion rates after the second dose were 80 % in the 9-month and 0 % in the shorter dose-interval 12-month group (p < 0.001) (n = 16/20 and n = 0/8, respectively). Vi-TT is highly immunogenic at both 9 and 12 months of age. Stronger response to a booster in the 9-month group is likely due to the longer interval between doses. [ABSTRACT FROM AUTHOR]

Nanoconjugates emerge as innovative theranostic probes, seamlessly combining diagnostic precision with the targeted therapeutic potential to revolutionize cancer treatment strategies. The present article delineates the design and fabrication of NIONP-CaCD conjugate between naphthalimide based organic nanoparticles (NIONPs) and Ca2+-doped carbon dots (CaCDs). Naphthalimide based lysosome targeting unit appended boronic acid tethered amphiphile was synthesized that formed NIONP organic nanoparticles via J-aggregation in DMSO–water. CaCDs were synthesized via hydrothermal method. These two nanomaterials were linked via boronic acid–diol covalent interaction by Lewis acid–base chemistry between phenylboronic acid based NIONPs and hydroxyl group functionalized CaCDs to develop NIONP-CaCD nanoconjugate. This blue emitting NIONP-CaCD conjugate was used in bioimaging and in pro-drug–free drug combination cancer therapy. Hydroxychloroquine (HCQ) was encapsulated within this NIONP-CaCD conjugate with a higher loading capacity in comparison to the individual cargo carrier (NIONPs or CaCDs). The disintegration of NIONP-CaCD conjugate to its native constituents took place through the cleavage of the boronate–diol bond at the lysosomal pH range (4.5–5.0), resulting in the liberation of HCQ and CaCDs. This pro-drug–free drug nanoformulation NIONP-CaCD-HCQ resulted in ∼3.0-fold improvement in cancer cell death in comparison to standalone therapy by individually loaded cargo. Notably, it also exhibited a ∼2.0-fold higher killing efficacy against cancer cells (A549 and HepG2) compared to normal cells (NIH3T3). This notable anticancer potential of NIONP-CaCD-HCQ could be attributed to Ca2+ overload induced apoptosis (calcicoptosis) in conjunction with lysosomal cell death by HCQ. [ABSTRACT FROM AUTHOR]

Human serum albumin (HSA) is a multifunctional protein, known to be a natural carrier for a number of endogenous and exogenous compounds, including drugs. HSA-based drugs formulation is a clinically validated approach to improve pharmacological properties and biodistribution (such as in Abraxane). Based on this, one might like to modify HSA in a way that its distribution is more favorable for certain therapeutic purposes. Levofloxacin (LV), a broad-spectrum antibiotic drug, could benefit from extended systemic exposure, and stronger interactions with plasma proteins could be useful for this purpose. We engrafted monomeric or polymeric cyclodextrins (CDs) on the surface of HSA molecules to strengthen the LV adsorption (the CD−LV dissociation constant is three orders of magnitude lower than that of HSA−LV). We found that (HSA−HPolS)conj+LV exhibited the highest activity against E. coli, whereas (HSA−HPCD)conj+LV was the most effective against B. subtilis, and both HSA conjugates were more potent than LV alone or LV with HSA. Further fine-tuning of HSA could yield an improvement in biodistribution and thus a more favorable risk/benefit ratio. [ABSTRACT FROM AUTHOR]

Docetaxel (DTX) is a semi‐synthetic analogue of paclitaxel which has attracted extensive attention in the treatment of cancer. However, the current clinically used DTX formulations display low tumor targeting ability, leading to unsatisfactory therapeutic outcomes with adverse effects, which poses significant challenges to the clinical application. In this study, three galactosamine (Gal) and docetaxel conjugates with different linkers were synthesized, namely DTX‐(suc‐Gal)2, DTX‐(DTDPA‐Gal)2, and DTX‐(DSeDPA‐Gal)2. These three conjugates were characterized by 1H NMR, FT‐IR and HRMS. The in vitro drug release study shows that DTX‐(DTDPA‐Gal)2 and DTX‐(DSeDPA‐Gal)2 exhibit glutathione (GSH)‐responsive drug release and DTX‐(DSeDPA‐Gal)2 displays higher GSH‐responsiveness. The in vitro antitumor activity study shows that DTX‐(DTDPA‐Gal)2 and DTX‐(DSeDPA‐Gal)2 exhibit enhanced cytotoxicity, cell apoptosis rate and G2/M phase arrest against HepG2 cells as compared to DTX‐(suc‐Gal)2, DTX‐(DSeDPA‐Gal)2 displays the highest cytotoxicity, cell apoptosis rate and G2/M phase arrest among these three conjugates. In addition, DTX‐(DSeDPA‐Gal)2 exhibits higher selectivity to HepG2 cells as compared to free DTX. The DTX‐(DSeDPA‐Gal)2 developed in this study has been proven to be an effective DTX conjugate for selective killing hepatoma cells. [ABSTRACT FROM AUTHOR]

New indocyanine green (ICG) (IR820) is one of the ICG derivatives and attracts increasing attention for cancer management. However, the unsatisfactory tumor targeting ability of IR820 significantly limits its applications for cancer theranostics. Biotin receptor is overexpressed on the membrane of various tumor cells and biotin modified nanocarriers have been reported to enhance the tumor targeting ability on several tumor types. In this work, biotin‐new ICG conjugate (Biotin‐SS‐IR820) was prepared for tumor‐targeted IR820 delivery. Biotin and IR820 were coupled through cystamine. The synthesized Biotin‐SS‐IR820 was characterized by 1H NMR, FT‐IR and HRMS. The in vitro singlet oxygen generation study shows that Biotin‐SS‐IR820 exhibits similar singlet oxygen generation as compared to IR820 upon 660 nm laser irradiation (0.8 W/cm2). The cellular uptake study shows that Biotin‐SS‐IR820 shows enhanced cellular uptake amount as compared to IR820 on 4T1 cells. As a result, Biotin‐SS‐IR820 displays enhanced in vitro photodynamic therapeutic effect against 4T1 cells as compared to IR820. In in vivo biodistribution study, Biotin‐SS‐IR820 shows enhanced tumor accumulation as compared to IR820. Biotin‐SS‐IR820 developed in this work shows promising prospects for targeted delivery of IR820 to biotin receptor overexpressed tumors. [ABSTRACT FROM AUTHOR]

Human serum albumin (HSA) is a multifunctional protein, known to be a natural carrier for a number of endogenous and exogenous compounds, including drugs. HSA-based drugs formulation is a clinically validated approach to improve pharmacological properties and biodistribution (such as in Abraxane). Based on this, one might like to modify HSA in a way that its distribution is more favorable for certain therapeutic purposes. Levofloxacin (LV), a broad-spectrum antibiotic drug, could benefit from extended systemic exposure, and stronger interactions with plasma proteins could be useful for this purpose. We engrafted monomeric or polymeric cyclodextrins (CDs) on the surface of HSA molecules to strengthen the LV adsorption (the CD−LV dissociation constant is three orders of magnitude lower than that of HSA−LV). We found that (HSA−HPolS)conj+LV exhibited the highest activity against E. coli, whereas (HSA−HPCD)conj+LV was the most effective against B. subtilis, and both HSA conjugates were more potent than LV alone or LV with HSA. Further fine-tuning of HSA could yield an improvement in biodistribution and thus a more favorable risk/benefit ratio.

AbstractMost chemotherapeutic agents are nonspecific distribution and cause systemic toxicities. Polysaccharide-based conjugates are promising strategies to overcome these drawbacks. To this end, two synergistic drugs docetaxel (DTX) and docosahexaenoic acid (DHA) were independently covalently bonded through individual linkers to dextran (100 kDa) to produce a novel dual-drug conjugate dextran–DHA–DTX. The single-drug conjugates dextran–DHA and dextran–DTX were also prepared for comparison. Fluorescent dye Cy7.5-based conjugates dextran–Cy7.5 and dextran–DHA–Cy7.5 were synthesized for cellular uptake study. The dual-drug conjugate dextran–DHA–DTX self-assembled into nanoparticles with the diameter of 102.3 ± 8.3 nm and demonstrated enhanced water solubility and improved pharmacokinetic profiles. Cellular uptake results showed that the dual-drug conjugate entered cells more than the parent DTX by determining the intracellular DTX contents via HPLC/MS analysis and by determining the fluorescent intensity of dextran-Cy7.5 and dextran–DHA–Cy7.5. Importantly, the dual-drug conjugate dextran–DHA–DTX significantly accumulated in tumor tissues and dramatically reduced the DTX concentrations in normal tissues. The dual-drug conjugate completely eradicated all the MCF-7 xenograft tumors without obvious side effects and showed more superior antitumor activity than parent DTX and single-drug conjugate dextran–DTX and dextran–DHA. Both in vitro and in vivo studies showed that DHA enhanced the antitumor activity of dextran–DTX. The polysaccharide dextran-based dual-drug conjugates may represent an effective way to improve the chemotherapeutic agents.

The effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the two drugs were synthesised. HCPT combined with CRI synergistically inhibited the cell growth and proliferation of H1975, HCC827, and H460 without aggravating adverse effect on the normal cells. The combination synergistically enhanced the cell apoptosis rate through releasing Cyto-C by activation of Bcl-2 family-mediated mitochondrial signalling, which was associate with inactivating of EGFR related downstream signalling pathways including AKT, ERK, JNK, and p38 MAPK. Based on this synergy, the conjugates of HCPT and CRI (compounds CH-1 and CH-2) with different chemical bonds were synthesised. Compound CH-1 exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate CH-1was a potential target drug for the treatment of lung cancer.

BACKGROUND: Streptococcus pneumoniae is a leading cause of severe infections among children. Despite vaccination, HIV-exposed, uninfected (HEU) children have a higher incidence of invasive pneumococcal disease than HIV-unexposed, uninfected (HUU) children. We sought to compare the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV-13) in HEU and HUU infants. METHODS: We conducted a prospective cohort study of 134 mother-infant dyads in Botswana. Infants received PCV-13 doses at 2, 3, and 4 months through routine clinical care. We measured IgG antibodies specific to vaccine serotypes in sera collected from infants at 0, 5, and 12 months of age. We calculated the proportion of infants with protective IgG levels (≥0.35 µg/mL) to specific pneumococcal serotypes. RESULTS: At birth, fewer than half of infants had protective IgG levels to serotypes 1 (38%), 3 (46%), 4 (33%), 5 (23%), 6B (40%), 7F (44%), 9 V (44%), and 23F (46%). Compared to HUU infants (n = 97), HEU infants (n = 37) had lower antibody concentrations at birth to serotypes 5 (p = 0.046) and 19A (p = 0.008) after adjustment for maternal age and infant birth weight. More than 80% of HEU and HUU infants developed protective antibody levels to each of the 13 vaccine serotypes following PCV-13 vaccination. Median concentrations of antibodies to pneumococcal serotypes declined by 55-93% between 5 and 12 months of age, with fewer than half of infants having protective antibody levels to serotypes 1 (47%), 3 (28%), 9 V (44%), 18C (24%), and 23F (49%) at 12 months of age. CONCLUSIONS: Both HEU and HUU infants developed protective antibody responses to PCV-13 administered in a 3 + 0 schedule. However, antibody concentrations to many pneumococcal serotypes waned substantially by 12 months of age, suggesting that a PCV-13 booster dose in the second year of life may be needed to maintain protective pneumococcal antibody levels in older infants and young children.

An international randomized phase II trial of Globo H (GH) vaccine, adagloxad simolenin/OBI-821 in 349 patients with metastatic breast cancer showed longer progression-free survival (PFS) in vaccinated patients who developed anti-Globo H (anti-GH) IgG than those who did not and the placebo group. The impacts of anti-GH IgM and GH expression on peak anti-GH IgG and clinical outcome were further evaluated. The titers of anti-GH IgG and IgM were determined by ELISA. GH expression in tumor was examined by immunohistochemical staining. Immunophenotyping was conducted by flow cytometry. Adagloxad simolenin elicited anti-GH IgM which peaked at titers ≥1:80 between weeks 5 and 13. The mean anti-GH IgG titer peaked at week 41 and decreased thereafter on the completion of vaccination. One log increase in peak IgM was associated with 10.6% decrease in the HR of disease progression (HR: 0.894, 95% CI: 0.833 to 0.960, p=0.0019). Patients with anti-GH IgM ≥1:320 within first 4 weeks after vaccination had significantly higher maximum anti-GH IgM (p

Objective: This study explores vitamin drug conjugates, linking drugs to targeting moieties (Niacin and Pantothenic acid), aiming to enhance TB drug efficacy, reduce dosing frequency, and minimize toxicity. Methods: Isoniazid-Niacin (INH-NIA), Isoniazid-Pantothenic Acid (INH-PA), and Pyrazinamide-Niacin (PYZ-NIA) conjugates were synthesized. Their anti-mycobacterial activity against Mycobacterium smegmatis was evaluated. Molecular docking and molecular dynamics simulations assessed binding affinity and stability with MTb proteases. Drug-likeness and ADME properties were examined. Results: INH-NIA and PYZ-NIA demonstrated significant anti-mycobacterial activity, while INH-PA showed lower activity. Docking and simulations confirmed strong binding with MTb proteases. Drug-likeness and ADME properties supported their potential as antitubercular agents. Discussion: Combining antitubercular drugs with specific vitamins in vitamin drug conjugates offers a promising approach to enhance drug efficacy and reduce resistance. These conjugates provide targeted delivery and improved bioavailability, addressing critical challenges in TB treatment. Molecular dynamics simulations validate the stability of drug-target complexes, reinforcing their potential as antitubercular agents. Conclusions: Vitamin drug conjugates, especially INH-NIA and PYZ-NIA, hold significant promise in combating TB. Their innovative approach may revolutionize TB treatment by addressing drug resistance and improving patient outcomes. Further research is warranted to explore and develop these conjugates as effective tools in the fight against TB. This study underscores the importance of innovative strategies in addressing drug-resistant MTb strains and advancing TB treatment options. [ABSTRACT FROM AUTHOR]

The synthesis and antiplasmodial evaluation of new hybrids combining the pharmacophore structures of artemisinin, ciprofloxacin or norfloxacin, and 7-chloroquinoline are reported in this study. The first step for all of the syntheses is the obtainment of key piperazine esters intermediates bearing the drugs ciprofloxacin and norfloxacin. Using these platforms, 18 final compounds were synthesized through a multistep procedure with overall yields ranging between 8 and 20%. All compounds were screened for their antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum FcB1 strain. Compounds 20, 21, 22, and 28, bearing an artesunate fragment with ciprofloxacin, exhibited IC50 values in the range of 3.5–5.4 nM and excellent selectivity indices. Among the compounds bearing the artesunate moiety on the norfloxacin, two of them, 23 and 24, afforded IC50 values of 1.5 nM and 1.9 nM, respectively. They also showed excellent selectivity indices. The most potent compounds were also evaluated against the CQ-resistant Dd2 strain of Plasmodium falciparum, demonstrating that those compounds incorporating the artesunate fragment were the most potent. Finally, the combination of artesunate with either ciprofloxacin or norfloxacin moieties in a single molecular entity proved to substantially enhance the activity and selectivity when compared to the administration of the unconjugated counterparts artesunate/ciprofloxacin and artesunate/norfloxacin. [ABSTRACT FROM AUTHOR]

BACKGROUND: The aim of this study was to investigate the effects of covalent and non‐covalent interactions between myofibrillar protein (MP) and cyanidin‐3‐O‐glucoside (C3G) on protein structure, binding sites, and digestion properties. Four methods of inducing covalent cross‐linking were used in the preparation of MP‐C3G conjugates, including tyrosinase‐catalyzed oxidation, alkaline pH shift treatment, free radical grafting, and ultrasonic treatment. A comparison was made between MP‐C3G conjugates and complexes, and the analysis included sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE), C3G binding ratio, liquid chromatography–tandem mass spectrometry (LC–MS/MS), protein side‐chain amino acids, circular dichroism spectroscopy, three‐dimensional fluorescence, particle size, and in vitro simulated digestion. RESULTS: Covalent bonding between C3G and amino acid side chains in MP was confirmed by LC–MS/MS. In covalent bonding, tryptophan residues, free amino groups and sulfhydryl groups were all implicated. Among the 22 peptides covalently modified by C3G, 30 modification sites were identified, located in lysine, histidine, tryptophan, arginine and cysteine. In vitro simulated digestion experiments showed that the addition of C3G significantly reduced the digestibility of MP, with the covalent conjugate showing lower digestibility than the non‐covalent conjugate. Moreover, the digestibility of protein decreased more during intestinal digestion, possibly because covalent cross‐linking of C3G and MP further inhibited trypsin targeting sites (lysine and arginine). CONCLUSION: Covalent cross‐linking of C3G with myofibrillar proteins significantly affected protein structure and reduced protein digestibility by occupying more trypsin binding sites. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

As of June 2023, two pneumococcal conjugate vaccines, 20- (PCV20) and 15- (PCV15) valent formulations, are recommended for US infants under a 3 + 1 schedule. This study evaluated the health and economic impact of vaccinating US infants with a new expanded valency PCV20 formulation. A population-based, multi cohort, decision-analytic Markov model was developed to estimate the public health impact and cost-effectiveness of PCV20 from both societal and healthcare system perspectives over 10 years. Epidemiological data were based on published studies and unpublished Active Bacterial Core Surveillance System (ABCs) data. Vaccine effectiveness was based on PCV13 effectiveness and PCV7 efficacy studies. Indirect impact was based on observational studies. Costs and disutilities were based on published data. PCV20 was compared to both PCV13 and PCV15 in separate scenarios. Replacing PCV13 with PCV20 in infants has the potential to avert over 55,000 invasive pneumococcal disease (IPD) cases, 2.5 million pneumonia cases, 5.4 million otitis media (OM) cases, and 19,000 deaths across all ages over a 10-year time horizon, corresponding to net gains of 515,000 life years and 271,000 QALYs. Acquisition costs of PCV20 were offset by monetary savings from averted cases resulting in net savings of $20.6 billion. The same trend was observed when comparing PCV20 versus PCV15, with a net gain of 146,000 QALYs and $9.9 billion in net savings. A large proportion of the avoided costs and cases were attributable to indirect effects in unvaccinated adults and elderly. From a health-care perspective, PCV20 was also the dominant strategy compared to both PCV13 and PCV15. Infant vaccination with PCV20 is estimated to further reduce pneumococcal disease and associated healthcare system and societal costs compared to both PCV13 and PCV15. [ABSTRACT FROM AUTHOR]

Due to complexity of tumor diseases and resistance of targeted drug, targeted drug usually cannot meet the needs of cancer treatment. Therefore, the conjugate constructed by two anticancer agents maybe a better solution for the tumor diseases. As natural anticancer agents, icaritin and norcantharidin are selected for the construction of conjugate. In the condition of EDCI/DMAP, icaritin is reacted with norcantharidin esters to give the desired 7-esters selectively in a moderate yield. MTT method was used to test the cytotoxicity and intensity on Hep G2 and MCF-7 in vitro. Some of the compounds (4a, 4i and 4j) show a better inhibition against Hep G2 and MCF-7 cell lines in vitro, and are deserved to be a potential drug candidate to develop in vivo. [ABSTRACT FROM AUTHOR]

On a geodesic sphere in a complex projective space, we have Sasakian magnetic fields induced by the almost contact metric structure. In this paper, we investigate their magnetic flows on the unit sphere subbundle of the bundle of the contact distribution over this geodesic sphere, and show that they are smoothly conjugate to each other. [ABSTRACT FROM AUTHOR]

The basis of the present study is a straightforward method involving fewer chemical species for conjugating gold nanoparticles (AuNPs) with the antimicrobial peptide LL-37 designated as LL-37@AuNPs. Investigating the microstructure characteristics of the resulting materials and their potential as antibacterial and wound-healing substances are the main objectives of this study. Zeta (ζ) potential, Fourier transform infrared (FTIR), X-ray diffraction (XRD), field effect scanning electron microscopy (FE-SEM), energy dispersive X-ray diffraction (EDS), transmission electron microscopy (TEM), and UV-Vis spectrophotometry were used to analyze the physico–chemical properties of LL-37@AuNPs. The magnitude of LL-37′s zeta potential and the LL-37@AuNPs show that the specimens are electrically stable and resistant to flocculation and coagulation. The surface plasmon resonance (RPS) of AuNPs, which is positioned at a wavelength of about 531 nm, was found to be unaffected by the presence of the LL-37 antimicrobial peptide. The FTIR data show the functional group characteristics of the LL-37@AuNPs vibration bands, and the XRD diffractogram confirms the formation of the LL-37@AuNPs conjugate nanocomposite. Based on FE-SEM and TEM data, the bulk of AuNPs were found to have a circular shape, with an average size of about 22.88 ± 8.21 nm. It was discovered that the LL-37@AuNPs had a good ability to inhibit S. aureus from growing. The wound-healing percentage reached 85% on day 12 of the trial, significantly greater than the results of the negative controls. LL-37@AuNPs(4) is the sample that had the highest percentage of wound healing between days 3 and 12. Moreover, sample LL-37@AuNPs(4) contains 0.45 µL of LL-37, whereas sample LL-37@AuNPs(2) contains 0.22 µL of LL-37. The faster wound-healing rate in LL-37@AuNPs(4) was believed to be due to a higher concentration of LL-37, which was able to stop S. aureus from developing while suppressing the inflammation surrounding the wound. The study's findings reveal that LL-37@AuNPs might be made using a straightforward process, making them a powerful antibacterial and therapeutic substance. However, before this discovery is applied in the field of medicine, a more thorough investigation is necessary. [ABSTRACT FROM AUTHOR]

While there are hundreds of synthetic steroids conjugates with acids, sugars, proteins and other molecules, only two types of conjugates occur in living organisms, namely sulfates and glucuronides. Steroid glucuronidation in the human liver is the main mechanism controlling the levels and biological activity of unconjugated hormones, and glucuronides are their main excretion products. This process is generally irreversible. On the other hand, sulfates possess their own biological activity that differs from that of the unconjugated steroid, emphasizing the importance of steroid sulfatases and sulfotransferases. Due to their negative charge, steroid sulfates cannot cross the blood-cell barrier and have to use transporters. Their efflux is mediated by specific transporters of the ATP binding cassette protein group, which thus are further factors controlling their physiological effects. Steroid sulfates, especially dehydroepiandrosterone sulfate (DHEAS) are neuroactive steroids, with well-known effects as allosteric modulators of some neurotransmitter receptors, functioning as ion channels, such as gamma-aminobutyric acid, type A (GABAA) receptors or N-methyl-D-aspartate (NMDA) receptors. In this minireview, we highlight some recent findings of non-genomic steroid sulfate actions through specific G-protein coupled receptors (GPCR), which we believe show the way of further research. A few studies have even indicated that sulfates such as DHEAS may even indirectly regulate gene expression via ligand binding to the membrane receptor and, through G-protein and second messenger formation, activate proteins like cAMP Regulated Elements Binding protein (CREB), which then binds to regulated DNA elements of the expressed gene, in a "classical" genomic effect. [ABSTRACT FROM AUTHOR]

The effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the two drugs were synthesised. HCPT combined with CRI synergistically inhibited the cell growth and proliferation of H1975, HCC827, and H460 without aggravating adverse effect on the normal cells. The combination synergistically enhanced the cell apoptosis rate through releasing Cyto-C by activation of Bcl-2 family-mediated mitochondrial signalling, which was associate with inactivating of EGFR related downstream signalling pathways including AKT, ERK, JNK, and p38 MAPK. Based on this synergy, the conjugates of HCPT and CRI (compounds CH-1 and CH-2) with different chemical bonds were synthesised. Compound CH-1 exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate CH-1was a potential target drug for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Most chemotherapeutic agents are nonspecific distribution and cause systemic toxicities. Polysaccharide-based conjugates are promising strategies to overcome these drawbacks. To this end, two synergistic drugs docetaxel (DTX) and docosahexaenoic acid (DHA) were independently covalently bonded through individual linkers to dextran (100 kDa) to produce a novel dual-drug conjugate dextran–DHA–DTX. The single-drug conjugates dextran–DHA and dextran–DTX were also prepared for comparison. Fluorescent dye Cy7.5-based conjugates dextran–Cy7.5 and dextran–DHA–Cy7.5 were synthesized for cellular uptake study. The dual-drug conjugate dextran–DHA–DTX self-assembled into nanoparticles with the diameter of 102.3 ± 8.3 nm and demonstrated enhanced water solubility and improved pharmacokinetic profiles. Cellular uptake results showed that the dual-drug conjugate entered cells more than the parent DTX by determining the intracellular DTX contents via HPLC/MS analysis and by determining the fluorescent intensity of dextran-Cy7.5 and dextran–DHA–Cy7.5. Importantly, the dual-drug conjugate dextran–DHA–DTX significantly accumulated in tumor tissues and dramatically reduced the DTX concentrations in normal tissues. The dual-drug conjugate completely eradicated all the MCF-7 xenograft tumors without obvious side effects and showed more superior antitumor activity than parent DTX and single-drug conjugate dextran–DTX and dextran–DHA. Both in vitro and in vivo studies showed that DHA enhanced the antitumor activity of dextran–DTX. The polysaccharide dextran-based dual-drug conjugates may represent an effective way to improve the chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Summary: Double-stranded RNAs (dsRNA)-based strategies appeared as promising therapies to induce an inflammation in the tumor microenvironment. However, currently described systems generally lack active targeting of tissues, and their clinical translation is thus limited to intratumoral injection. Herein, we developed an antibody-siRNA-5′triphosphate conjugate with multiple modes of action, combining cell surface EphA2-specific internalization, leading to a simultaneous gene silencing and activation of the receptor retinoic acid-inducible gene I (RIG-I). Recognition of cytosolic siRNA-5′triphosphate by RIG-I triggers the expression of interferons and pro-inflammatory cytokines, inducing an inflammation of the tumor environment and activating neighboring immune cells. In addition, these RIG-I-specific effects synergized with siRNA-mediated PLK1 silencing to promote cancer cell death by apoptosis. Altogether, such immune-stimulating antibody-RNA conjugate opens a novel modality to overcome some limitations encountered by dsRNA molecules currently in clinical trials.

BackgroundWhile secondary pneumococcal pneumonia occurs less commonly after coronavirus disease 2019 (COVID-19) than after other viral infections, it remains unclear whether other interactions occur between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Streptococcus pneumoniae.MethodsWe probed potential interactions between these pathogens among adults aged ≥65 years by measuring associations of COVID-19 outcomes with pneumococcal vaccination (13-valent conjugate vaccine [PCV13] and 23-valent pneumococcal polysaccharide vaccine [PPSV23]). We estimated adjusted hazard ratios (aHRs) using Cox proportional hazards models with doubly robust inverse-propensity weighting. We assessed effect modification by antibiotic exposure to further test the biologic plausibility of a causal role for pneumococci.ResultsAmong 531 033 adults, there were 3677 COVID-19 diagnoses, leading to 1075 hospitalizations and 334 fatalities, between 1 March and 22 July 2020. Estimated aHRs for COVID-19 diagnosis, hospitalization, and mortality associated with prior PCV13 receipt were 0.65 (95% confidence interval [CI], .59-.72), 0.68 (95% CI, .57-.83), and 0.68 (95% CI, .49-.95), respectively. Prior PPSV23 receipt was not associated with protection against the 3 outcomes. COVID-19 diagnosis was not associated with prior PCV13 within 90 days following antibiotic receipt, whereas aHR estimates were 0.65 (95% CI, .50-.84) and 0.62 (95% CI, .56-.70) during the risk periods 91-365 days and >365 days, respectively, following antibiotic receipt.ConclusionsReduced risk of COVID-19 among PCV13 recipients, transiently attenuated by antibiotic exposure, suggests that pneumococci may interact with SARS-CoV-2.

BackgroundPeople with HIV (PWH) are at increased risk for invasive pneumococcal disease (IPD). Thirteen-valent pneumococcal conjugate vaccine (PCV13) was recommended for use in US children in 2010 and for PWH aged 19 years or older in 2012. We evaluated the population-level impact of PCV13 on IPD among PWH and non-PWH aged 19 years or older.MethodsWe identified IPD cases from 2008 to 2018 through the Active Bacterial Core surveillance platform. We estimated IPD incidence using the National HIV Surveillance System and US Census Bureau data. We measured percent changes in IPD incidence from 2008 to 2009 to 2017-2018 by HIV status, age group, and vaccine serotype group, including serotypes in recently licensed 15-valent (PCV15) and 20-valent (PCV20) PCVs.ResultsIn 2008-2009 and 2017-2018, 8.4% (552/6548) and 8.0% (416/5169) of adult IPD cases were among PWH, respectively. Compared with non-PWH, a larger proportion of IPD cases among PWH were in adults aged 19-64 years (94.7%-97.4% vs. 56.0%-60.1%) and non-Hispanic Black people (62.5%-73.0% vs. 16.7%-19.2%). Overall and PCV13-type IPD incidence in PWH declined by 40.3% (95% confidence interval: -47.7 to -32.3) and 72.5% (95% confidence interval: -78.8 to -65.6), respectively. In 2017-2018, IPD incidence was 16.8 (overall) and 12.6 (PCV13 type) times higher in PWH compared with non-PWH; PCV13, PCV15/non-PCV13, and PCV20/non-PCV15 serotypes comprised 21.5%, 11.2%, and 16.5% of IPD in PWH, respectively.ConclusionsDespite reductions post-PCV13 introduction, IPD incidence among PWH remained substantially higher than among non-PWH. Higher-valent PCVs provide opportunities to reduce remaining IPD burden in PWH.

Despite advances in Electron Microscopy (EM) that enable to image protein assemblies within vitreous sections of cells at nearly atomic resolution, labelling is still necessary to locate small proteins or rare complexes. Gold immunolabelling has been used for decades to localise specific proteins within cellular sections. However, current gold particle-antibody conjugates are not built with enough chemical precision to match the current resolution offered by cryo-EM methodology. Furthermore, as a close to native specimen state can only be achieved by strict preservation of a frozen hydrated state, it is required to deliver gold labelling agents into living cells prior to their vitrification. Several 1.4 nm gold nanoparticle-antibody conjugates were synthesised. Their abilities to bind to and label their corresponding epitopes within living cells after cytosolic delivery by electroporation are documented here.

Abstract Solutions of a group of conjugate time-varying matrix equations are discussed in this paper. Through mathematical derivation, the solutions to this group of equations are equivalent to the solutions to a class of conjugate time-invariant matrix equations. Further, the related conditions of solvability are obtained and the general explicit solutions are represented by using quasicontrollability and quasiobservability matrices. A detailed algorithm is presented to make the calculation process clear, and the effectiveness of the algorithm is verified by a concrete example. The proposed algorithm can provide complete solutions to the considered equation in explicit parametric form and its main computation includes solving an ordinary linear algebraic equation and some matrix multiplication operations.

Taxanes are a class of potent anticancer agents used in different cancers. Their low water solubility is the major challenge in formulation development that leads to the use of surfactants and organic solvents which causes severe hypersensitivity reactions. In this study, paclitaxel (PTX) was conjugated to a water-soluble and biocompatible polymer, dextran, to enhance solubility. Levothyroxine was also conjugated to dextran to provide targeted delivery. The cytotoxicity was studied on HepG2 and A375 cell lines before and after treating cell lines with levothyroxine. Results showed approximately 1250-fold water solubility enhancement by dextran conjugation. Drug conjugates presented higher cytotoxicity on A375 cell lines than its free drug counterparts at 10 and 50 nM concentrations after 24 hours. Pre-treatment with levothyroxine decreased the cytotoxicity on A375 as an integrin receptor rich cell line but did not show any significant effect on HepG2 cells which is low in expressing integrin receptor. In conclusion, preparation of levothyroxine targeted dextran conjugate might be an effective strategy for PTX delivery to different cell lines.

Photocatalysis is one of the most effective ways to solve environmental problems by solving pollutants. This article designed and prepared a conjugated system of 2,4,6-triaminopyrimidine-g-C3N4 (TAP-CN) to modify ZnO NWs. We systematically studied the photocatalytic performance of ZnO NWs modified with different ratios of TAP-CN. The results showed that 9 wt% TAP-CN-30/ZnO NWs had the best degradation effect on Rhodamine B dye. The degradation rate was 99.36% in 80 min. The excellent degradation performance was attributed to the TAP-CN conjugated system promoting photo-generated charge transfer. This work provided guidance for designing efficient composite catalysts for application in other renewable energy fields.

Atherosclerosis, a noncommunicable disease caused by cholesterol plaque, can cause chronic diseases. The antiplatelet medicines used in its treatment can cause complications. Marine collagen peptides can be used as a natural atherosclerosis remedy. The present study investigated the preparation and characterization of hydrolyzed collagen (HC) from jellyfish and its conjugation with black jelly mushroom extract (BJME). Their cytotoxicity and ability to prevent cholesterol-induced endothelial cell injury were also examined. HC was prepared using Alcalase or papain hydrolysis (0.2–0.4 units/g of dry matter (DM)). Higher yield, degree of hydrolysis, and antioxidant activities (AAs) were found in the HC obtained from Alcalase, especially at 0.4 units/g DM (A-0.4), compared to other processes (p < 0.05). Thus, A-0.4 was further conjugated with BJME (1–4%, w/w of HC). The HC-2%BJME conjugate showed the highest surface hydrophobicity and AAs compared to other samples. The FTIR spectra and size distribution also confirmed the conjugation between HC and BJME. When EA.hy926 endothelial cells were treated with HC or HC-2%BJME (25–1000 µg/mL), HC-2%BJME had no cytotoxicity, whereas HC at 1000 µg/mL induced cytotoxicity (p < 0.05). Both samples also exhibited protective ability against cholesterol-induced apoptosis and VE-cadherin downregulation of cells. Therefore, HC and conjugate could be natural agents for preventing atherosclerosis.

Organic pollutants were one of the main sources of environmental pollutants. The degradation of organic pollutants through photocatalytic technology was one of the effective solutions. By preparing zinc oxide(ZnO) nanowires modified with sodium-doped conjugated 2,4,6-triaminopyrimidin-g-C3N4 (NaTCN) heterojunction (ZnO/NaTCN), the photocatalytic performance of NaTCN modified with different ratios of ZnO was systematically studied. The photocatalytic performance was studied through the degradation performance of methyl blue (MB) dye. The results showed that 22.5 wt% ZnO/NaTCN had the best degradation effect on MB dye. The degradation rate of MB reached 98.54% in 70 min. After three cycles, it shows good cycling stability (degradation rate is 96.99%) for dye degradation. It was found that there are two types of active species: ·OH and h+, of which h+ is the main active species produced by photocatalytic degradation of dyes. The excellent degradation performance was attributed to the fact that ZnO facilitated the extraction and transport of photogenerated carriers. The doping of sodium facilitated charge transfer. The NaTCN conjugated system promoted the extraction and transfer of photogenerated carriers. It provided guidance for designing efficient composite catalysts for use in other renewable energy fields.

IntroductionStreptococcus pneumoniae is a leading cause of pneumonia among children. However, owing to diagnostic limitations, the protection conferred by pneumococcal conjugate vaccines (PCVs) against pediatric pneumonia attributable to vaccine-serotype pneumococci remains unknown.MethodsWe analyzed data on vaccination and nasopharyngeal pneumococcal detection among children

Abstract Background Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and is notorious for its resistance to both chemotherapy and small-molecule inhibitor targeted therapies. Subcellular targeted cancer therapy may thwart the resistance to produce a substantial effect. Methods We tested whether the resistance can be circumvented by subcellular targeted cancer therapy with DZ-CIS, which is a chemical conjugate of the tumor-cell specific heptamethine carbocyanine dye (HMCD) with cisplatin (CIS), a chemotherapeutic drug with limited use in ccRCC treatment because of frequent renal toxicity. Results DZ-CIS displayed cytocidal effects on Caki-1, 786-O, ACHN, and SN12C human ccRCC cell lines and mouse Renca cells in a dose-dependent manner and inhibited ACHN and Renca tumor formation in experimental mouse models. Noticeably, in tumor-bearing mice, repeated DZ-CIS use did not cause renal toxicity, in contrast to the CIS-treated control animals. In ccRCC tumors, DZ-CIS treatment inhibited proliferation markers but induced cell death marker levels. In addition, DZ-CIS at half maximal inhibitory concentration (IC50) sensitized Caki-1 cells to small-molecule mTOR inhibitors. Mechanistically, DZ-CIS selectively accumulated in ccRCC cells’ subcellular organelles, where it damages the structure and function of mitochondria, leading to cytochrome C release, caspase activation, and apoptotic cancer cell death. Conclusions Results from this study strongly suggest DZ-CIS be tested as a safe and effective subcellular targeted cancer therapy.

Cabazitaxel (CTX) is a medication used for treating metastatic prostate cancer. However, its effectiveness is majorly limited by its poor water solubility and lack of tumor targeting. In this study, three unsaturated fatty acids, GLA, ALA and DHA, were separately connected with CTX and then covalently attached to bifunctionalized dextran through a linker to produce three dual drug conjugates named dextran-GLA-CTX, dextran-ALA-CTX and dextran-DHA-CTX. The three conjugates displayed enhanced solubility of CTX in water and improved antitumor effects compared to the conventional CTX formulation. The results also confirmed that dextran-GLA-CTX exhibited the strongest antitumor activity, while dextran-DHA-CTX displayed less efficacy, as evaluated through xenografted nude mice bearing PC-3 and DU145 prostate cancer cells. Additionally, dextran-GLA-CTX showed greater inhibition of tumor growth than dextran-CTX. Moreover, the dextran-GLA-CTX conjugate was found to prolong the half-life of CTX in plasma and selectively accumulate in tumors. This study revealed that unsaturated fatty acids can enhance the antitumor activity of dextran-based conjugates grafted with CTX.

Contaminated fungi on dried salted fish of three species including Talang queenfish (TQF, Scomberroides commersonianus), Hamilton's thryssa fish (HTF, Thryssa hamiltonii), and Cobia fish (CF, Rachycentron canadum) were isolated and identified. One hundred and sixty‐nine isolates were obtained from TQF and HTF, respectively, while no fungi were detected in CF. The dominant genera were Aspergillus spp. (n = 79), Penicillium spp. (n = 60), and non‐sporulating fungi (n = 30). The representative groups of Aspergillus spp. (n = 6) and Penicillium spp. (n = 3) based on different morphological characteristics were selected for species identification by molecular methods involving ITS1‐5.8s‐ITS2 region and Matrix‐Assisted Laser Desorption/Ionization Time‐of Flight Mass Spectrometer (MALDI‐TOF MS) analysis. The nine isolates were identified to be Aspergillus versicolor (n = 2), Aspergillus montevidensis (n = 3), Penicillium citrinum (n = 3), and Aspergillus sp. (n = 1). The antifungal activity of chitooligosaccharide‐gallic acid (COS‐GAL) conjugate against A. versicolor F1/10M9, A. montevidensis F1/30M20, and P. citrinum F1/23M14 was examined. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values were in the range of 0.625–2.5 mg/mL and 1.25–10 mg/mL, respectively. COS‐GAL conjugate at the concentration of 5 mg/mL completely inhibited the spore germination of A. versicolor F1/10M9 and P. citrinum F1/23M14 after 72 h of treatment. COS‐GAL conjugate at 4 × MIC mainly affected the mycelium of A. versicolor F1/10M9 and P. citrinum F1/23M14 after treatment with COS‐GAL conjugate for 3 days by coating mycelium surface and reducing the size of mycelium. Therefore, COS‐GAL conjugate could be used as a food additive to inhibit or prevent the growth of fungi contaminated in dried salted fish or other relevant products. Practical Application: During processing, dried salted fish can be contaminated with fungi, which may cause food poisoning and food spoilage. The contaminated fungi are capable of producing mycotoxin that is harmful to consumers. Synthetic food preservatives have long been used to inhibit fungal growth, but the side effects to consumers are of concern. Chitooligosaccharide is a nontoxic chitosan derivative produced from shrimp shell and its conjugate namely chitooligosaccharide‐gallic acid conjugate showed high efficacy in inhibiting the growth of fungi including Aspergillus spp. and Penicillium spp. Therefore, it can serve as a natural alternative preservative for the prevention of fungal growth in dried salted fish. [ABSTRACT FROM AUTHOR]