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S. pneumoniae (SP) serotypes 15B and 15C are frequent causative agents of invasive pneumococcal disease (IPD), otitis media, and nasopharyngeal colonization in the post PCV13 era. The principal difference between serotypes 15B and 15C is the presence of an O-acetyl group on the pentasaccharide repeating unit of 15B polysaccharide. It remains unclear if antibodies against SP15B polysaccharide demonstrate functional cross reaction with SP15C strains. We compared functional activity of polyclonal rabbit anti-capsular 15B sera against SP15B and SP15C isolates. Using flow cytometry we measured complement factors C3c and C4d deposition on SP15B and 15C in the presence of polyclonal rabbit anti capsular 15B sera. We measured the binding of C3c, common to all complement pathways, and C4d, specific to classical pathway, on SP serotypes 15B and 15C when co-incubated with polyclonal rabbit anti capsular 15B sera and antibody depleted complement. Both the proportion of bacteria with complement deposition and the fluorescence intensity were measured. We also measured agglutination as the increase in forward and side scatter. Polyclonal rabbit anti-capsular 15B sera activated classical pathway resulting in deposition of C4d and C3c at high intensity on all SP15B cells but only achieved limited deposition and intensity of C4 with SP15C. Similarly, polyclonal rabbit anti-capsular 15B sera induced agglutination of SP15B strains in a dose dependent manner and limited agglutination of SP15C. Anti-capsular 15B sera induce limited C4d and C3c deposition, and minimal agglutination with SP15C strains, reflecting lower classical pathway activation in contrast to high C4d and C3c deposition and agglutination of SP15B. These observations support limited functional cross reactivity of anti-15B to SP15C strains and are consistent with the reduction in opsonophagocytic killing of SP15C reported following immunization with vaccines containing 15B polysaccharide. •Antibodies against SP serotype 15B activated both classical and alternative pathway of complement activation on the surface of SP15B.•15B antibodies showed relatively less complement binding and agglutination with 15C compared with 15B.•Study suggest antibodies against SP15B may not confer protection against SP 15C by complement dependent killing.

DNA origami may enable more versatile gene delivery applications through its ability to create custom nanoscale objects with specific targeting, cell-invading, and intracellular effector functionalities. Toward this goal here we describe the expression of genes folded in DNA origami objects delivered to mammalian cells. Genes readily express from custom-sequence single-strand scaffolds folded within DNA origami objects, provided that the objects can denature in the cell. We demonstrate enhanced gene expression efficiency by including and tuning multiple functional sequences and structures, including virus-inspired inverted-terminal repeat-like (ITR) hairpin motifs upstream or flanking the expression cassette. We describe gene-encoding DNA origami bricks that assemble into multimeric objects to enable stoichiometrically controlled co-delivery and expression of multiple genes in the same cells. Our work provides a framework for exploiting DNA origami for gene delivery applications. DNA origami may enable more versatile gene delivery applications through its ability to create custom nanoscale objects. Here the authors show that genes folded in DNA origami with custom scaffolds express efficiently when delivered to mammalian cells and can be assembled into multimeric arrays to deliver and express defined ratios of multiple genes simultaneously.

Breast cancer (BC) is the most common cancer in women worldwide and the most frequent cause of cancer death in women in low- and middle-income countries (LMIC). The incidence of BC in Africa is on the rise, expected to double by 2050, primarily owing to late presentation and weak health infrastructure in sub-Saharan Africa (SSA). This study addresses the lack of recent data on BC cases in the Eastern Cape Province of South Africa. The objectives of this study were to describe the clinicopathological characteristics and molecular subtypes of BC and, in addition, to examine the association between the clinicopathological characteristics and the molecular subtypes of BC in a single tertiary hospital in the Eastern Cape Province of South Africa. A two-year (2022-2023) retrospective cross-sectional clinical record review study was conducted on patients treated for invasive BC at a tertiary hospital in the Eastern Cape Province, South Africa. The demographic, clinical and pathological characteristics and molecular subtypes were reported. Associations were investigated between the BC molecular subtypes identified and the clinicopathological characteristics of the patients. A total of 282 patients met the study's inclusion criteria. Most patients were female (98.6%) and African (88.1%). The mean age of the patients was 58.7 years, with BC most prevalent in the age group >70 (25.2%) and postmenopausal (77.4%). Breast lump was the most common presenting complaint (98.6%), with 61% of patients presenting three months after noticing the anomaly. The most common tumour size (59.4%) was > 5 cm (mean = 6.37 ± 3.6), with the most common clinical T stage being T4 (50.4%). Lymph node involvement was seen in 50.4% of cases. Patients mostly presented in Stages III and IV of the disease (60.1%). Invasive ductal carcinoma not otherwise specified (NOS) was the most common histopathological subtype (86.2%). Grade 2 (56.2%) and Grade 3 (29.5%) BC accounted for the majority of cases. Luminal B was found in 47.4% of cases, Luminal A in 28.5%, triple negative breast cancer (TNBC) in 18.6% and human epidermal growth factor receptor 2 (HER2) enriched in 5.5% of cases, respectively. In our setting, most patients consulted at a late stage of the disease with a large tumour size, positive lymph node status and a high histological grade. Luminal B tumours are the most common molecular subtype. These results indicate the need for more intensive breast cancer awareness campaigns, early detection, and timely referral and treatment.

Broad-spectrum antiviral platforms that can decrease or inhibit viral infection would alleviate many threats to global public health. Nonetheless, effective technologies of this kind are still not available. Here, we describe a programmable icosahedral canvas for the self-assembly of icosahedral shells that have viral trapping and antiviral properties. Programmable triangular building blocks constructed from DNA assemble with high yield into various shell objects with user-defined geometries and apertures. We have created shells with molecular masses ranging from 43 to 925 MDa (8 to 180 subunits) and with internal cavity diameters of up to 280 nm. The shell interior can be functionalized with virus-specific moieties in a modular fashion. We demonstrate this virus-trapping concept by engulfing hepatitis B virus core particles and adeno-associated viruses. We demonstrate the inhibition of hepatitis B virus core interactions with surfaces in vitro and the neutralization of infectious adeno-associated viruses exposed to human cells. Programmable triangular DNA blocks self-assemble into distinct icosahedral shells with specific geometry and apertures that can encapsulate viruses and decrease viral infection.

Gold nanorods are one of the most widely explored inorganic materials in nanomedicine for diagnostics, therapeutics and sensing1. It has been shown that gold nanorods are not cytotoxic and localize within cytoplasmic vesicles following endocytosis, with no nuclear localization2,3, but other studies have reported alterations in gene expression profiles in cells following exposure to gold nanorods, via unknown mechanisms4. In this work we describe a pathway that can contribute to this phenomenon. By mapping the intracellular chemical speciation process of gold nanorods, we show that the commonly used Au–thiol conjugation, which is important for maintaining the noble (inert) properties of gold nanostructures, is altered following endocytosis, resulting in the formation of Au(i)–thiolates that localize in the nucleus5. Furthermore, we show that nuclear localization of the gold species perturbs the dynamic microenvironment within the nucleus and triggers alteration of gene expression in human cells. We demonstrate this using quantitative visualization of ubiquitous DNA G-quadruplex structures, which are sensitive to ionic imbalances, as an indicator of the formation of structural alterations in genomic DNA.

Protein delivery into cells is a potentially transformative tool for treating \"undruggable\" targets in diseases associated with protein deficiencies or mutations. The vast majority of these targets are accessed via the cytosol, a challenging prospect for proteins with therapeutic and diagnostic relevance. In this review we will present promising non-viral approaches for intracellular and ultimately cytosolic delivery of proteins using nanocarriers. We will also discuss the mechanistic properties that govern the efficacy of nanocarrier-mediated protein delivery, applications of nanomaterials, and key challenges and opportunities in the use of nanocarriers for intracellular protein delivery.

Introduction The Intolerance of Uncertainty Scale - Short Version (IUS-12) is a measure of trait intolerance of uncertainty. Objective The purpose of the present study was to conduct a cross-cultural adaptation of the IUS-12 for use in Brazil and to investigate the scale's psychometric properties. Methods The research was conducted via an online research platform with a sample (n = 704; 80.1% female and 19.9% male) from different states in all five regions of Brazil. Participants were adults between 18 and 59 years of age (mean = 26.74; standard deviation = 8.36) who completed the Brazilian version of the IUS-12 online along with other anxiety-related measures. Results Confirmatory factor analysis demonstrated that the original two-dimensional structure fit the sample well. The total score for the scale had good internal consistency (Cronbach's alpha [α] = 0.88), as did both subscales (i.e. Prospective IU α = 0.79; Inhibitory IU α = 0.86). Conclusions The results demonstrated strong positive correlations with measures of anxiety-related constructs, contributing to the transdiagnostic understanding of IU. The IUS-12 appears to be a useful tool for assessment of IU and its availability has several implications of theoretical importance and practical utility for understanding of psychopathology and uncertainty.

This study aims to investigate the gene expression of sperm-borne phospholipase C zeta (PLCζ), WW domain-binding protein 2N-Terminal Like (WBP2NL), and Tumor necrosis factor (TNF-α), as a negative control, in spermatozoa and their relationship with fertility and seminal quality in stallions. Ejaculates from 40 Criollo stallions were used, whose fertility was assessed on the basis of their pregnancy rate per cycle in at least two breeding seasons. Pregnancy rates ranged from 20% to 90% and were used to divide the stallions into two groups: High rates (≥ 50%) (n = 25), and Low rates (< 50%) (n = 15). A computer-assisted sperm analysis system - (CASA) analyzed semen after collection. Also were evaluated the physical and functional integrity of the plasmatic membrane and sperm morphology alterations. All stallions expressed PLCζ, WBP2NL, and TNF-α. PLCζ positively correlates with conception rate, total motility (TM), progressive motility (PM), plasmatic membrane functionality, and integrity. A simple linear regression was detected between pregnancy rate and PLCζ expression (P = 0.003), TM (P < 0.001) and PM (P < 0.001). PLCζ gene expression was higher (P = 0,012) in the High rates group than in the Low group. WBP2NL and TNF-α did not correlate with seminal quality and stallion’s fertility. It was concluded that PLCζ gene expression in the spermatozoa might be used as a biomarker of fertility and seminal quality in stallions. Parameters of sperm kinetics also showed, positive correlation between TM, PM and pregnancy rate.

Background Tumor necrosis factor (TNF) inhibitors are a mainstay in the treatment of rheumatoid arthritis (RA), as well as in the management of spondyloarthritis (SpA) and inflammatory bowel diseases (IBD). Unfortunately, a portion of patients taking these drugs require escalating doses within the approved label to achieve response, while others lose response altogether. This may be due to the development of antibodies against TNFi agents. Objectives Our objective was to examine the immunogenicity of TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) in RA, SpA, and IBD, and to examine the potential effect of anti-drug antibodies (ADABs) on the loss of clinical response through a systematic literature review and meta-analysis. Methods We conducted a comprehensive literature search using three databases (PubMed, Web of Science, and the Cochrane library) to identify studies examining the immunogenicity of TNF inhibitors in autoimmune diseases between 1966 and 31 December 2013. Inclusion criteria required that studies be in English, be randomized controlled trials, observational studies, or case reports involving more than five patients, and that the patients be aged 18 years or older. Studies were excluded if they were strictly genetic with no clinical correlate, if the patients had concomitant cancer within 5 years of the study, or if the patients had a renal disease requiring dialysis. Double extraction was followed by a third extraction if needed. Consensus was reached by discussion when disagreements occurred. Random-effect models were generated for the meta-analysis of 68 studies to estimate the odds ratio (OR) of the ADAB effects on TNF inhibitor response. Regression analysis was used to compare among the drugs and diseases. Results A total of 68 studies (14,651 patients) matched the inclusion/exclusion criteria. Overall, the cumulative incidence of ADABs was 12.7 % [95 % confidence interval (CI) 9.5–16.7]. Of the patients using infliximab, 25.3 % (95 % CI 19.5–32.3) developed ADABs compared with 14.1 % (95 % CI 8.6–22.3) using adalimumab, 6.9 % (95 % CI 3.4–13.5) for certolizumab, 3.8 % (95 % CI 2.1–6.6) for golimumab, and 1.2 % (95 % CI 0.4–3.8) for etanercept. ADABs reduced the odds of clinical response by 67 % overall, although most of the data were derived from articles involving infliximab (nine) and adalimumab (eight). The summary effect for infliximab yielded an estimated OR (with ADABs vs. without) of 0.42 (95 % CI 0.30–0.58); the summary effect for adalimumab yielded an estimated OR (as above) of 0.13 (95 % CI 0.08–0.22); and the OR (as above) for golimumab was 0.42 (95 % CI 0.22–0.81). All figures were statistically significant. ADABS decreased response by 27 % in RA and 18 % in SpA, both of which were statistically significant. However, the effect of ADABS on response was not statistically significant for IBD when we only included the studies that reported the duration of exposure in the regression analysis. The use of concomitant immunosuppressives (methotrexate, 6-mercaptopurine, azathioprine, and others) reduced the odds of ADAB formation in all patients by 74 %. The OR for risk with immunosuppressives versus without was 0.26 (95 % CI 0.21–0.32). Conclusion ADABs developed in 13 % of patients. All five TNF inhibitors were associated with ADABs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADABs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADAB formation.

A growing number of studies suggest that individuals can develop long‐term foraging specializations independently of phenotypic or environmental variation, yet little is known about how the foraging niche is acquired. The early learning of the foraging niche hypothesis suggests a key role of vertical cultural transmission in shaping the foraging niche of vertebrates. In birds, direct evidence from natural conditions is limited to a single study that cross‐fostered two related species. To date, no study has tested whether the diet received as an offspring determines the diet delivered as a parent within a single species. We tested the early learning of the foraging niche hypothesis using a Mediterranean population of great tits Parus major, which show great diet variability and moderate consistency in the diet they provide to their offspring across years. To do this, we recorded prey delivered to 9–14 day‐old chicks over twelve years. Then we assessed vertical transmission of dietary specialization using data (percentage of caterpillars, spiders, and other prey types, as well as mean prey size) from individuals recorded as a chick and as an adult. We standardised the data to control for environmental factors and ran a Linear Model for each prey type to measure individuals' consistency within the group (relative consistency), correlating the diet they received as a chick and the one they provided to their own chicks at the adult stage. The correlations between the diet received as a chick and the diet provided as a parent were either not significant or negative. Hence, although individuals showed relatively consistent foraging niches across years regarding their parental provisioning behaviour, these diet preferences were not correlated to the diet they received in the nest. Further research is needed to determine whether the foraging niche is acquired during the post‐fledgling stage.