Duckworthbossen5662

trasound-induced cancer therapy.Helicobacter pylori is a causative factor of various gastrointestinal tract diseases. As clinical antibiotic-based therapy for H. pylori infection might induce bacterial drug resistance, the in vivo eradication of H. pylori remains a huge challenge. In the present study, monoclonal antibody-conjugated liposomes loaded with indocyanine green (ICG) (HpAb-LiP-ICG) were successfully developed for targeted photoacoustic (PA) imaging-guided sonodynamic therapy (SDT) of H. pylori infection in vivo. HpAb-LiP-ICG showed high stability and favorable biocompatibility in acidic environment (pH 1.5) and was used for treating H. pylori-infected mice through oral administration. PA imaging showed that HpAb-LiP-ICG could precisely recognize and target H. pylori in the stomach. Following the targeting of HpAb-LiP-ICG to H. pylori, ICG was activated to generate singlet oxygen (1O2) for eliminating H. pylori under ultrasound (US) irradiation. Pathological analysis revealed that the HpAb-LiP-ICG-mediated SDT eradicated H. pyloriide effects, thus highlighting the clinical translational prospects of the prepared HpAb-LiP-ICG nanoliposome in near future.β-lactamase mediated resistance in Escherichia coli is a significant problem that requires immediate attention. Herein, we aim to characterize and understand the dynamics of the genetic determinants of β-lactam resistance (i.e. ESBL, AmpC, and MBL) in E. coli. Out of 203 E. coli isolates, genetic determinants of β-lactam resistance were identified in 50% (n = 101) of isolates. ESBL, AmpC, and MBL resistance determinants were detected in 78%, 40%, and 18% of isolates, respectively with blaCTX-M group 4 (48%), blaCMY (40%), and blaSIM (33%) as the most prevalent β-lactam resistance genes. Among these isolates, 45% harbored plasmid replicon types, with L/M (40%) and Y (33%) as the most dominant replicon types. Integrons were detected in 40% of such isolates, with Class-1 and Class-3 representing 62% and 55%, respectively. Overall, we observed high rate of genetic determinants of β-lactam-resistance in E. coli isolates recovered from patients in clinical settings. The co-occurrence of antimicrobial resistance genes and mobile genetic elements in a high percentage of isolates is a major concern and relates to complex resistance mechanisms. To combat the serious threat of antimicrobial resistance, it is imperative to develop strategies for robust surveillance and understand the molecular basis of resistance acquisition and transmission.Watchful epidemiological surveillance of macrolide-resistant Group A Streptococcus (MRGAS) clones is important owing to the evolutionary and epidemiological dynamic of GAS. Meanwhile, data on the global distribution of MRGAS emm types according to macrolide resistance phenotypes and genotypes are scant and need to be updated. For this, the present systematic review analyses a global set of extensively characterized MRGAS isolates from patients of diverse ages and clinical presentations over approximately two decades (2000 to 2020) and recaps the peculiar epidemiological features of the dominant MRGAS clones. Based on the inclusion and exclusion criteria, 53 articles (3593 macrolide-resistant and 15,951 susceptible isolates) distributed over 23 countries were dissected with a predominance of high-income countries over low-income ones. Although macrolide resistance in GAS is highly variable in different countries, its within-GAS distribution seems not to be random. emm pattern E, 13 major emm types (emm12, 4, 28, 77, 75, 11, 22, 92, 58, 60, 94, 63, 114) and 4 emm clusters (A-C4, E1, E6, and E2) were significantly associated with macrolide resistance. emm patterns A-C and D, 14 major emm types (emm89, 3, 6, 2, 44, 82, 87, 118, 5, 49, 81, 59, 227, 78) and 3 well-defined emm clusters (A-C5, E3, and D4) were significantly associated with macrolide susceptibility. Scrutinizing the tendency of each MRGAS emm type to be significantly associated with specific macrolide resistance phenotype or genotype, interesting vignettes are also unveiled. The 30-valent vaccine covers ~95% of MRGAS isolates. The presented data urge the importance of comprehensive nationwide sustained surveillance of MRGAS circulating clones particularly in Low and Middle income countries where sampling bias is high and GAS epidemiology is obfuscated and needs to be demystified.Recent reports have highlighted the role of the lymphatic system and its resident immune cells in the development of inflammatory arthritis. Directing therapeutics to the joint-draining lymphatics could improve access to lymphatic-resident pro-inflammatory immune cells, improve local treatment efficacy and enable the administration of lower drug doses to achieve the same or a better effect. Here, we assessed the delivery of disease modifying anti-rheumatic drugs (DMARDs) to the joint-draining lymphatics as a function of therapeutic size and route of administration (intravenous (IV), subcutaneous (SC) and intra-articular (IA) injection). The model drugs included the low molecular weight conventional DMARD methotrexate and the larger biologic DMARDs etanercept and rituximab. Plasma pharmacokinetics, thoracic lymph fluid concentrations and lymph node deposition of the DMARDS were assessed in male Sprague-Dawley rats after IV, IA or SC injection at or near the knee joint. Administration by IA injection resulted in rapid and higher absorption of all drugs into the systemic circulation, compared to SC administration. The large DMARDs etanercept and rituximab were preferentially transported from the IA and SC injection sites via the lymphatics, but a greater percentage of the absorbed dose was recovered in lymph after IA (49-58%) compared to SC administration (17-20%). Methotrexate was almost exclusively transported from the injection site via the blood after IA injection, consistent with its small size which presents minimal barriers to diffusion across the synovium into blood vessels. Importantly, IA but not SC administration resulted in biologic DMARD access to the knee joint-draining iliac lymph fluid and iliac lymph node that is dysfunctional in inflammatory knee arthritis. Overall, IA injection of biologic DMARDs may provide a simple strategy to improve lymph and lymph node access and thus the treatment of inflammatory arthritis.The fragmentation of therapeutic antibodies, particularly in the complementarity determining region (CDR), is considered a critical quality attribute. However, our understanding of CDR fragmentation remains limited. selleck chemical Here, we report the mechanism behind CDR fragmentation of a therapeutic IgG1 formulation, which is prone to fragmentation in heavy-chain CDR during storage, and screened excipients to control fragmentation based on the mechanism. In the degraded samples, fragments were generated from the cleavage around Tyr102, and a high level of oxidation was observed. Trp100 correlated most strongly with fragments among all the oxidized sites in multiple batches of mAb1 drug products. Oxidant-induced selective upregulation of mAb1 Trp100 oxidation level increased fragment level. This trend was rescued by the addition of Trp, indicating that Trp100 oxidation induced mAb1 fragmentation. A minor change in the mAb1 structure explored the potential mechanism of the regulatory relationship between Trp100 oxidation and fragmentation. Moreover, there was no obvious Trp100 oxidation or fragments in the mAb1 formulation without polysorbate 80 (PS80). Accordingly, substitution of PS80 with new surfactants, a combination of antioxidants, or EDTA with PS80, maintained mAb1 stability. This study demonstrated that mAb1 CDR fragmentation results from Trp100 oxidation and provides new excipients to resolve mAb fragmentation during formulation development.Microneedlepatches, also called microarray patches(MAP),are an emergingtechnology for deliveryand samplingof drugs, vaccines and other materials. This review focuses on the materials and methods used to fabricate dissolvable microneedles(DMN)for pharmaceutical use.We outlinethe relative use ofexcipients, active pharmaceutical ingredients (API) and methods usedfor DMN fabrication. An extensive search of primary literature, up to April 2021,identified 328 papers under the key terms "dissolvable microneedles" or "polymeric microneedles".We based the classification of materials on pharmacopoeia definitions.The majority (76%) ofthe identifiedpublications examined licensed or model therapeutic small molecule drugs. Mostreports (58%)focused ondrugs or vaccinesthat are licensed for clinical use. Therelativeuse of excipientswith drug-containing compared to vaccine-containing DMN is discussed.Tenpolymers and sugarswereused for both drug and vaccine DMN.Themost frequentmethods to produce DMNwerecasting into moulds using centrifugationorvacuum filling. Novel methods reported include centrifugal lithography and 3D printing. This review provides insight intomaterialselection,thefeasibilityofproductionmethodsat industrial scaleand outlines considerations for novel DMN patch fabrication.Predicting drug-target interactions (DTIs) is essential for both drug discovery and drug repositioning. Recently, deep learning methods have achieved relatively significant performance in predicting DTIs. Generally, it needs a large amount of approved data of DTIs to train the model, which is actually tedious to obtain. In this work, we propose DeepFusion, a deep learning based multi-scale feature fusion method for predicting DTIs. To be specific, we generate global structural similarity feature based on similarity theory, convolutional neural network and generate local chemical sub-structure semantic feature using transformer network respectively for both drug and protein. Data experiments are conducted on four sub-datasets of BIOSNAP, which are 100%, 70%, 50% and 30% of BIOSNAP dataset. Particularly, using 70% sub-dataset, DeepFusion achieves ROC-AUC and PR-AUC by 0.877 and 0.888, which is close to the performance of some baseline methods trained by the whole dataset. In case study, DeepFusion achieves promising prediction results on predicting potential DTIs in case study.Refined grounded cognition accounts propose that abstract concepts might be grounded in brain circuits involved in mentalizing. In the present event-related potential (ERP) study, we compared the time course of neural processing in response to semantically predefined abstract mental states and verbal association concepts during a lexical decision task. In addition to scalp ERPs, source estimates of underlying volume brain activity were determined to reveal spatio-temporal clusters of greater electrical brain activity to abstract mental state vs. verbal association concepts, and vice versa. Source estimates suggested early (onset 194 ms), but short-lived enhanced activity (offset 210 ms) to verbal association concepts in left occipital regions. Increased occipital activity might reflect retrieval of visual word form or access to visual conceptual features of associated words. Increased estimated source activity to mental state concepts was obtained in visuo-motor (superior parietal, pre- and postcentral areas) and mentalizing networks (lateral and medial prefrontal areas, insula, precuneus, temporo-parietal junction) with an onset of 212 ms, which extended to later time windows. The time course data indicated two processing phases An initial conceptual access phase, in which linguistic and modal brain circuits rapidly process features depending on their relevance, and a later conceptual elaboration phase, in which elaborative processing within feature-specific networks further refines the concept. This study confirms the proposal that abstract concepts are based on representations in distinct neural circuits depending on their semantic feature content. The present research also highlights the importance of investigating sets of abstract concepts with a defined semantic content.