Insufficient Uptake Research Articles

Scale-up synthesis of a low-cost cobalt formate framework for efficient C3H6/C2H4 separation and shaping performance study

The separation of propylene (C3H6) from ethylene (C2H4) is one of the most vital processes to obtain high-purity C2H4 in the petrochemical industry, which is commonly limited by the insufficient C3H6 uptake or poor C3H6/C2H4 selectivity due to the weak C3H6 binding affinity. Herein, a low-cost cobalt formate framework (termed as CoFA) was synthesized up to 40 g for efficient C3H6/C2H4 separation. CoFA with multiple accessible Oδ- sites and contracted zigzag pore channels provides a unique single-molecule C3H6 nanotrap with benchmark high C3H6 adsorption affinity. The C3H6 uptake at 0.01 bar reaches as high as 59.4 cm3 cm−3, ranking second among the materials in the context of C3H6/C2H4 separation. Breakthrough experiments confirm its excellent separation capacity for equimolar C3H6/C2H4 mixtures. The separation performance is retained under 5 cycles and under humid conditions. Theoretical calculations reveal that the perfectly size-matched pore cavities combined with multiple hydrogen bonding sites enable this single-molecule C3H6 nanotrap to maximize the C3H6 binding affinity. The shaping properties of CoFA were investigated by using four different binders with PES as the best one to shape CoFA with retained capacity and selectivity.

Tricine-modified chitosan as a strategy for enhancing hydrophilicity and gene delivery

In this study, we investigated the effect of chitosan modification with tricine on transfection efficiency by preserving its ability to form complexes with plasmid DNA (pDNA) and increasing its hydrophilicity. The inherent limitations of chitosan, such as poor solubility at physiological pH, insufficient cellular uptake, and strong ionic interactions with pDNA, typically result in low transfection efficiency. To overcome these challenges, Tricine, a hydrophilic molecule containing a secondary amine group, was conjugated to chitosan. Chitosan of three different molecular weights (low, medium, and high) was modified with tricine. Structural characterization of the modified chitosan was conducted using Fourier Transformed Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR) analyses. The effects of tricine modification were assessed in terms of hydrophilicity/hydrophobicity, proton buffering capacity, particle size, PDI and zeta potential. Tricine modified low molecular weight chitosan nanoparticles (nLMWChiTri), which exhibit suitable properties for gene transfer studies, were evaluated regarding pDNA complexation ability, cytotoxicity and in vitro transfection efficiency. The results demonstrated that tricine modification enhanced the gene transfer potential of chitosan, making it competitive with the commercial transfection agent Lipofectamine™ 2000 and offering a promising strategy for non-viral gene therapy applications. Furthermore, the biocompatibility and biodegradability of chitosan, combined with the improved hydrophilicity provided by tricine, makes nLMWChiTri a safer and more sustainable option for repeated use in gene delivery, overcoming the major limitations associated with other synthetic vectors such as Lipofectamine™ 2000.

Self-Tumor Antigens in Solid Tumors Turned into Vaccines by α-gal Micelle Immunotherapy.

A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen "α-gal epitope" (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called "anti-Gal" (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. Such an immunotherapy will convert tumors into a personalized anti-TA vaccine for the period prior to their resection.

Factors Related to the Rise of Congenital Syphilis From the Perspectives of Prenatal Providers and Birthing Parents in Chicago, IL, USA.

Rates of congenital syphilis (CS) in the United States have risen sharply in recent years. There has been sparse research centering the voices and experiences of birthing parents who have delivered infants with CS and prenatal providers in Chicago or the surrounding Midwestern United States to date. Additionally, there has been little research on the role of extrinsic factors, such as stigma and attitudes surrounding CS in an individual's community, in their entry into and retention in the CS prevention cascade. Semistructured interviews seeking to gather perspectives and factors related to the rise of CS were conducted with birthing parents who delivered infants with CS at a major academic medical institution (AMI) and the prenatal providers who served them. This was supplemented by retrospective data of birthing parent outcomes. Barriers elicited during the interviews included insufficient penicillin uptake, limited transportation, poor communication between providers and patients, gaps in patient understanding or knowledge around CS contraction and treatment, missed appointments, appointment burden for patients, life stressors of patients, housing instability, childcare difficulties, and stigma related to the CS diagnosis. The quantitative data revealed differing proportions of CS outcomes and care between those with care within the AMI, those with care outside the AMI, and those who had no prenatal care. This study found numerous perspectives and factors that may explain the rise of CS along various stages of the syphilis care continuum through in-depth interviews of prenatal providers and birthing parents.

Addressing disparity in attitudes and utilization of family planning among married couples in the pastoralist community of Fentale District, Eastern Ethiopia.

Despite progress in national reproductive health programs, pastoralist regions like Fentale District in Eastern Ethiopia face challenges with low contraceptive coverage, attributed to insufficient positive attitudes and uptake among couples. This cross-sectional study was conducted from October 1 to December 25, 2021, in Fentale District, Eastern Ethiopia. It involved 1,496 couples selected using multistage sampling. Data were entered into EPI Data and analyzed with SPSS (v23.0) and STATA (v14.0), employing descriptive statistics, bivariate analysis, and binary logistic regression to identify predictors of contraceptive attitudes and use. The study's response rate was 93.8%, with 1,404 pastoralist couples participating, equally split between women and men. A nomadic-pastoralist lifestyle was common (64.6%), and family planning discussions were rare (93.2%). Gender disparities in contraceptive attitudes and use were evident. Contraception use was reported by 27.4%, with women (41.2%) outnumbering men (13.5%). Women showed more positive attitudes towards contraception (87.9% vs. 31.9% for men). Only 33% had favorable attitudes towards different contraceptive methods, with women more likely to be positive. Modern contraception use was low (18.2%), with women (34.8%) predominating over men (1.7%). Among users, women had a more favorable attitude (78.5% vs. 6.6% for men). Health extension workers were key information providers. Predictors of contraceptive attitudes and use included sex, education, occupation, electronic device ownership, migration frequency, treatment preferences, and family planning discussions. The limited positive attitude towards and use of family planning in Fentale District may stem from unfavorable attitudes, low adoption, and couple disparities. Key factors include gender, education, occupation, electronic device ownership, migration, treatment preferences, and family planning discussions. Targeted educational campaigns for men are needed to address these issues and reduce the gender gap in contraceptive attitudes and use.

Anti-inflammation Mechanisms of Flavones Are Highly Sensitive to the Position Isomers of Flavonoids: Acacetin vs Biochanin A.

Acacetin (ACA) and biochanin A (BCA) are isomeric monomethoxyflavones with different structural positions of the 4'-methoxy-phenyl group. Both of them are present in many commonly consumed foods, such as citrus fruits and vegetables, and have been discovered with anti-inflammatory activities, but their mechanisms of action are not clearly elucidated at the molecular level. Herein, we reported the structure-activity relationship of ACA and BCA regarding their potency in inhibiting nitric oxide (NO) production, proinflammatory enzyme expression, and mRNA expression of proinflammatory cytokines in the lipopolysaccharide (LPS)-induced RAW 264.7 cells. Furthermore, transcriptome analysis was conducted to map out the overall pathways impacted by these two isomers. Our results showed that ACA possessed higher suppressive activity in nitric oxide (NO) production (IC50 = 23.93 ± 1.74 μM for ACA and IC50 = 71.41 ± 8.07 μM for BCA), inducible nitric oxide synthase (iNOS) expression, and proinflammatory interleukin (IL)-1β mRNA expression, but lower inhibitory activity in IL-6 mRNA expression as compared with BCA. Although two compounds were revealed to bind to c-Src protein according to drug affinity responsive target stability (DARTS) and western blotting results, molecular docking and molecular dynamics (MD) simulation showed that they had different binding sites, which subsequently resulted in different signaling transduction. ACA primarily exerted anti-inflammatory activity through the mitogen-activated protein kinase (MAPK) signaling pathway, the tumor necrosis factor (TNF) signaling pathway, and the hypoxia-inducible factor (HIF)-1 signaling pathway, while BCA was particularly involved in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, the nuclear factor kappa B (NF-κB) signaling pathway, the TNF signaling pathway, and the toll-like receptor (TLR) signaling pathway. Moreover, two isomers remained stable in the cell culture medium and did not encounter the biotransformation process in RAW 264.7 cells. However, BCA exhibited insufficient cellular uptake ability and transport efficiency in macrophages compared to ACA. Taken together, ACA is more promising for controlling inflammation and worthy of further study for human use.

Identification of TonB-dependent siderophore receptor inhibitors against Flavobacterium columnare using a structure-based high-throughput virtual screening method.

TonB-dependent siderophore receptors play a critical transport role for Flavobacterium columnare virulence formation and growth, and have become valuable targets for the development of novel antimicrobial agents. Traditional Chinese medicine has demonstrated notable efficacy in the treatment of fish diseases and includes potential antibacterial agents. Herein, we performed molecular docking-based virtual screening to discover novel TonB-dependent siderophore receptor inhibitors from traditional Chinese medicine and provide information for developing novel antibacterial agents. Firstly, we efficiently obtained 11 potential inhibitors with desirable drug-like characteristics from thousands of compounds in the TCM library based on virtual screening and property prediction. The antibacterial activity of Enoxolone, along with its interaction characteristics, were determined via an MIC assay and molecular dynamic simulation. Transcriptional profiling, along with validation experiments, subsequently revealed that an insufficient uptake of iron ions by bacteria upon binding to the TonB-dependent siderophore receptors is the antibacterial mechanism of Enoxolone. Finally, Enoxolone's acceptable toxicity was illustrated through immersion experiments. In summary, we have used virtual screening techniques for the first time in the development of antimicrobial agents in aquaculture. Through this process, we have identified Enoxolone as a promising compound targeting the TonB-dependent siderophore receptor of F. columnare. In addition, our findings will provide new ideas for the advancement of innovative antimicrobial medications in aquaculture.

Co-encapsulation of granzyme B and perforin in nanocapsules for tumour therapy: biomimicking immune cells

Granzyme B (GrB)-based immunotherapy is of interest for cancer treatment. However, insufficient cellular uptake and a lack of targeting remain challenges to make use of GrB for solid tumour therapy. As GrB induced cell death requires the help of perforin (PFN), we designed a system (nGPM) for the co-delivery of GrB and PFN. Therefore, GrB and PFN were loaded in a porous polymeric nanocapsule rich in acetylcholine analogues and matrix metalloproteinase-2 (MMP-2) responsive peptides. The neutrally charged nGPM nanocapsules showed as long circulating time and accumulated at the tumour sites. Once in the tumour the outside shell of nanocapsules became degraded by overexpressed MMP-2 proteases, resulting in the release of GrB and PFN. We found that the PFN complex formed small pores on the surface of tumour cells which allow GrB to enter the cytoplasm of tumour cells inducing cell apoptosis and tumour suppression significantly.

Epidemiology of and programmatic response to tuberculosis in Solomon Islands: analysis of surveillance data, 2016-2022.

To identify progress and challenges in the national response to tuberculosis (TB) in Solomon Islands through an epidemiological overview of TB in the country. A descriptive analysis was conducted using the national TB surveillance data for 2016-2022. Case notifications, testing data, treatment outcomes and screening activities were analysed. The number of case notifications was 343 in 2022, with an average annual reduction of the case notification rate between 2016 and 2022 of 4.7%. The highest case notification rate was reported by Honiara City Council (126/100 000 population) in 2022. The number of people with presumptive TB tested by Xpert® rapidly increased from zero in 2016 to 870 in 2022. Treatment success rate remained consistently high between 2016 and 2022, ranging from 92% to 96%. Screening for HIV and diabetes mellitus (DM) among TB patients in 2022 was 14% and 38%, respectively. Most patients (97%) were hospitalized during the intensive phase of treatment in 2022; in contrast, during the continuation phase, the proportion of patients treated at the community level increased from 1% in 2016 to 63% in 2022. Despite an increase in household contact investigations, from 381 in 2016 to 707 in 2021, the uptake of TB preventive treatment (TPT) was minimal (7% among eligible child contacts). This epidemiological analysis in Solomon Islands reveals both notable achievements and challenges in the country's TB programme. One major achievement is a potential actual reduction in TB incidence. Challenges identified were potential underdetection of cases in rural areas, suboptimal community-based care, and insufficient contact tracing and uptake of TPT. It is crucial to address these challenges (e.g. by optimizing resources) to advance the national TB response.

Abstract 2585: First in human study with a novel peptide binder to glypican-3, demonstrates high specificity as a PET imaging agent in patients with hepatocellular carcinoma

Abstract Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The American Association for the Study of Liver Disease recommends surveillance for high-risk individuals with abdominal ultrasound, triple phase contrast CT or MRI. However, these imaging techniques have limited sensitivity in classifying lesions smaller than 2 centimeters. The use of [18F]FDG Positron Emission Tomography (PET) is constrained due to insufficient uptake by HCC lesions over background liver uptake. Hence, there is an urgent need for more precise radiotracers for HCC. This study introduces the development of a novel radiotracer that binds to glypican-3 (GPC3), a cell membrane-anchored oncofetal protein overexpressed in HCC with minimal normal tissue expression. Methods: [68Ga]Ga-RYZ-GPC3 is composed of a small macrocyclic peptide binder with high affinity to GPC3 linked with a tetraxetan moiety capable of chelating a variety of radioisotopes including positron-emitting 68Ga and other radiometals. The unlabeled binder to GPC3 was synthesized by the sponsor and provided to three imaging centers in India as part of investigator-initiated trials reviewed and approved by each site’s institutional review board and ethics committee. Labeling with 68Ga and quality checks of the product was performed locally at each center. Patients with high clinical suspicion or with confirmed HCC who gave informed consent received injections of 1.5-5.5 mCi of [68Ga]Ga-RYZ-GPC3 and underwent PET-CT scanning at predetermined intervals. Some patients underwent companion [18F]FDG PET-CT scans in accordance with local guidelines. Results: A total of 64 patients underwent [68Ga]Ga-RYZ-GPC3 PET-CT scans. The median age within the cohort was 61 (41-83), 22% were female. Liver cirrhosis was present in 72% of patients, attributed to hepatitis B, hepatitis C or NASH in 17%, 13% and 20% of cases. Notably, 92% of patients exhibited at least one positive lesion on [68Ga]Ga-RYZ-GPC3 scans. The median SUVmax of GPC3-avid liver lesions was 15.5 (range 1.1 to 137.0) while the median liver SUVmean was 1.6 (0.3-7.9). Physiologic uptake was predominantly observed in the kidneys, the primary route of clearance, with a median SUVmean of 10.9 (2.2-20.7). Additionally, 20 patients underwent [18F]FDG PET-CT scan for comparison. The median SUVmax of lesions on 68Ga-RYZ-GPC3 vs [18F]FDG PET was 11.0 (1.1-137.0) vs 3.8 (1.2-12.2). Conclusion: Early human imaging results in patients with HCC indicate that [68Ga]Ga-RYZ-GPC3 has high tumor lesion specificity compared to normal liverand demonstrates the potential of [68Ga]Ga-RYZ-GPC3 to improve detection of HCC over conventional [18F]FDG PET-CT. In addition, the binder could be complexed with a therapeutic radioisotope as a novel targeted therapeutic option for HCC. Further investigation of this first-in-class binder to HCC is warranted. Citation Format: Chandresakhar Bal, Sanjana Ballal, Kumar Kallur, Anna Karmann, Ye Yuan, Jessica Rearden, Kathryn Shah, Charlotte Lorenz, Susan Moran, Ken Song, Ishita Sen. First in human study with a novel peptide binder to glypican-3, demonstrates high specificity as a PET imaging agent in patients with hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2585.

“To do so in a patient-centred way is not particularly lucrative”: The effects of neoliberal health care on PrEP implementation and delivery

BackgroundHIV pre-exposure prophylaxis (PrEP) is a highly effective biomedical intervention used by HIV-negative people to prevent HIV acquisition. Despite increased use of PrEP worldwide, several barriers to PrEP implementation have resulted in insufficient uptake, inadequate adherence, and frequent discontinuation. Our objective was to interrogate the social, political, and economic conditions shaping PrEP implementation and delivery among gay, bisexual, queer and other men who have sex with men (GBQM) in Ontario, Canada. MethodsSix focus groups and three interviews with 20 stakeholders in Ontario (e.g., healthcare professionals, clinicians, community-based organization staff, and government staff) were conducted between July and October 2021. Participants were asked about the personal, workplace, and structural factors shaping PrEP delivery strategies for GBQM. Transcripts were analyzed using reflexive thematic analysis informed by the political economy of PrEP and employed a critique of neoliberalism. ResultsParticipants critiqued the problematic arrangements of the current healthcare system in Canada. Neoliberal governmentality and policies have resulted in inequitable PrEP care by establishing funding structures prioritizing profit and requiring patients and providers to function as individual entrepreneurs. Consequently, healthcare disparities are compounded for marginalized peoples who lack the resources and capacity to navigate existing healthcare systems. Participants identified several pathways to improve the implementation of PrEP, including greater institutional and governmental supports for PrEP and healthcare, leveraging communities and collaboration, and moving beyond risk-based health frameworks. ConclusionSocio-political-economic changes reflecting post-neoliberal principles are needed to overcome existing barriers to PrEP care, and sexual and reproductive healthcare more broadly.

Insufficient Pulmonary Rehabilitation Uptake After Severe Exacerbation of COPD: A Multicentre Study in the South West Region of France.

Pulmonary rehabilitation (PR) is a type of multidisciplinary care strongly recommended after severe exacerbation of chronic obstructive pulmonary disease (COPD). Recently, a national French study reported a very low rate of PR uptake (8.6%); however, important clinical data were missing. Here, we aimed to identify the main factors associated with insufficient PR uptake after hospitalisation for COPD exacerbation. This multicentre retrospective study included patients hospitalised with COPD exacerbation between 1 January 2017 and 31 December 2018, as identified by both coding and a detailed review of medical records. PR was defined as inpatient care in a specialised centre or unit within 90 days of discharge. Multivariate logistic regression was used to identify associations between PR uptake and patient characteristics, such as comorbidities, non-invasive ventilation (NIV), inhaled treatment, and forced expiratory volume in 1 second (FEV1). Among the 325 patients admitted for severe COPD exacerbation, 92 (28.3%) underwent PR within 90 days of discharge. In univariate analysis, relative to those who underwent PR, patients without PR had significantly more comorbidities, were less often treated with triple bronchodilator therapy or NIV, and had a higher FEV1. In multivariate analysis, variables independently associated with the lack of PR uptake were the presence of comorbidities (adjusted odds ratio (aOR) = 1.28 [1.10-1.53], p = 0.003) and a higher FEV1 (aOR = 1.04 [1.02-1.06], p < 0.001). There was no significant correlation between PR uptake and departmental PR centre capacity (notably, some departments had no PR facilities). These data highlight the lack of PR in the early stages of COPD. Collaboration among all healthcare providers involved in patient management is crucial for improved PR uptake.

Lutetium-177-PSMA therapy for recurrent/metastatic salivary gland cancer: a prospective pilot study.

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [68Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [177Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUVmax on [68Ga]Ga-PSMA-11 PET/CT above liver SUVmean. Patients were planned to receive four cycles ~ 7.4 GBq [177Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [177Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [177Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake.

The synergic effects of presynaptic calcium channel antagonists purified from spiders on memory elimination of glutamate-induced excitotoxicity in the rat hippocampus trisynaptic circuit

The hippocampus is a complex area of the mammalian brain and is responsible for learning and memory. The trisynaptic circuit engages with explicit memory. Hippocampal neurons express two types of presynaptic voltage-gated calcium channels (VGCCs) comprising N and P/Q-types. These VGCCs play a vital role in the release of neurotransmitters from presynaptic neurons. The chief excitatory neurotransmitter at these synapses is glutamate. Glutamate has an essential function in learning and memory under normal conditions. The release of neurotransmitters depends on the activity of presynaptic VGCCs. Excessive glutamate activity, due to either excessive release or insufficient uptake from the synapse, leads to a condition called excitotoxicity. This pathological state is common among all neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Under these conditions, glutamate adversely affects the trisynaptic circuitry, leading to synaptic destruction and loss of memory and learning performance. This study attempts to clarify the role of presynaptic VGCCs in memory performance and reveals that modulating the activity of presynaptic calcium channels in the trisynaptic pathway can regulate the excitotoxic state and consequently prevent the elimination of neurons and synaptic degradation. All of these can lead to an improvement in learning and memory function. In the current study, two calcium channel blockers—omega-agatoxin-Aa2a and omega-Lsp-IA—were extracted, purified, and identified from spiders (Agelena orientalis and Hogna radiata) and used to modulate N and P/Q VGCCs. The effect of omega-agatoxin-Aa2a and omega-Lsp-IA on glutamate-induced excitotoxicity in rats was evaluated using the Morris water maze task as a behavioral test. The local expression of synaptophysin (SYN) was visualized for synaptic quantification using an immunofluorescence assay. The electrophysiological amplitudes of the field excitatory postsynaptic potentials (fEPSPs) in the input-output and LTP curves of the mossy fiber and Schaffer collateral circuits were recorded. The results of our study demonstrated that N and P/Q VGCC modulation in the hippocampus trisynaptic circuit of rats with glutamate-induced excitotoxicity dysfunction could prevent the destructive consequences of excitotoxicity in synapses and improve memory function and performance.

Cd44 Targeted Plga Nano-Medicine For Cancer Chemotherapy- A Comprehensive Review

In order to deliver therapeutic agents to tumour tissues more specifically, the scientific community has focused a lot of attention recently on unravelling the mystery of cluster of differentiation-44 (CD44). Additionally, drug delivery researchers are interested in using nanomedicines to target this receptor because of its over-expression in a variety of solid tumors. Conventional nanomedicines based on biodegradable polymers such as poly (lactide-co-glycolide) (PLGA) are often associated with insufficient cellular uptake by cancer cells, due to lack of active targeting moiety on their surface. Therefore, to address this limitation, CD44 targeted PLGA nanomedicines has gained considerable interest for enhancing the efficacy of chemotherapeutic agents.&#x0D; We have thoroughly covered the most recent developments in the design and synthesis of CD44-targeted PLGA nanomedicines in this review, which are being used to enhance tumor-targeted drug delivery. Additionally, we have talked about employing PLGA-based nanomedicines to co-target CD44 with additional targeting molecules such folic acid, human epidermal growth factor 2 (HER2), and monoclonal antibodies. Recent research on poly (lactic-co-glycolic acid) encapsulated platinum nanoparticles for the treatment of cancer was also covered in this review. We talk about the role that newly created nanomedicines can play in enhancing the efficacy and PK of existing therapy regimens. We offer insight into the development of more potent therapeutic regimens to enhance the clinical outcomes of cancer treatments by explaining the state-of-the-art of nanomedicine and analyzing their clinical benefits and problems.

COVID-19 Vaccination Uptake and Its Effect on Morbidity and Mortality among Frontline Healthcare Workers in Kaduna State, Nigeria

The COVID-19 pandemic has placed tremendous burdens on healthcare workers (HCWs), accounting for over 1.4 million HCW infections and 10% of global fatalities. HCWs faced elevated infection risk, psychological distress, long working hours, fatigue, stigma, and violence. While vaccines are pivotal in reducing severe illness, HCW vaccine hesitancy, given their role as advocates, jeopardizes vaccination coverage global goals and healthcare systems. Addressing this vaccine uptake is imperative through education, transparent communication, and support to safeguard HCWs’ safety and pandemic containment. This study assessed COVID-19 vaccination uptake among frontline HCWs in Kaduna State, Nigeria, and its impact on morbidity and mortality. Utilizing a descriptive cross-sectional approach, we analyzed secondary data from the Surveillance Outbreak Response Management and Analysis System (SORMAS). The study encompassed HCWs in Kaduna State, excluding pregnant and lactating individuals, following national guidelines. Among 8095 HCWs tested for COVID-19, most were aged 31-40 years (35%), female (60.2%), and urban residents (70.3%). COVID-19 vaccination uptake was low at 17.4%, with 82.6% unvaccinated. COVID-19 infection was significantly associated with vaccination (p = 0.039). Although unvaccinated participants exhibited a higher mortality rate (60%) than vaccinated ones (40%), this difference was not statistically significant (p = 0.209). In conclusion, this study unveiled insufficient vaccination uptake among HCWs, potentially impeding pandemic response. While vaccination seemed to positively impact disease outcomes, it didn’t significantly affect the infection risk. Addressing HCW vaccine hesitancy remains critical for achieving immunization goals and ensuring healthcare system safety. Keywords: Covid-19, Vaccines, Vaccination uptake, Healthcare workers (HCW), Infection.

Recombinant surface display vaccine enhances the immersion immune effect against grass carp reovirus in grass carp (Ctenopharyngodon idella)

Grass carp (Ctenopharyngodon idella) is subject to a hemorrhagic disease caused by grass carp reovirus (GCRV), which can lead to mass mortality in grass carp culture, causing significant economic loss. Vaccination is the most promising strategy for the prevention of infectious diseases. Immersion vaccination is considered the most effective disease prevention method for juvenile fish because it can be implemented on many fish at once and administered without causing stress. However, immune responses by immersion vaccination are markedly less robust due to the skin barrier and insufficient antigen uptake. The display of heterologous proteins on the cell surface has been explored as a delivery system for viral antigens in veterinary and human vaccine studies. To improve the efficacy of the immersion vaccine, the major capsid protein (VP7) of GCRV was co-displayed with Aeromonas hydrophila outer membrane protein a (OmpA) and major adhesion protein (Mah) on the outer membrane surface of nonpathogenic Escherichia coli BL21 using the anchoring motif of ice-nucleation protein (Inp). The immune responses and protection efficiency against GCRV infection via both the injection and immersion routes were evaluated. The results indicated that the activities of anti-oxidant enzymes (ACP, AKP, SOD and T-AOC), as well as the expression of immune-related genes (TNF-α, IL-1β, MHCI and IgM) and specific VP7 antibody levels, were strongly increased in the grass carp from 7 to 21 days post-injection inoculation in a dose dependent manner. The cumulative mortality rates of injection-vaccinated groups were much lower than those of the control group after the GCRV challenge, and the relative percent survival (RPS) was greater than 80 %. Vitally, the surface co-display of vp7-Mah protein conferred marked protection to grass carp against GCRV infection after immersion administration (RPS >50 %); this was consistent with the production of high level of specific serum antibodies, non-specific immune responses, and the expression of immune-related genes. Moreover, the invasion analysis further showed that surface co-display of the vp7-Mah protein indeed significantly improved the invasion of E. coli BL21 (DE3) in vitro. Altogether, this study demonstrated that surface display GCRV core antigen vaccine system accompanied by invasion component from aquatic pathogenic microorganism is an effective prophylactic against GCRV viral diseases via the immersion administration approach.

Aminated yeast β-D-glucan for macrophage-targeted delivery of CpG oligodeoxynucleotides and synergistically enhanced cancer immunotherapy

CpG oligodeoxynucleotides (CpG ODNs) activate immune system and show strong potential in cancer immunotherapy. However, therapeutic efficacy of CpG ODNs is hampered due to rapid nuclease degradation and insufficient cellular uptake. Delivery of CpG ODNs into antigen presenting cells (APCs) is vital to enhance their therapeutic efficacy. Herein, we developed a super-convenient yet efficient strategy for macrophage-targeted delivery of CpG ODNs and synergistically enhanced cancer immunotherapy. Aminated yeast β-D-glucan (NH2-Glu) was simply synthesized through functionalization of β-D-glucan with DETA, which exhibited a dendrimer-like shape with size of about 80 nm. NH2-Glu complexed negatively-charged CpG ODNs. The as-prepared NH2-Glu/CpG complexes were positively charged, uniformly dispersed and exhibited good stability against nuclease degradation. Due to the specific recognition with dectin-1 expressed on macrophages, NH2-Glu/CpG complexes targeted macrophage and exhibited significantly enhanced cellular uptake due to dectin-1-mediated endocytosis. NH2-Glu/CpG complexes showed potent immunostimulatory activity. Contributed by the inherent immunostimulatory and antitumor activity, yeast β-D-glucan functioned synergistically with CpG ODNs in inducing antitumor immunity. NH2-Glu/CpG complexes remarkably inhibited tumor growth without causing toxic effect. In summary, this work provides a facile yet efficient macrophage-targeted CpG ODNs delivery system for cancer immunotherapy.

Why Is Iron Deficiency/Anemia Linked to Alzheimer's Disease and Its Comorbidities, and How Is It Prevented?

Impaired iron metabolism has been increasingly observed in many diseases, but a deeper, mechanistic understanding of the cellular impact of altered iron metabolism is still lacking. In addition, deficits in neuronal energy metabolism due to reduced glucose import were described for Alzheimer's disease (AD) and its comorbidities like obesity, depression, cardiovascular disease, and type 2 diabetes mellitus. The aim of this review is to present the molecular link between both observations. Insufficient cellular glucose uptake triggers increased ferritin expression, leading to depletion of the cellular free iron pool and stabilization of the hypoxia-induced factor (HIF) 1α. This transcription factor induces the expression of the glucose transporters (Glut) 1 and 3 and shifts the cellular metabolism towards glycolysis. If this first line of defense is not adequate for sufficient glucose supply, further reduction of the intracellular iron pool affects the enzymes of the mitochondrial electron transport chain and activates the AMP-activated kinase (AMPK). This enzyme triggers the translocation of Glut4 to the plasma membrane as well as the autophagic recycling of cell components in order to mobilize energy resources. Moreover, AMPK activates the autophagic process of ferritinophagy, which provides free iron urgently needed as a cofactor for the synthesis of heme- and iron-sulfur proteins. Excessive activation of this pathway ends in ferroptosis, a special iron-dependent form of cell death, while hampered AMPK activation steadily reduces the iron pools, leading to hypoferremia with iron sequestration in the spleen and liver. Long-lasting iron depletion affects erythropoiesis and results in anemia of chronic disease, a common condition in patients with AD and its comorbidities. Instead of iron supplementation, drugs, diet, or phytochemicals that improve energy supply and cellular glucose uptake should be administered to counteract hypoferremia and anemia of chronic disease.

Thyroid: Functional Food (Family Welfare, Family Physician, Nurse, Computational Validation, and Drug Discovery)

Background: Thyroid hormone is related to metabolism, a poly-organ normal function including blood chemistry, hemodynamics and erythropoiesis. Hypertrophic gland causes iodine deficiency and rarely cancer. Hypothalamus signals pituitary gland to produce thyroidstimulating hormone (TSH), which regulates hormone production. Insufficient TSH uptake and/or inefficient conversion is pathophysiology. Current standard medication for pathophysiology is long-period ‘hormone replacement therapy’ (HRT) with no prophylaxis, no cure, no synergic medicaments, and no functional foods (FFs). Purpose: Reporting a few functional foods and examine its theoretical affinity with safety and discussing (ground breaking) role of nurses. Methods: Home - and clinic- based observation of use of FFs (alongside HRT) which are, (a) Star Anise –Illicium verumtree (b) Cinnamon bark - Cinnamon verum/cassia, and (c) Fruit &amp; flower of Myristica fragrans and computational validation of the principal moieties which are, (i) caffeic acid and (ii) Cinnamic acids. Results: Clinical &amp; home-based family member’s observations confirm an apparent better effect of ‘FF’ supplementation along with ‘feel good factor’. Theoretical-computational interaction is observed between TSH with compounds (i) &amp; (ii); binding affinity being -5 kcal/Mol with a minimum of 4 ‘H’ bonds at ~ 2 Å distance and a stable-high ‘inhibition constant’ of &gt;180µm. Conclusion: Goiter is chronic; treated as out-patient; sporadic approach; and expensive. FFs which are, (a), (b), (c) and compounds (i) &amp; (ii) present with likeness; compatibility with TSH as drug discovery candidates at the molecular level and also as ‘synergic’ with TSH. ‘a-b-c’ beholds to the immediate possibility of use as ‘functional foods’ targeting TSH uptake and/or efficient conversion. Goiter needs case specific nursing interventions. Implications for Nursing: Thus far, nursing role is needed for treatment of goiter. Predominantly a female who silently is suffering from Goiter has mood-swings, non-compliant with medication, with work-hour loss. Nurse’s assuring voice; close company guidance; In-Silico validated FF use opens wide a new vestibule between goiter care and drug discovery with nurse as the vital connect. Nurse’s role is indispensable in bottom-up drug discovery models