Sorption of heavy metals is a crucial controller method for environmental pollution. Contamination by heavy metals is one of the most critical and discussed environmental issue nowadays that fits in ...the context of bioaccumulation. Some examples of these contaminants are lead, cadmium, and chromium. In order to avoid increasing the level of these contaminants in rainwater networks, the Brazilian Council of Environment (CONAMA) establishes that it is essential that industries that produce effluents remove these metals before returning the effluent to the network. Given this, a new technology is proposed for the removal of heavy metals. A magnetic nanocomposite is produced by adding maghemite nanoparticles to an aluminosilicate matrix and subjected to heavy metal‐contaminated effluents to sorption through this material. In order to evaluate the efficiency of removal of heavy metals by aluminosilicates, the effluents are analyzed by atomic absorption spectroscopy, and the results show a 99% sorption capacity. Finally, lethality tests, using Artemia salina, are performed. The best results are from the chromium and lead absorption tests.
Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain ...(RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization
. One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies
. Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and-to our knowledge-rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.
Genome-wide association studies have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack ...of mechanistic insights for many GWAS loci limits their translation into the clinic. Among these loci with unknown functions is
-four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 (
; chr6q16.1), which reached genome-wide significance in a recent coronary artery disease/ myocardial infarction GWAS meta-analysis.
is also associated with several vascular diseases, consistent with the widespread pleiotropy observed for GWAS loci.
We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and ex vivo analysis of human coronary artery tissues to implicate
as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments in coronary artery smooth muscle cells.
We prioritized
as the top candidate causal gene at the
locus through expression quantitative trait locus colocalization methods.
gene expression was enriched in the smooth muscle cells and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating smooth muscle cell contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream coronary artery disease/myocardial infarction loci, such as
and
that have roles in vascular remodeling.
Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of
We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling gene programs. These transacting mechanisms may explain a portion of the heritable risk for complex vascular diseases.
Background
A functional cure for chronic HBV could be achieved by boosting HBV-specific immunity.
In vitro
studies show that immunotherapy could be an effective strategy. However, these studies ...include strategies to enrich HBV-specific CD8 T cells, which could alter the expression of the anti-PD-1/anti-PD-L1 antibody targets. Our aim was to determine the efficacy of PD-L1 blockade
ex vivo
.
Methods
HBV-specific CD8 T cells were characterized
ex vivo
by flow cytometry for the simultaneous analysis of six immune populations and 14 activating and inhibitory receptors.
Ex vivo
functionality was quantified by ELISpot and by combining peptide pool stimulation, dextramers and intracellular flow cytometry staining.
Results
The functionality of HBV-specific CD8 T cells is associated with a higher frequency of cells with low exhaustion phenotype (LAG3
-
TIM3
-
PD-1
+
), independently of the clinical parameters. The accumulation of HBV-specific CD8 T cells with a functionally exhausted phenotype (LAG3
+
TIM3
+
PD-1
+
) is associated with lack of
ex vivo
functionality. PD-L1 blockade enhanced the HBV-specific CD8 T cell response only in patients with lower exhaustion levels, while response to PD-L1 blockade was abrogated in patients with higher frequencies of exhausted HBV-specific CD8 T cells.
Conclusion
Higher levels of functionally exhausted HBV-specific CD8 T cells are associated with a lack of response that cannot be restored by blocking the PD-1:PD-L1 axis. This suggests that the clinical effectiveness of blocking the PD-1:PD-L1 axis as a monotherapy may be restricted. Combination strategies, potentially including the combination of anti-LAG-3 with other anti-iR antibodies, will likely be required to elicit a functional cure for patients with high levels of functionally exhausted HBV-specific CD8 T cells.
Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and ...immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.
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•Integration benchmarking and generation of new scRNA atlas of human atherosclerosis•GWAS data integration reveals etiologic SMC populations and effector genes for CAD•LTBP1 and CRTAC1 as markers of modulated SMCs and atherosclerosis progression
The authors generate a comprehensive map of cell diversity in human atherosclerosis. This atlas provides insights into the heterogeneity of smooth muscle cells and their genetic contribution to atherosclerosis and reveals candidate markers of disease progression.
To assess changes in SARS-CoV-2 spike binding antibody prevalence in the Dominican Republic and implications for immunologic protection against variants of concern, we prospectively enrolled 2,300 ...patients with undifferentiated febrile illnesses in a study during March 2021-August 2022. We tested serum samples for spike antibodies and tested nasopharyngeal samples for acute SARS-CoV-2 infection using a reverse transcription PCR nucleic acid amplification test. Geometric mean spike antibody titers increased from 6.6 (95% CI 5.1-8.7) binding antibody units (BAU)/mL during March-June 2021 to 1,332 (95% CI 1,055-1,682) BAU/mL during May-August 2022. Multivariable binomial odds ratios for acute infection were 0.55 (95% CI 0.40-0.74), 0.38 (95% CI 0.27-0.55), and 0.27 (95% CI 0.18-0.40) for the second, third, and fourth versus the first anti-spike quartile; findings were similar by viral strain. Combining serologic and virologic screening might enable monitoring of discrete population immunologic markers and their implications for emergent variant transmission.
Semiconducting polymer nanoparticles (SPNs) are explored for applications in cancer theranostics because of their high absorption coefficients, photostability, and biocompatibility. However, SPNs are ...susceptible to aggregation and protein fouling in physiological conditions, which can be detrimental for in vivo applications. Here, a method for achieving colloidally stable and low‐fouling SPNs is described by grafting poly(ethylene glycol) (PEG) onto the backbone of the fluorescent semiconducting polymer, poly(9,9′‐dioctylfluorene‐5‐fluoro‐2,1,3‐benzothiadiazole), in a simple one‐step substitution reaction, postpolymerization. Further, by utilizing azide‐functionalized PEG, anti‐human epidermal growth factor receptor 2 (HER2) antibodies, antibody fragments, or affibodies are site‐specifically “clicked” onto the SPN surface, which allows the functionalized SPNs to specifically target HER2‐positive cancer cells. In vivo, the PEGylated SPNs are found to have excellent circulation efficiencies in zebrafish embryos for up to seven days postinjection. SPNs functionalized with affibodies are then shown to be able to target HER2 expressing cancer cells in a zebrafish xenograft model. The covalent PEGylated SPN system described herein shows great potential for cancer theranostics.
Semiconducting polymer nanoparticles (SPNs) are a promising tool for theranostic applications. Here, a method of imparting colloidal stability, low‐protein fouling, and high circulation efficiencies onto SPNs is described via a one‐step, postpolymerization reaction. This method can also afford azide‐functionalized SPNs, which allows for subsequent “click” reactions to achieve specific human epidermal growth factor receptor 2 (HER2) targeting in vitro and in vivo.
Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional ...impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.
Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a ...protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp−/−) and small (Abcc6−/−) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.
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•Impaired autophagy initiation is a determinant of vascular calcification•Chromatin rearrangement at autophagy genes in calcified VSMCS•Chromatin relaxation by GSK343 restores autophagy initiation gene expression•Pharmacologic or genetic enhancement of autophagy inhibits vascular calcification
Cardiovascular medicine; Human Genetics; Molecular physiology
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•Restenosis limits the efficacy of PTA or stent treatment of atherosclerosis in peripheral and coronary artery disease.•Paclitaxel DCBs effectively reduce restenosis; however, ...recently, their overall safety profile has been called into question.•In an in vivo molecular-structural imaging study of 25 rabbits with experimental atherosclerosis, DCB-PTA, plain PTA, or sham-PTA was investigated using serial intravascular NIRF-OCT and IVUS.•DCB-PTA reduced lesion inflammation on NIRF-OCT and halted lesion progression on IVUS, compared with PTA or sham-PTA.•These findings indicated the potential for DCBs to serve effectively and safely as a regional anti-atherosclerosis therapy.
Paclitaxel drug-coated balloons (DCBs) reduce restenosis, but their overall safety has recently raised concerns. This study hypothesized that DCBs could lessen inflammation and reduce plaque progression. Using 25 rabbits with cholesterol feeding- and balloon injury-induced lesions, DCB-percutaneous transluminal angioplasty (PTA), plain PTA, or sham-PTA (balloon insertion without inflation) was investigated using serial intravascular near-infrared fluorescence−optical coherence tomography and serial intravascular ultrasound. In these experiments, DCB-PTA reduced inflammation and plaque burden in nonobstructive lesions compared with PTA or sham-PTA. These findings indicated the potential for DCBs to serve safely as regional anti-atherosclerosis therapy.
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