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1.
J Transl Med ; 22(1): 618, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38961476

ABSTRACT

BACKGROUND: Cell free DNA (cfDNA)-based assays hold great potential in detecting early cancer signals yet determining the tissue-of-origin (TOO) for cancer signals remains a challenging task. Here, we investigated the contribution of a methylation atlas to TOO detection in low depth cfDNA samples. METHODS: We constructed a tumor-specific methylation atlas (TSMA) using whole-genome bisulfite sequencing (WGBS) data from five types of tumor tissues (breast, colorectal, gastric, liver and lung cancer) and paired white blood cells (WBC). TSMA was used with a non-negative least square matrix factorization (NNLS) deconvolution algorithm to identify the abundance of tumor tissue types in a WGBS sample. We showed that TSMA worked well with tumor tissue but struggled with cfDNA samples due to the overwhelming amount of WBC-derived DNA. To construct a model for TOO, we adopted the multi-modal strategy and used as inputs the combination of deconvolution scores from TSMA with other features of cfDNA. RESULTS: Our final model comprised of a graph convolutional neural network using deconvolution scores and genome-wide methylation density features, which achieved an accuracy of 69% in a held-out validation dataset of 239 low-depth cfDNA samples. CONCLUSIONS: In conclusion, we have demonstrated that our TSMA in combination with other cfDNA features can improve TOO detection in low-depth cfDNA samples.


Subject(s)
DNA Methylation , Genome, Human , Neoplasms , Neural Networks, Computer , Humans , DNA Methylation/genetics , Neoplasms/genetics , Neoplasms/blood , Neoplasms/diagnosis , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/genetics , Organ Specificity/genetics , Algorithms
2.
Environ Res ; 231(Pt 1): 115984, 2023 Aug 15.
Article in English | MEDLINE | ID: mdl-37156354

ABSTRACT

In the quest of improving the photocatalytic efficiency of photocatalysts, the combination of two and more semiconductors recently has garnered significant attention among scientists in the field. The doping of conductive metals is also an effective pathway to improve photocatalytic performance by avoiding electron/hole pair recombination and enhancing photon energy absorption. This work presented a design and fabrication of porphyrin@g-C3N4/Ag nanocomposite using acid-base neutralization-induced self-assembly approach from monomeric porphyrin and g-C3N4/Ag material. g-C3N4/Ag material was synthesized by a green reductant of Cleistocalyx operculatus leaf extract. Electron scanning microscopy (SEM), X-ray diffraction (XRD), FT-IR spectroscopy, and UV-vis spectrometer were utilized to analyse the properties of the prepared materials. The prepared porphyrin@g-C3N4/Ag nanocomposite showed well integration of porphyrin nanostructures on the g-C3N4/Ag's surface, in which porphyrin nanofiber was of the diameter in nanoscales and the length of several micrometers, and Ag NPs had an average particle size of less than 20 nm. The photocatalytic behavior of the resultant nanocomposite was tested for the degradation of Rhodamine B dye, which exhibited a remarkable RhB photodegrading percentage. The possible mechanism for photocatalysis of the porphyrin@g-C3N4/Ag nanocomposite toward Rhodamine B dye was also proposed and discussed.


Subject(s)
Nanocomposites , Porphyrins , Spectroscopy, Fourier Transform Infrared , Coloring Agents , Electrons
3.
Proc Natl Acad Sci U S A ; 115(2): 361-366, 2018 01 09.
Article in English | MEDLINE | ID: mdl-29279375

ABSTRACT

The wMel strain of Wolbachia can reduce the permissiveness of Aedes aegypti mosquitoes to disseminated arboviral infections. Here, we report that wMel-infected Ae. aegypti (Ho Chi Minh City background), when directly blood-fed on 141 viremic dengue patients, have lower dengue virus (DENV) transmission potential and have a longer extrinsic incubation period than their wild-type counterparts. The wMel-infected mosquitoes that are field-reared have even greater relative resistance to DENV infection when fed on patient-derived viremic blood meals. This is explained by an increased susceptibility of field-reared wild-type mosquitoes to infection than laboratory-reared counterparts. Collectively, these field- and clinically relevant findings support the continued careful field-testing of wMel introgression for the biocontrol of Ae. aegypti-born arboviruses.


Subject(s)
Aedes/virology , Dengue Virus/physiology , Dengue/virology , Mosquito Vectors/virology , Wolbachia/physiology , Aedes/microbiology , Animals , Dengue/blood , Dengue/transmission , Humans , Logistic Models , Mosquito Vectors/microbiology , Pest Control, Biological/methods , Time Factors , Viremia/blood , Viremia/virology
4.
J Med Internet Res ; 23(2): e20445, 2021 02 23.
Article in English | MEDLINE | ID: mdl-33620328

ABSTRACT

BACKGROUND: Work engagement is important for employee well-being and work performance. However, no intervention study has investigated the effect of an eMental Health intervention on work engagement among workers in low- and middle-income countries (LMICs). OBJECTIVE: The aim of the study was to examine the effects of a newly developed smartphone-based stress management program (ABC Stress Management) on improving work engagement among hospital nurses in Vietnam, an LMIC. METHODS: Full-time registered nurses (n=949) were randomly assigned to one of 2 intervention groups or a control group. The intervention groups were a 6-week, 6-lesson program offering basic cognitive behavioral therapy (CBT-based stress management skills), provided in either free-choice (program A) or fixed order (program B). Work engagement was assessed at baseline and 3-month and 7-month follow-ups in each of the 3 groups. RESULTS: The scores of work engagement in both intervention groups improved from baseline to 3-month follow-up, and then decreased at the 7-month follow-up, while the score steadily increased from baseline to 7-month follow-up in the control group. Program B showed a significant intervention effect on improving work engagement at the 3-month follow-up (P=.049) with a small effect size (Cohen d= 0.16; 95% CI 0.001 to 0.43]). Program A showed nonsignificant trend (d=0.13; 95% CI -0.014 to 0.41; P=.07) toward improved engagement at 3 months. Neither program achieved effectiveness at the 7-month follow-up. CONCLUSIONS: The study demonstrated that a fixed order (program B) delivery of a smartphone-based stress management program was effective in improving work engagement in nurses in Vietnam. However, the effect was small and only temporary. Further improvement of this program is required to achieve a greater effect size and more sustained, longer lasting impact on work engagement. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000033139; tinyurl.com/55gxo253. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2018-025138.


Subject(s)
Smartphone/standards , Stress, Psychological/therapy , Telemedicine/methods , Work Engagement , Adult , Female , Humans , Male , Nurses , Vietnam
5.
Proc Natl Acad Sci U S A ; 110(30): E2772-81, 2013 Jul 23.
Article in English | MEDLINE | ID: mdl-23840057

ABSTRACT

Sirtuins are protein deacetylases regulating metabolism and stress responses. The seven human Sirtuins (Sirt1-7) are attractive drug targets, but Sirtuin inhibition mechanisms are mostly unidentified. We report the molecular mechanism of Sirtuin inhibition by 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (Ex-527). Inhibitor binding to potently inhibited Sirt1 and Thermotoga maritima Sir2 and to moderately inhibited Sirt3 requires NAD(+), alone or together with acetylpeptide. Crystal structures of several Sirtuin inhibitor complexes show that Ex-527 occupies the nicotinamide site and a neighboring pocket and contacts the ribose of NAD(+) or of the coproduct 2'-O-acetyl-ADP ribose. Complex structures with native alkylimidate and thio-analog support its catalytic relevance and show, together with biochemical assays, that only the coproduct complex is relevant for inhibition by Ex-527, which stabilizes the closed enzyme conformation preventing product release. Ex-527 inhibition thus exploits Sirtuin catalysis, and kinetic isoform differences explain its selectivity. Our results provide insights in Sirtuin catalysis and inhibition with important implications for drug development.


Subject(s)
Carbazoles/pharmacology , NAD/metabolism , Sirtuins/antagonists & inhibitors , Acetylation , Carbazoles/chemistry , Models, Molecular , Stereoisomerism
6.
J Med Entomol ; 52(6): 1203-12, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26336261

ABSTRACT

We studied the winter activity of Aedes albopictus (Skuse) from November 2008 to April 2009 in Bat Trang village of Hanoi, Vietnam. We selected 12 houses and collected: 1) adults with BG sentinel traps, 2) pupae from household water containers, and 3) eggs with ovitraps. Aedes albopictus adults, pupae, and eggs were not collected from early January to early February. Though the egg hatching probability tended to be initially high at longer day length, the maximum probability gradually shifted to shorter day length, as the observation period elapsed. When females were reared under long day length and their eggs were immersed 1 or 5 wk after oviposition, >50% of eggs hatched within 20 days. However, when females were reared under short day length and their eggs were immersed after 1 wk, hatching was suppressed for 60 days. When females were reared under short day length, the median hatching day occurred earlier in eggs kept dry for 5 and 10 wk after oviposition than in those dried for only 1 wk. This indicates that the extended dry periods accelerate egg hatching. Our results showed that hatchability gradually changed with day length, suggesting that selection for overwintering is not as strong relative to Ae. albopictus living in the temperate zone, where winter conditions are less favorable than in tropical and subtropical areas.


Subject(s)
Aedes/physiology , Diapause, Insect , Animals , Female , Ovum/physiology , Photoperiod , Seasons , Vietnam
7.
BMJ Paediatr Open ; 8(1)2024 02 21.
Article in English | MEDLINE | ID: mdl-38388007

ABSTRACT

AIM: To determine neurodevelopmental outcome at 18 months after therapeutic hypothermia for hypoxic-ischaemic encephalopathy (HIE) infants in Vietnam, a low-middle-income country. METHOD: Prospective cohort study investigating outcomes at 18 months in severely asphyxiated outborn infants who underwent therapeutic hypothermia for HIE in Hanoi, Vietnam, during the time period 2016-2019. Survivors were examined at discharge and at 6 and 18 months by a neonatologist, a neurologist and a rehabilitation physician, who were blinded to the infants' clinical severity during hospitalisation using two assessment tools: the Ages and Stages Questionnaire (ASQ) and the Hammersmith Infant Neurological Examination (HINE), to detect impairments and promote early interventions for those who require it. RESULTS: In total, 130 neonates, 85 (65%) with moderate and 45 (35%) with severe HIE, underwent therapeutic hypothermia treatment using phase change material. Forty-three infants (33%) died during hospitalisation and in infancy. Among the 87 survivors, 69 (79%) completed follow-up until 18 months. Nineteen children developed cerebral palsy (8 diplegia, 3 hemiplegia, 8 dyskinetic), and 11 had delayed neurodevelopment. At each time point, infants with a normal or delayed neurodevelopment had significantly higher ASQ and HINE scores (p<0.05) than those with cerebral palsy. CONCLUSION: The rates of mortality and adverse neurodevelopment rate were high and comparable to recently published data from other low-middle-income settings. The ASQ and HINE were useful tools for screening and evaluation of neurodevelopment and neurological function.


Subject(s)
Asphyxia Neonatorum , Cerebral Palsy , Hypothermia, Induced , Hypoxia-Ischemia, Brain , Infant, Newborn , Infant , Pregnancy , Female , Child , Humans , Cerebral Palsy/therapy , Vietnam/epidemiology , Prospective Studies , Asphyxia/therapy , Asphyxia Neonatorum/therapy , Hypothermia, Induced/adverse effects , Hypoxia-Ischemia, Brain/therapy
8.
Nat Commun ; 15(1): 4310, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773068

ABSTRACT

Oligoclonal mixtures of broadly-neutralizing antibodies can neutralize complex compositions of similar and dissimilar antigens, making them versatile tools for the treatment of e.g., infectious diseases and animal envenomations. However, these biotherapeutics are complicated to develop due to their complex nature. In this work, we describe the application of various strategies for the discovery of cross-neutralizing nanobodies against key toxins in coral snake venoms using phage display technology. We prepare two oligoclonal mixtures of nanobodies and demonstrate their ability to neutralize the lethality induced by two North American coral snake venoms in mice, while individual nanobodies fail to do so. We thus show that an oligoclonal mixture of nanobodies can neutralize the lethality of venoms where the clinical syndrome is caused by more than one toxin family in a murine challenge model. The approaches described may find utility for the development of advanced biotherapeutics against snakebite envenomation and other pathologies where multi-epitope targeting is beneficial.


Subject(s)
Antibodies, Neutralizing , Coral Snakes , Single-Domain Antibodies , Animals , Single-Domain Antibodies/immunology , Mice , Antibodies, Neutralizing/immunology , Coral Snakes/immunology , Disease Models, Animal , Antivenins/immunology , Elapid Venoms/immunology , Female , Snake Bites/immunology , Snake Bites/therapy , Epitopes/immunology , Mice, Inbred BALB C , Cell Surface Display Techniques
9.
Future Sci OA ; 10(1): 2395244, 2024 Dec 31.
Article in English | MEDLINE | ID: mdl-39254097

ABSTRACT

The emergence of multicancer early detection (MCED) tests holds promise for improving early cancer detection and public health outcomes. However, positive MCED test results require confirmation through recommended cancer diagnostic imaging modalities. To address these challenges, we have developed a consultation and work-up protocol for definitive diagnostic results post MCED testing, named SPOT-MAS. Developed through circulating tumor DNA (ctDNA) analysis and in line with professional guidelines and advisory board consensus, this protocol standardizes information to aid general practitioners in accessing, interpreting and managing SPOT-MAS results. Clinical effectiveness is demonstrated through a series of identified cancer cases. Our research indicates that the protocol could empower healthcare professionals to confidently interpret circulating tumor DNA test results for 5 common types of cancer, thereby facilitating the clinical integration of MCED tests.


New tests can now screen for multiple types of cancer early, offering hope for better health outcomes. If one of these tests shows a positive result, doctors need to confirm it with imaging tests. We have developed a guide to help doctors understand and confirm these results. This guide could help healthcare professionals interpret results for five common types of cancer, making it easier to use these tests in regular medical practice.

10.
Acta Crystallogr D Biol Crystallogr ; 69(Pt 8): 1423-32, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23897466

ABSTRACT

Sirtuins are NAD(+)-dependent protein deacetylases that regulate metabolism and aging processes and are considered to be attractive therapeutic targets. Most available sirtuin modulators are little understood mechanistically, hindering their improvement. SRT1720 was initially described as an activator of human Sirt1, but it also potently inhibits human Sirt3. Here, the molecular mechanism of the inhibition of Sirt3 by SRT1720 is described. A crystal structure of Sirt3 in complex with SRT1720 and an NAD(+) analogue reveals that the compound partially occupies the acetyl-Lys binding site, thus explaining the reported competition with the peptide substrate. The compound packs against a hydrophobic protein patch and binds with its opposite surface to the NAD(+)  nicotinamide, resulting in an exceptionally tight sandwich-like interaction. The observed arrangement rationalizes the uncompetitive inhibition with NAD(+), and binding measurements confirm that the nicotinamide moiety of NAD(+) supports inhibitor binding. Consistently, no inhibitor is bound in a second crystal structure of Sirt3 that was solved complexed with ADP-ribose and crystallized in the presence of SRT1720. These results reveal a novel sirtuin inhibitor binding site and mechanism, and provide a structural basis for compound improvement.


Subject(s)
Adenosine Diphosphate Ribose/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , NAD/analogs & derivatives , Sirtuin 3/chemistry , Sirtuin 3/metabolism , Adenosine Diphosphate Ribose/metabolism , Binding Sites , Binding, Competitive , Crystallography, X-Ray , Heterocyclic Compounds, 4 or More Rings/metabolism , Humans , NAD/chemistry , Protein Conformation
11.
Proc Natl Acad Sci U S A ; 107(47): 20281-6, 2010 Nov 23.
Article in English | MEDLINE | ID: mdl-21059944

ABSTRACT

The receptor activator of nuclear factor-κB (RANK) and its ligand RANKL, which belong to the tumor necrosis factor (TNF) receptor-ligand family, mediate osteoclastogenesis. The crystal structure of the RANKL ectodomain (eRANKL) in complex with the RANK ectodomain (eRANK) combined with biochemical assays of RANK mutants indicated that three RANK loops (Loop1, Loop2, and Loop3) bind to the interface of a trimeric eRANKL. Loop3 is particularly notable in that it is structurally distinctive from other TNF-family receptors and forms extensive contacts with RANKL. The disulfide bond (C125-C127) at the tip of Loop3 is important for determining the unique topology of Loop3, and docking E126 close to RANKL, which was supported by the inability of C127A or E126A mutants of RANK to bind to RANKL. Inhibitory activity of RANK mutants, which contain loops of osteoprotegerin (OPG), a soluble decoy receptor to RANKL, confirmed that OPG shares the similar binding mode with RANK and OPG. Loop3 plays a key role in RANKL binding. Peptide inhibitors designed to mimic Loop3 blocked the RANKL-induced differentiation of osteoclast precursors, suggesting that they could be developed as therapeutic agents for the treatment of osteoporosis and bone-related diseases. Furthermore, some of the RANK mutations associated with autosomal recessive osteopetrosis (ARO) resulted in reduced RANKL-binding activity and failure to induce osteoclastogenesis. These results, together with structural interpretation of eRANK-eRANKL interaction, provided molecular understanding for pathogenesis of ARO.


Subject(s)
Bone and Bones/metabolism , Models, Molecular , Oligopeptides/pharmacology , Osteopetrosis/metabolism , Osteoprotegerin/metabolism , Peptides, Cyclic/pharmacology , RANK Ligand/chemistry , Animals , Cell Differentiation/drug effects , Cell Differentiation/genetics , Crystallography , Mice , Mutagenesis, Site-Directed , Osteoclasts/cytology , Osteoclasts/drug effects , Osteopetrosis/genetics , RANK Ligand/antagonists & inhibitors , Receptor Activator of Nuclear Factor-kappa B/genetics
12.
PLoS One ; 18(4): e0284532, 2023.
Article in English | MEDLINE | ID: mdl-37058526

ABSTRACT

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its subtypes are linked to mutations in dozens of different genes, including the gene coding for ganglioside-induced differentiation-associated protein 1 (GDAP1). The main GDAP1-linked CMT subtypes are the demyelinating CMT4A and the axonal CMT2K. Over a hundred different missense CMT mutations in the GDAP1 gene have been reported. However, despite implications for mitochondrial fission and fusion, cytoskeletal interactions, and response to reactive oxygen species, the etiology of GDAP1-linked CMT is poorly understood at the protein level. Based on earlier structural data, CMT-linked mutations could affect intramolecular interaction networks within the GDAP1 protein. We carried out structural and biophysical analyses on several CMT-linked GDAP1 protein variants and describe new crystal structures of the autosomal recessive R120Q and the autosomal dominant A247V and R282H GDAP1 variants. These mutations reside in the structurally central helices ⍺3, ⍺7, and ⍺8. In addition, solution properties of the CMT mutants R161H, H256R, R310Q, and R310W were analysed. All disease variant proteins retain close to normal structure and solution behaviour. All mutations, apart from those affecting Arg310 outside the folded GDAP1 core domain, decreased thermal stability. In addition, a bioinformatics analysis was carried out to shed light on the conservation and evolution of GDAP1, which is an outlier member of the GST superfamily. GDAP1-like proteins branched early from the larger group of GSTs. Phylogenetic calculations could not resolve the exact early chronology, but the evolution of GDAP1 is roughly as old as the splits of archaea from other kingdoms. Many known CMT mutation sites involve conserved residues or interact with them. A central role for the ⍺6-⍺7 loop, within a conserved interaction network, is identified for GDAP1 protein stability. To conclude, we have expanded the structural analysis on GDAP1, strengthening the hypothesis that alterations in conserved intramolecular interactions may alter GDAP1 stability and function, eventually leading to mitochondrial dysfunction, impaired protein-protein interactions, and neuronal degeneration.


Subject(s)
Charcot-Marie-Tooth Disease , Humans , Mutation , Nerve Tissue Proteins/metabolism , Phylogeny , Protein Stability
13.
ACS Omega ; 8(28): 25048-25058, 2023 Jul 18.
Article in English | MEDLINE | ID: mdl-37483229

ABSTRACT

2-Methylquinazolin-4(3H)-one was prepared by the reaction of anthranilic acid, acetic anhydride, and ammonium acetate. The reaction of 2-methylquinazolin-4(3H)-one with N-aryl-2-chloroacetamides in acetone in the presence of potassium carbonate gave nine N-aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide compounds. The structures of these compounds were elucidated on the basis of their IR, 1H nuclear magnetic resonance (NMR), 13C NMR, and high-resolution mass spectrometry (HR-MS) spectral data. These synthesized compounds containing the 2-methyl-3,4-dihydroquinazolin-4-one moiety exhibited activity against Aedes aegypti mosquito larvae with LC50 values of 2.085-4.201 µg/mL after 72 h exposure, which is also confirmed using a quantitative structure-activity relationship (QSAR) model. Interestingly, these compounds did not exhibit toxicity to the nontarget organism Diplonychus rusticus. In silico molecular docking revealed acetylcholine binding protein (AChBP) and acetylcholinesterase (AChE) to be potential molecular targets. These data indicated the larvicidal potential and environmental friendliness of these N-aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide derivatives.

14.
Elife ; 122023 10 11.
Article in English | MEDLINE | ID: mdl-37819044

ABSTRACT

Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published assays to date demanded a very high-depth sequencing, resulting in an elevated price of test. Herein, we developed a multimodal assay called SPOT-MAS (screening for the presence of tumor by methylation and size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (~0.55×) of cell-free DNA. We applied SPOT-MAS to 738 non-metastatic patients with breast, colorectal, gastric, lung, and liver cancer, and 1550 healthy controls. We then employed machine learning to extract multiple cancer and tissue-specific signatures for detecting and locating cancer. SPOT-MAS successfully detected the five cancer types with a sensitivity of 72.4% at 97.0% specificity. The sensitivities for detecting early-stage cancers were 73.9% and 62.3% for stages I and II, respectively, increasing to 88.3% for non-metastatic stage IIIA. For tumor-of-origin, our assay achieved an accuracy of 0.7. Our study demonstrates comparable performance to other ctDNA-based assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening.


Subject(s)
Circulating Tumor DNA , Early Detection of Cancer , Neoplasms , Humans , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/genetics , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , Early Detection of Cancer/methods , Liver Neoplasms , Neoplasms/blood , Neoplasms/diagnosis , Neoplasms/genetics
15.
Endocrinol Metab (Seoul) ; 37(4): 620-629, 2022 08.
Article in English | MEDLINE | ID: mdl-35871605

ABSTRACT

BACKGRUOUND: Hepatic stellate cells (HSCs) are the central players interacting with multiple cell types in liver fibrosis. The crosstalk between HSCs and macrophages has recently become clearer. Irisin, an exercise-responsive myokine, was known to have a potentially protective role in liver and renal fibrosis, especially in connection with stellate cells. This study investigated the effects of irisin on the interaction between HSCs and macrophages. METHODS: Tamm-Horsfall protein-1 (THP-1) human monocytes were differentiated into macrophages, polarized into the inflammatory M1 phenotype with lipopolysaccharide. Lieming Xu-2 (LX-2) cells, human HSCs, were treated with conditioned media (CM) from M1 macrophages, with or without recombinant irisin. HSCs responses to CM from M1 macrophages were evaluated regarding activation, proliferation, wound healing, trans-well migration, contractility, and related signaling pathway. RESULTS: CM from M1 macrophages significantly promoted HSC proliferation, wound healing, transwell migration, and contractility, but not activation of HSCs. Irisin co-treatment attenuated these responses of HSCs to CM. However, CM and irisin treatment did not induce any changes in HSC activation. Further, irisin co-treatment alleviated CM-induced increase of phopho-protein kinase B (pAKT), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1). CONCLUSION: These findings suggested that irisin may play a protective role in the pathogenesis of liver fibrosis, especially when working in the crosstalk between HSCs and macrophages.


Subject(s)
Fibronectins , Hepatic Stellate Cells , Fibronectins/metabolism , Fibronectins/pharmacology , Humans , Liver Cirrhosis/pathology , Macrophages/metabolism , Macrophages/pathology
17.
Environ Sci Pollut Res Int ; 29(28): 42037-42054, 2022 Jun.
Article in English | MEDLINE | ID: mdl-34741733

ABSTRACT

This research developed an agent-based model (ABM) for simulating pollutant loads from pig farming. The behavior of farmer agents was captured using concepts from the theory of planned behavior. The ABM has three basic components: the household or farmer agent, the land patches, and global parameters that capture the environmental context. The model was evaluated using a sensitivity analysis and then validated using data from a household survey, which showed that the predictive ability of the model was good. The ABM was then used in three scenarios: a baseline scenario, a positive scenario in which the number of pigs was assumed to remain stable but supporting policies for environmental management were increased, and a negative scenario, which assumed the number of pigs increases but management measures did not improve relative to the baseline. The positive scenario showed reductions in the discharged loads for many sub-basins of the study area while the negative scenario indicated that increased loads will be discharged to the environment. The scenario results suggest that to maintain the development of pig production while ensuring environmental protection for the district, financial, and technical support must be provided to the pig producers. The experience and education level of the farmers were significant factors influencing behaviors related to manure reuse and treatment, so awareness raising through environmental communication is needed in addition to technical measures.


Subject(s)
Environmental Pollutants , Agriculture/methods , Animals , Farmers , Farms , Humans , Swine , Systems Analysis
18.
FEBS Open Bio ; 12(7): 1306-1324, 2022 07.
Article in English | MEDLINE | ID: mdl-35509130

ABSTRACT

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R and CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behavior, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side-chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and, eventually, insufficient motor and sensory neuron function.


Subject(s)
Charcot-Marie-Tooth Disease , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/metabolism , Humans , Mutation/genetics , Nerve Tissue Proteins/genetics
19.
Gigascience ; 112022 12 13.
Article in English | MEDLINE | ID: mdl-36509548

ABSTRACT

Venomous snakes are important parts of the ecosystem, and their behavior and evolution have been shaped by their surrounding environments over the eons. This is reflected in their venoms, which are typically highly adapted for their biological niche, including their diet and defense mechanisms for deterring predators. Sub-Saharan Africa is rich in venomous snake species, of which many are dangerous to humans due to the high toxicity of their venoms and their ability to effectively deliver large amounts of venom into their victims via their bite. In this study, the venoms of 26 of sub-Saharan Africa's medically most relevant elapid and viper species were subjected to parallelized toxicovenomics analysis. The analysis included venom proteomics and in vitro functional characterization of whole venom toxicities, enabling a robust comparison of venom profiles between species. The data presented here corroborate previous studies and provide biochemical details for the clinical manifestations observed in envenomings by the 26 snake species. Moreover, two new venom proteomes (Naja anchietae and Echis leucogaster) are presented here for the first time. Combined, the presented data can help shine light on snake venom evolutionary trends and possibly be used to further improve or develop novel antivenoms.


Subject(s)
Elapidae , Proteomics , Animals , Humans , Ecosystem , Antivenins/chemistry , Africa South of the Sahara
20.
Environ Sci Pollut Res Int ; 28(36): 50302-50315, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33959840

ABSTRACT

Water pollution within and nearby different livestock farm types was assessed comprehensively for the first time in Vietnam. The samples of wastewater, ground water, and surface water were collected from 130 pig farms, 80 poultry farms, and 40 cow farms. Water quality was first assessed by individual parameter evaluation method in which measured values of water quality parameters were compared with the permissible limits in the national technical regulations on livestock's effluent (QCVN 62), surface water quality, and ground water quality. Subsequently, the overall quality of surface and ground water samples was evaluated by mean of water quality index (WQI). The results showed the large variations in effluent's quality, implying the considerable differences in wastewater treatment efficiency within and among farm types. Effluent from livestock farms was highly polluted by organic matters (expressed as BOD5 and COD) and especially by microorganisms (expressed as total coliform-CF). Almost all wastewater samples contained higher number of CF than QCVN 62 (3900 MPN/100ml), with mean concentration of CF in effluent from cow farms, pig farms, and poultry farms were 1.2e+07 ± 5.0e+07 MPN/100ml, 8.8e+04 ± 7.1e+04 MPN/100ml, 1.5e+06 ± 4.2e+06 MPN/100ml, respectively. Improperly treated livestock's waste was likely to have impacts on quality of ground water and receiving surface water bodies. High CF contamination in effluent leads to 70% of the ground water samples in cow farms and poultry farms classified as unsuitable for drinking water supply by WQI values. Although effluent from poultry farms had smaller quantity and better quality, their receiving surface water bodies exhibited the worst quality, with average WQI of 37.5 ± 16.2 compared to 49.9 ± 12 of pig farms and 50.3 ± 20.8 of cow farms. This result suggests that livestock's effluent was not only pollution source of surface water bodies nearby livestock farms.


Subject(s)
Livestock , Water Quality , Animals , Cattle , Farms , Female , Poultry , Swine , Wastewater
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