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Lenalidomide, a thalidomide derivative, is prescribed as maintenance therapy for multiple myeloma (MM). Patients with MM receiving lenalidomide were found to develop a distinct therapy-related B cell acute lymphoblastic leukemia (B-ALL). However, the molecular mechanism by which lenalidomide drives B-ALL is unknown. We show that thalidomide treatment of B cell lines increased CD34 expression and fibronectin adhesion. This resembled the effects of Ikzf1 loss of function mutations in B-ALL. IKZF1 is a transcription factor that can act as both a transcriptional activator and a repressor depending upon the target loci. In our experiments, thalidomide-induced degradation of IKZF1 increased the expression of its transcriptional repression targets Itga5 and CD34 explaining the increased adhesion and stemness. Strikingly, withdrawal of thalidomide lead to the mis-localization of IKZF1 to the cytoplasm. Moreover, chromatin immunoprecipitation data showed a long-term effect of thalidomide treatment on IKZF1 target loci. This included decreased chromatin occupancy at early B cell factor 1 (EBF1) and Spi1 (PU.1). Consequently, B-cell lineage specifying transcription factors including Pax5, Spi1 and EBF1 were downregulated even after 7 days of thalidomide withdrawal. Our study thus provides a molecular mechanism of thalidomide-induced B-ALL whereby thalidomide alters the chromatin occupancy of IKZF1 at key B-cell lineage transcription factors leading to a persistent block in B-cell differentiation.
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Inadequate DNA damage response related to ataxia telangiectasia mutated gene restricts hepatic regeneration in acute liver failure. Resolving mechanistic gaps in liver damage and repair requires additional animal models that are unconstrained by ultrarapid and unpredictable mortalities or substantial divergences from human pathology. This study used Fischer 344 rats primed with the antitubercular drug, rifampicin, plus phenobarbitone, and monocrotaline, a DNA adduct-forming alkaloid. Rifampicin and monocrotaline can cause liver failure in people. This regimen resulted in hepatic oxidative stress, necrosis, DNA double-strand breaks, liver test abnormalities, altered serum cytokine expression, and mortality. Healthy donor hepatocytes were transplanted ectopically in the peritoneal cavity to study whether they could supply metabolic support and rebalance inflammatory or protective cytokines affecting liver regeneration events. Hepatocyte transplantation increased candidate cytokine levels (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, IL-10, and IL-12), leading to Atm, Stat3, and Akt signaling in hepatocytes and nonparenchymal cells, lowering of inflammation, and improvements in intermediary metabolism, DNA repair, and hepatocyte proliferation. Such control of DNA damage and inflammation, along with stimulation of hepatic growth, offers paradigms for cell signaling to restore hepatic homeostasis and regeneration in acute liver failure. Further studies of molecular pathways of high pathobiological impact will advance the knowledge of liver regeneration.
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Ataxia Telangiectasia , Falência Hepática Aguda , Ratos , Humanos , Animais , Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patologia , Monocrotalina/metabolismo , Rifampina/metabolismo , Citocinas/metabolismo , Falência Hepática Aguda/metabolismo , Fígado/metabolismo , Regeneração Hepática/fisiologia , Hepatócitos/patologia , Ratos Endogâmicos F344 , Inflamação/patologiaRESUMO
Inflammation is the primary driver of skeletal muscle wasting, with oxidative stress serving as both a major consequence and a contributor to its deleterious effects. In this regard, regulation of both can efficiently prevent atrophy and thus will increase the rate of survival [1]. With this idea, we hypothesize that preincubation of Cinnamaldehyde (CNA), a known compound with anti-oxidative and anti-inflammatory properties, may be able to prevent skeletal muscle loss. To examine the same, C2C12 post-differentiated myotubes were treated with 25 ng/ml Tumor necrosis factor-alpha (TNF-α) in the presence or absence of 50 µM CNA. The data showed that TNF-α mediated myotube thinning and a lower fusion index were prevented by CNA supplementation 4 h before TNF-α treatment. Moreover, a lower level of ROS and thus maintained antioxidant defense system further underlines the antioxidative function of CNA in atrophic conditions. CNA preincubation also inhibited an increase in the level of inflammatory cytokines and thus led to a lower level of inflammation even in the presence of TNF-α. With decreased oxidative stress and inflammation by CNA, it was able to maintain the intracellular level of injury markers (CK, LDH) and SDH activity of mitochondria. In addition, CNA modulates all five proteolytic systems [cathepsin-L, UPS (atrogin-1), calpain, LC3, beclin] simultaneously with an upregulation of Akt/mTOR pathway, in turn, preserves the muscle-specific proteins (MHCf) from degradation by TNF-α. Altogether, our study exhibits attenuation of muscle loss and provides insight into the possible mechanism of action of CNA in curbing TNF-α induced muscle loss, specifically its effect on proteolysis and protein synthesis.
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Acroleína/análogos & derivados , Músculo Esquelético , Fator de Necrose Tumoral alfa , Humanos , Fator de Necrose Tumoral alfa/metabolismo , Proteólise , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Estresse Oxidativo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Inflamação/metabolismoRESUMO
BACKGROUND: Achieving effective control and elimination of malaria in endemic regions necessitates a comprehensive understanding of local mosquito species responsible for malaria transmission and their susceptibility to insecticides. METHODS: The study was conducted in the highly malaria prone Ujina Primary Health Center of Nuh (Mewat) district of Haryana state of India. Monthly entomological surveys were carried out for adult mosquito collections via indoor resting collections, light trap collections, and pyrethrum spray collections. Larvae were also collected from different breeding sites prevalent in the region. Insecticide resistance bioassay, vector incrimination, blood meal analysis was done with the collected vector mosquitoes. RESULTS: A total of 34,974 adult Anopheles mosquitoes were caught during the survey period, out of which Anopheles subpictus was predominant (54.7%). Among vectors, Anopheles stephensi was predominant (15.5%) followed by Anopheles culicifacies (10.1%). The Human Blood Index (HBI) in the case of An. culicifacies and An. stephensi was 6.66 and 9.09, respectively. Vector incrimination results revealed Plasmodium vivax positivity rate of 1.6% for An. culicifacies. Both the vector species were found resistant to DDT, malathion and deltamethrin. CONCLUSION: The emergence of insecticide resistance in both vector species, compromises the effectiveness of commonly used public health insecticides. Consequently, the implementation of robust insecticide resistance management strategies becomes imperative. To effectively tackle the malaria transmission, a significant shift in vector control strategies is warranted, with careful consideration and adaptation to address specific challenges encountered in malaria elimination efforts.
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Anopheles , Inseticidas , Malária , Piretrinas , Animais , Humanos , Inseticidas/farmacologia , Resistência a Inseticidas , Malária/prevenção & controle , DDT , Controle de Mosquitos/métodos , Mosquitos Vetores , Nitrilas , Índia/epidemiologiaRESUMO
Characterization of crop-growing environments in relation to crop's genotypic performance is crucial to harness positive genotype-by-environment interactions (GEI) in systematic breeding programs. Given that, the study aimed to delineate the impact of diverse environments on crop phenology and yield traits of dwarf-statured field pea, pinpointing location(s) favoring higher yield and distinctiveness within breeding lines. We tested twelve field pea breeding lines across twenty locations in India, covering Central Zone (CZ), North Western Plain Zone (NWPZ), North Eastern Plain Zone (NEPZ), and Northern Hill Zone (NHZ). Across these locations, maximum and minimum temperatures during flowering (TMAXF, TMINF) and reproductive period (TMAXRP, TMINRP) ranged 18.9-28.3, 3.3-18.0, 15.0-30.8, and 7.9-22.1oC, respectively. Meanwhile, notable variations in phenological and agronomic traits (coefficient of variation) were observed: flowering (31%), days to maturity (21%), reproductive period (18%), grain yield (48%), and 100-seed weight (18%). Combined ANOVA demonstrated an oversized impact of environment (81%) on yield, while genotype and GEI effects were 2% and 14%, respectively. The variables TMINF, TMINRP, and cumulative growing degree-day showed positive correlations with yield, while extended vegetative and maturity durations negatively influenced yield (p < 0.05). Additionally, linear mixed-models and PCA results explained that instability in crop phenology had significant influence on field pea yield. Seed weight was markedly varied within the locations (9.9-20.8 g) and both higher and lower seed weights were associated with lower yields (Optimal = 17.1 g). HA-GGE biplot-based on environment focus-scaling demonstrated three mega-environments and specific locations viz. Kota (CZ), SK Nagar (CZ), Raipur (CZ), Sehore (CZ), and Pantnagar (NWPZ) as the ideal testing-environments with high efficiency in selecting new genotypes with wider adaptability. The study findings highlight distinct impact of environments on crop phenology and agronomic traits of field pea (dwarf-type), hold substantial value in designing efficient field pea (dwarf-type) breeding program at mega-environment scale.
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BACKGROUND OBJECTIVES: In urban areas, upsurge in population has resulted in more breeding sites for malaria vectors, and hence this scenario potentially undermine malaria elimination and control programs. The change in land use due to urbanization may result in the presence and distribution of malaria vectors. Understanding potential malaria vectors is essential for current and future malaria transmission control strategies. This study investigated the effects of rapid urbanization on malaria vectors An. culicifacies s.l. and An. stephensi L. in Ghaziabad district. METHODS: Ghaziabad district which presents several levels of urbanization was selected for this study. Entomological investigations were conducted seasonally from 2014-2016 in the rural, urban, and peri-urban regions. Vector incrimination study was done using ELISA (confirmation by PCR) on suspected Anopheles vectors viz. An. culicifacies, An. stephensi, An. annularis and An. subpictus. RESULTS: An. culicifacies showed alteration in distribution influenced by rural and agricultural land whereas An. stephensi was found to be influenced by artificial habitats and population growth. INTERPRETATION CONCLUSION: The study also confirms the association between the abundance of malaria vectors and land use change.
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Anopheles , Malária , Mosquitos Vetores , Urbanização , Anopheles/fisiologia , Anopheles/crescimento & desenvolvimento , Índia/epidemiologia , Animais , Mosquitos Vetores/fisiologia , Mosquitos Vetores/crescimento & desenvolvimento , Malária/transmissão , Malária/epidemiologia , Estações do Ano , Ecossistema , Humanos , População Rural , Distribuição AnimalRESUMO
BACKGROUND OBJECTIVES: Aedes aegypti and Aedes albopictus are two sympatric mosquito species that compete with each other for resources when their breeding habitats overlap. This study examines what happens when sympatric Aedes aegypti and Aedes albopictus mosquitoes' mate with each other and other species by looking at insemination rates, fecundity, and hatchability rate. METHODS: We performed controlled mating experiments in laboratory setting, assessing both conspecific and interspecific crosses. We measured insemination rates, egg numbers, and hatching success to examine the reproductive interference dynamics between these two distinct mosquito species. RESULTS: In the context of conspecific mating, it was observed that both female Ae. aegypti and Ae. albopictus exhibited high insemination rates, with percentages of 98% and 94%, respectively. However, interspecific mating exhibited interesting asymmetries: Ae. albopictus males achieved a notable insemination success rate of 28% when mating with Ae. aegypti females, while Ae. aegypti males achieved only 8% insemination success with Ae. albopictus females. Additionally, females that mated with interspecific males had reduced production of viable eggs compared to conspecific mating. Most notably, interspecific mating resulted in the production of infertile eggs, while conspecific mating led to successful hatching. INTERPRETATION CONCLUSION: The study reveals that, Ae. aegypti and Ae. albopictus can asymmetrically interfere with each other's reproduction, causing a 'satyr' effect. This understanding of interspecific competition and reproductive interference in these mosquito species could impact their coexistence in shared breeding habitats.
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BACKGROUND: Endocrine-resistant breast cancers have elevated expression of XBP1, where it drives endocrine resistance by controlling the expression of its target genes. Despite the in-depth understanding of the biological functions of XBP1 in ER-positive breast cancer, effectors of endocrine resistance downstream of XBP1 are poorly understood. The aim of this study was to identify the XBP1-regulated genes contributing to endocrine resistance in breast cancer. METHODS: XBP1 deficient sub-clones in MCF7 cells were generated using the CRISPR-Cas9 gene knockout strategy and were validated using western blot and RT-PCR. Cell viability and cell proliferation were evaluated using the MTS assay and colony formation assay, respectively. Cell death and cell cycle analysis were determined using flow cytometry. Transcriptomic data was analysed to identify XBP1-regulated targets and differential expression of target genes was evaluated using western blot and qRT-PCR. Lentivirus and retrovirus transfection were used to generate RRM2 and CDC6 overexpressing clones, respectively. The prognostic value of the XBP1-gene signature was analysed using Kaplan-Meier survival analysis. RESULTS: Deletion of XBP1 compromised the upregulation of UPR-target genes during conditions of endoplasmic reticulum (EnR) stress and sensitized cells to EnR stress-induced cell death. Loss of XBP1 in MCF7 cells decreased cell growth, attenuated the induction of estrogen-responsive genes and sensitized them to anti-estrogen agents. The expression of cell cycle associated genes RRM2, CDC6, and TOP2A was significantly reduced upon XBP1 deletion/inhibition in several ER-positive breast cancer cells. Expression of RRM2, CDC6, and TOP2A was increased upon estrogen stimulation and in cells harbouring point-mutants (Y537S, D538G) of ESR1 in steroid free conditions. Ectopic expression of RRM2 and CDC6 increased cell growth and reversed the hypersensitivity of XBP1 KO cells towards tamoxifen conferring endocrine resistance. Importantly, increased expression of XBP1-gene signature was associated with poor outcome and reduced efficacy of tamoxifen treatment in ER-positive breast cancer. CONCLUSIONS: Our results suggest that RRM2 and CDC6 downstream of XBP1 contribute to endocrine resistance in ER-positive breast cancer. XBP1-gene signature is associated with poor outcome and response to tamoxifen in ER-positive breast cancer.
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Neoplasias da Mama , Tamoxifeno , Humanos , Feminino , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estrogênios/farmacologia , Células MCF-7 , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proteínas Nucleares/genética , Proteínas de Ciclo Celular/genética , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
Skeletal muscle atrophy, associated with increased morbidity, mortality and poor quality of life, is a metabolic disorder with no FDA approved drug. Oxidative stress is one of the key mediators of atrophy that influences various cell signaling molecules. The goal of this study is to identify potential antioxidant agents that could be used to treat atrophy. In this study in vitro and in situ screening of different cinnamaldehyde (CNA) derivatives for their antioxidant effects was done along with computational analysis to understand the relationship between their chemical structure and biological activity. Data show that 2-hydroxycinnamaldehyde (2HCNA) worked better than other CNA analogues at physiological pH, while 4-Fluoro-2-methoxycinnamaldehyde (4FoCNA) showed the maximum antioxidant activity under acidic conditions. However, these derivatives (2HCNA and 4FoCNA) were found to be toxic to the cultured myotubes (mature myofiber) under both physiological and pathophysiological conditions. Immunofluorescence, bright-field microscopic and biochemical studies conducted using live C2C12 cells showed that pre-incubation with other CNA analogues i.e. 2-methoxycinnamaldehyde (2MeCNA) and 2-benzyloxycinnamaldehyde (2BzCNA) not only maintained the normal morphology of myotubes but also protected them from H2O2-induced atrophy. These compounds (2MeCNA and 2BzCNA) showed higher stability and antioxidant potential, as indicated by computer simulation data analyzed by Density Functional Theory (DFT) based molecular modeling. Overall, the chemical, biological, and computational studies reveal the therapeutic potential of CNA analogues (BzCNA and MeCNA) against oxidative-stress induced muscle atrophy in C2C12 cells.
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Antioxidantes , Peróxido de Hidrogênio , Humanos , Antioxidantes/uso terapêutico , Peróxido de Hidrogênio/farmacologia , Simulação por Computador , Qualidade de Vida , Fibras Musculares Esqueléticas , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Estresse Oxidativo , Substâncias Protetoras/farmacologiaRESUMO
PURPOSE: To describe the mediolateral (ML) gap balance in pre-resection arthritic knees undergoing robot-assisted (RA) total knee arthroplasty (TKA) within the nine phenotypes of the Coronal Plane Alignment of the Knee (CPAK) classification. METHODS: A total of 1124 RA TKA cases were retrospectively reviewed. ML balance was calculated using a digital ligament tensioning device following tibial resection and prior to any femoral resection throughout flexion (10°, 40°, and 90°). Lateral distal femoral angle (LDFA) and medial proximal tibial angle (MPTA) were landmarked intra-operatively and adjusted for wear based on hip-knee-ankle angle (HKA). Knees were then subdivided into CPAK categories based on the arithmetic HKA (aHKA) and joint line obliquity (JLO). Differences in balance between CPAK phenotypes were compared. RESULTS: For aHKA, a greater medial gap was observed in varus compared to neutral or valgus knees at 10° (5.2 ± 3.0 mm vs 3.3 ± 3.2 mm vs - 0.4 ± 5.0 mm respectively; p < 0.0001). A similar trend was observed for JLO in distal apex compared to neutral and proximal apex knees at 10° (3.4 ± 3.6 vs 1.1 ± 5.0 vs - 2.4 ± 6.3 respectively; p < 0.0001). The greatest ML balance differences were found when combining JLO and aHKA at 10° (type I vs type VI: ∆6.6 mm; p < 0.0001). CONCLUSION: There is a high degree of variability in arthritic ML balance within and between each CPAK phenotype. A single alignment philosophy based on bony landmarks alone may not be sufficient to balance all knees. Utilisation of robotics and digital ligament tensioning devices serves as important adjuncts to characterize the patient-specific soft tissue profile.
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Artroplastia do Joelho , Osteoartrite do Joelho , Humanos , Tornozelo/cirurgia , Estudos Retrospectivos , Articulação do Joelho/cirurgia , Extremidade Inferior/cirurgia , Tíbia/cirurgia , Osteoartrite do Joelho/cirurgiaRESUMO
C/EBP homologous protein (CHOP), also known as growth arrest and DNA damage-inducible protein 153 (GADD153), belongs to the CCAAT/enhancer-binding protein (C/EBP) family. CHOP expression is induced by unfolded protein response (UPR), and sustained CHOP activation acts as a pivotal trigger for ER stress-induced apoptosis. MicroRNA-616 is located within an intron of the CHOP gene. However, the regulation of miR-616 expression during UPR and its function in breast cancer is not clearly understood. Here we show that the expression of miR-616 and CHOP (host gene of miR-616) is downregulated in human breast cancer. Both miR-5p/-3p arms of miR-616 are expressed with levels of the 5p arm higher than the 3p arm. During conditions of ER stress, the expression of miR-616-5p and miR-616-3p arms was concordantly increased primarily through the PERK pathway. Our results show that ectopic expression of miR-616 significantly suppressed cell proliferation and colony formation, whereas knockout of miR-616 increased it. We found that miR-616 represses c-MYC expression via binding sites located in its protein coding region. Furthermore, we show that miR-616 exerted growth inhibitory effects on cells by suppressing c-MYC expression. Our results establish a new role for the CHOP locus by providing evidence that miR-616 can inhibit cell proliferation by targeting c-MYC. In summary, our results suggest a dual function for the CHOP locus, where CHOP protein and miR-616 can cooperate to inhibit cancer progression.
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Neoplasias da Mama , MicroRNAs , Feminino , Humanos , Neoplasias da Mama/genética , Proliferação de Células/genética , Genes myc , MicroRNAs/genética , Resposta a Proteínas não Dobradas/genética , Proteínas Proto-Oncogênicas c-mycRESUMO
X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer.
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Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Proteína 1 de Ligação a X-Box/genética , Neoplasias da Mama/genética , Proliferação de Células/genética , Mama , MicroRNAs/genética , Proteínas de Ligação a RNARESUMO
BACKGROUND & OBJECTIVES: Aedes (Stegomyia) aegypti is a primary vector responsible for the transmission of various arboviral diseases in India. Without an effective drug or vaccine against these diseases, chemical insecticide-based vector control supplemented with source reduction remains the best option for their effective management. The development of insecticide resistance due to the continuous use of insecticides might affect the control operations. METHODS: Adults and larvae of Aedes aegypti were collected from different localities in Delhi. Larvae were exposed to discriminating (0.02mg/l) and application (1mg/l) doses of temephos. WHO tube assay was conducted for F1 adults using impregnated insecticide papers of dichlorodiphenyltrichloroethane (DDT), malathion, deltamethrin, permethrin, cyfluthrin, and lambda-cyhalothrin. RESULTS: Larvae of Ae. aegypti were found resistant (76.0%) to the discriminating dose of temephos, whereas suscep-tible (100.0%) to the application dose of the temephos. Adult Aedes (Fl) mosquitoes were resistant to DDT (23.7%), malathion (90.5%), deltamethrin (76.0%), permethrin (96.2 %) cyfluthrin (85.5%), and lambda-cyhalothrin (94.0%). INTERPRETATION & CONCLUSION: Indoor residual spray is not used in Delhi for vector control. Resistance in Aedes might be due to pesticide usage for agricultural activities in peripheral regions of Delhi. There is a need to investigate more on the insecticide resistance mechanisms for indirect resistance development. Understanding the insecticide susceptibility status of urban vectors is critical for planning effective control strategies.
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Aedes , Inseticidas , Piretrinas , Animais , Inseticidas/farmacologia , Permetrina/farmacologia , Malation/farmacologia , DDT/farmacologia , Temefós/farmacologia , Saúde Pública , Mosquitos Vetores , Piretrinas/farmacologia , Resistência a Inseticidas , Larva , ÍndiaRESUMO
The innate immune system plays a critical role in allograft rejection. Alloresponses involve numerous cytokines, chemokines, and receptors that cause tissue injury during rejection. To dissect these inflammatory mechanisms, we developed cell transplantation models in dipeptidylpeptidase-deficient F344 rats using mycophenolate mofetil and tacrolimus for partial lymphocyte-directed immunosuppression. Syngeneic hepatocytes engrafted in liver, whereas allogeneic hepatocytes were rejected but engrafted after immunosuppression. These transplants induced mRNAs for >40 to 50 cytokines, chemokines, and receptors. In allografts, innate cell type-related regulatory networks extended to granulocytes, monocytes, and macrophages. Activation of Tnfa and its receptors or major chemokine receptor-ligand subsets persisted in the long term. An examination of the contribution of Tnfa in allograft response revealed that it was prospectively antagonized by etanercept or thalidomide, which resolved cytokine, chemokine, and receptor cascades. In bioinformatics analysis of upstream regulator networks, the Cxcl8 pathway exhibited dominance despite immunosuppression. Significantly, Tnfa antagonism silenced the Cxcl8 pathway and decreased neutrophil and Kupffer cell recruitment, resulting in multifold greater engraftment of allogeneic hepatocytes and substantially increased liver repopulation in retrorsine/partial hepatectomy model. We conclude that Tnfa is a major driver for persistent innate immune responses after allogeneic cells. Neutralizing Tnfa should help in avoiding rejection and associated tissue injury in the allograft setting.
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Rejeição de Enxerto/imunologia , Hepatócitos/transplante , Imunidade Inata/imunologia , Imunologia de Transplantes/imunologia , Fator de Necrose Tumoral alfa/imunologia , Aloenxertos , Animais , Ratos , Ratos Endogâmicos F344 , Ratos Long-Evans , Transplante HomólogoRESUMO
Acute liver failure constitutes a devastating condition that needs novel cell and molecular therapies. To elicit synergisms in cell types of therapeutic interest, we studied hepatocytes and liver sinusoidal endothelial in mice with acetaminophen-induced acute liver failure. The context of regenerative signals was examined by transplants in peritoneal cavity because it possesses considerable capacity and allows soluble signals to enter the systemic circulation. Whereas transplanted hepatocytes and liver sinusoidal endothelial cells engrafted in peritoneal cavity, only the former could rescue mice in liver failure by improving injury outcomes, activating hepatic DNA damage repair, and inducing liver regeneration. The cytokines secreted by donor hepatocytes or liver sinusoidal endothelial cells differed and in hepatocytes from mice undergoing acetaminophen toxicity major cytokines were even rendered deficient (eg, G-CSF, VEGF, and others). Significantly, recapitulating hepatotoxicity-related DNA damage response in cultured cells identified impairments in ATM and JAK/STAT3 intersections since replacing cytokines produced less from injured hepatocytes restored these pathways to avoid acetaminophen hepatotoxicity. Similarly, hepatocyte transplantation in acute liver failure restored ATM and JAK/STAT3 pathways to advance DNA damage/repair and liver regeneration. The unexpected identification of novel hepatic G-CSF receptor expression following injury allowed paradigmatic studies of G-CSF supplementation to confirm the centrality of this paracrine ATM and STAT3 intersection. Remarkably, DNA damage/repair and hepatic regeneration directed by G-CSF concerned rebalancing of regulatory gene networks overseeing inflammation, metabolism, and cell viability. We conclude that healthy donor hepatocytes offer templates for generating specialized cell types to replace metabolic functions and regenerative factors in liver failure.
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Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Hepatócitos/citologia , Falência Hepática Aguda/terapia , Regeneração Hepática/efeitos dos fármacos , Acetaminofen/farmacologia , Animais , Sobrevivência Celular/fisiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Humanos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Regeneração Hepática/fisiologia , Fator de Transcrição STAT3/metabolismoRESUMO
The pivotal impact of organic cation rotation may result in structural complexity in two-dimensional (2D) halide-based hybrid perovskites. The crucial role of the orientation of the organic cation (MA = CH3NH3+) in the 2D Ruddlesden-Popper phase (2DRP) is explored using density functional theory (DFT) calculations. Our results propose that the MA cation rotation imposes the structural distortion in the PbI6 network, which is further responsible for the changes in nature and value of the electronic bandgap, charge density and optical absorption. The spin-orbit coupling effect results in a wide range of Rashba splitting parameters being obtained from 0.04 to 0.278 eV Å. The simulated optical absorption spectra suggest that absorption edge for the alignment of the MA molecule along the X-axis (having unidirectional hydrogen bonds) is higher than that of the alignment of the MA cation in the z-direction. Furthermore, the unidirectional hydrogen bonds between the MA cation and Pb-I framework significantly help to achieve the highest mobility of charge carriers up to â¼1437 cm2 V-1 s-1. Such high mobility leads to supremacy in the thermoelectric transport properties, which are investigated for the first time with the rotation of the MA cation. The calculated thermoelectric power factor at room temperature shows exceptionally high values (up to 2.04 mW m-1 K-2), leading to desired applications in thermoelectric devices. The rotation of the MA cation might be utilized as a useful tool for variation in optical absorption and transport coefficients. Therefore, our results spark the idea to develop 2D perovskites for real-time perspective in solar and heat energy utilization.
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With an inspiration of sensing toxic gases, this study is aimed at exploring the potential of a Janus MoSSe monolayer as a gas sensor. Here, we focused on the adsorption mechanism after the exposure to NH3, NO2, NO, HCN, CO2, CO, H2, H2S and SO2 on both the S and Se sites of MoSSe. We investigated the structural geometries and electronic, sensing and electron-transport properties before and after adsorption of the aforementioned gases by applying DFT calculations. The results revealed the higher binding strength of NO2/SO2 and NO on Se and S sites, respectively, among all the gas adsorptions on the MoSSe monolayer. Moreover, DOS revealed strong orbital contributions at EF, which confirmed the n/p-type semiconducting character for the NO/NO2 adsorbed MoSSe monolayer. Further, the specific work function alteration after the adsorption of NO2, SO2 and NO indicated that the MoSSe monolayer could be a potential candidate for Φ-type gas sensor at 300 K. Additionally, the higher electron transmission and prominent electrical response values of 76.4/56 µA and 82 µA suggested a maximum sensitivity of 98%/89% and 93% at a particular voltage for NO2/SO2 and NO on Se and S sites, respectively. Thus, our results promote surface selectivity, i.e. S or Se site, and better sensitivity with recycling potential could enable sensing application of the Janus MoSSe monolayer for toxic gases detection.
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Briófitas , Dióxido de Nitrogênio , Adsorção , Teoria da Densidade Funcional , GasesRESUMO
Blood lead level (BLL) is the primary biomarker for lead-exposure monitoring in occupationally exposed workers. We evaluated occupational lead-exposure (OE) impact on cardiopulmonary functions in lead-acid battery recycling unit workers. Seventy-six OE cases and 30 control subjects were enrolled for questionnaire-based socio-demographic, dietary, tobacco usage, and medical history data. Anthropometric measurements, systolic and diastolic blood pressure (SBP and DBP), and pulmonary function tests were performed. Venous blood was collected for BLL, hematological analysis, and biochemical analysis. OE caused a significant increase in BLL, SBP, DBP, and small airways obstruction in lung function tests. It also impaired platelet indices, affected renal and liver biochemical measurements, and promoted oxidative stress and DNA damage. Multilinear regression analysis suggested that BLL affected SBP (ß = 0.314, p = .034) and increased small airways obstruction (FEV1/FVC, ß = -0.37, p = .05; FEV25-75%, ß = -0.351, p = .016). Higher BLL appears to be an independent modulator of hypertension and poor pulmonary function upon occupational lead exposure in lead-acid battery recyclers.
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Hipertensão , Exposição Ocupacional , Pressão Sanguínea/fisiologia , Estudos Transversais , Humanos , Hipertensão/etiologia , Chumbo , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análiseRESUMO
INTRODUCTION: Assistive technologies are becoming more common in total hip replacement (THR) procedures, improving surgeons' abilities to achieve target implant orientations. These systems can be large, absorbing limited space in the operating theatre, and they can add complexity to surgery. MATERIALS AND METHODS: We developed a small footprint prototype system that can assist in the accurate placement of implant components using augmented reality (AR) technology into preoperatively planned positions. This technology augments the 3D pelvis and the cup in its target position and displays the real-time position of instruments. The accuracy of the developed prototype system was assessed through a cadaveric study, comparing the achieved implant positions to the preoperative target. All cadavers received preoperative 3D planning to identify the target cup position and orientation. Cadaveric surgeries were completed using the AR system to achieve the target cup placement. Postoperative computed tomography (CT) was used to measure the achieved component position for each hip. RESULTS: The mean absolute deviation (range) from target acetabular placement to the achieved acetabular placement was 2.9° (-8.7 to 3.3°), 3.0° (-5.7 to 7°) and 1.6mm (-1.2 to 3.5mm) for inclination, anteversion, and depth, respectively. Sixty-six percent of results were within +/-5° of the preoperative target orientation. CONCLUSION: We present a cadaver validation study on a small footprint prototype system using augmented reality to enable accurate cup placement and provide additional information intraoperatively. Our results are comparable with reported results for image-based navigation from the literature.
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PURPOSE: Robotic-assisted total knee arthroplasty (TKA) may improve the precision of bone preparation and component alignment when compared to the conventional surgical approach; however, the detailed cost analysis of robotic-assisted TKA is lacking. This study aims to compare in-hospital costs between robotic-assisted and computer-navigated TKA. METHODS: Patients undergoing primary TKA at a public hospital in Sydney between October 2018 and June 2019 were included. Patient demographics, surgical outcomes and in-hospital cost variables including, staff, critical care, emergency department, diagnostic, prosthesis, operating room, ward and other related costs until the discharge to the community were collected. Differences across in-hospital costs between robotic-assisted and computer-navigated TKA were compared using independent Student's t-tests. RESULTS: Of the 258 primary TKAs, 181 (70.2%) were computer-navigated and 77 (29.8%) robotic-assisted. Surgical time (p < 0.001) and operating time (p < 0.001) were both significantly shorter in computer-navigated TKA, while robotic-assisted TKA cases were more likely to be discharged directly home without extended in-patient rehabilitation (p = 0.014). When removing the capital costs of surgical equipment and maintenance, there was no difference in total in-hospital cost between computer-navigated ($19,512.3) and robotic-assisted TKA ($18,347.1; p = 0.179). When these capital costs were included, the mean in-hospital cost of robotic-assisted surgery was $21,507.6 compared to $19,659.7 for computer-navigated TKA (p = 0.034). CONCLUSIONS: The total in-hospital cost, during the implementation period of robotic-assisted TKA, is comparable with computer-navigated TKA. Robotic-assisted TKA was significantly more expensive when the upfront cost of the robotic system and maintenance costs were included. Longer term cost benefit of robotic-assisted TKA should be investigated in future studies.