Assessing the impact of emergency measures in varied population density areas during a large dengue outbreak.

Background: The patterns of dengue are affected by many factors, including population density and climate factors. Densely populated areas could play a role in dengue transmission due to increased human-mosquito contacts, the presence of more diverse and suitable vector habitats and breeding sites, and changes in land use. In addition to population densities, climatic factors such as temperature, relative humidity, and precipitation have been demonstrated to predict dengue patterns. To control dengue, emergency measures should focus on vector management. Most approaches to assessing emergency responses to dengue risks involve applying simulation models or describing emergency activities and the results of implementing those responses. Research using real-world data with analytical methods to evaluate emergency responses to dengue has been limited. This study investigated emergency control measures associated with dengue risks in areas with high and low population densities, considering their different control capacities. Methodology: Data from the 2015 dengue outbreak in Kaohsiung City, Taiwan, were utilized. The government database provided information on confirmed dengue cases, emergency control measures, and climatic data. The study employed a distributed lag non-linear model (DLNM) to assess the effect of emergency control measures and their time lags on dengue risk. Principal findings: The findings revealed that in areas with high population density, the absence of emergency measures significantly elevated the risks of dengue. However, implementing emergency measures, especially a higher number, was associated with lower risks. In contrast, in areas with low population density, the risks of dengue were only significantly elevated at the 1st week lag if no emergency control measures were implemented. When emergency activities were carried out, the risks of dengue significantly decreased only for the 1st week lag. Conclusions: Our findings reveal distinct exposure-lag-response patterns in the associations between emergency control measures and dengue in areas with high and low population density. In regions with a high population density, implementing emergency activities during a significant dengue outbreak is crucial for reducing the risk. Conversely, in areas of low population density, the necessity of applying emergency activities may be less pronounced. The implications of this study on dengue management could provide valuable insights for health authorities dealing with limited resources.

Transient plasticity response is regulated by histone deacetylase inhibitor in oxygen-glucose deprivation condition.

BACKGROUND: The pathological form of synaptic plasticity, ischemic long-term potentiation (iLTP), induced by oxygen and glucose deprivation (OGD), is implicated in the acute phase of stroke with the potentiation of N-methyl-D-aspartate receptor (NMDAR). While there has been widespread attention on the excitatory system, a recent study reported that γ-aminobutyric acid (GABA)ergic system is also involved in iLTP. Valproic acid (VPA), a histone deacetylase inhibitor, protects against ischemic damage. However, whether VPA regulates early phase plasticity in ischemic stroke remains unknown. The present study aims to investigate the potential role and mechanism of VPA in ischemic stroke. METHODS: A brief exposure of OGD on the hippocampal slices and the induction of photothrombotic ischemia (PTI) were used as ex vivo and in vivo models of ischemic stroke, respectively. RESULTS: Using extracellular recordings, iLTP was induced in the hippocampal Schaffer collateral pathway following OGD exposure. VPA treatment abolished hippocampal iLTP via GABAA receptor enhancement and extracellular signal-regulated kinase (ERK) phosphorylation. Administration of VPA reduced brain infarct volume and motor dysfunction in mice with PTI. Moreover, VPA protected against ischemic injury by upregulating the GABAergic system and ERK phosphorylation, as well as by reducing of matrix metalloproteinase in a PTI-induced ischemic stroke model. CONCLUSIONS: Together, this study revealed the protection of VPA in ex vivo OGD-induced pathological form of neuroplasticity and in vivo PTI-induced brain damage and motor dysfunction through rescuing GABAergic deficiency and the pathological hallmarks of ischemia.

Measuring the effects of typhoon trajectories on dengue outbreaks in tropical regions of Taiwan: 1998-2019.

Dengue fever is a rapidly spreading mosquito-borne contagion. However, the effects of extreme rainfall events on dengue occurrences have not been widely evaluated. With their immense precipitation and high winds, typhoons may have distinct effects on dengue occurrence from those during other heavy rain events. Frequented by typhoons and situated in the tropical climate zone, southern Taiwan is an appropriate study area due to its isolated geographic environment. Each subject to distinct orographic effects on typhoon structure and typhoon-induced precipitation, 9 typhoon trajectories around Taiwan have not been observed until now. This study analyzes typhoon-induced precipitation and examines historical typhoon events by trajectory to determine the effects of typhoons on dengue occurrences in different urban contexts of Tainan and Kaohsiung in high-epidemic southern Taiwan. We employed data from 1998 to 2019 and developed logistic regression models for modeling dengue occurrence while taking 28-day lag effects into account. We considered factors including typhoon trajectory, occurrence, and typhoon-induced precipitation to dengue occurrences. Our results indicate that typhoon trajectories are a significant risk factor for dengue occurrence. Typhoons affect dengue occurrence differently by trajectory. One out of four northbound (along the Taiwan Strait) and four out of five westbound (across Taiwan) typhoons were found to be positively correlated with dengue occurrences in southern Taiwan. We observe that typhoon-induced precipitation is not associated with dengue occurrence in southern Taiwan, which suggests that wind destruction during typhoon events may serve as the primary cause for their positive effects by leaving debris suitable for mosquito habitats. Our findings provide insights into the impact of typhoons by trajectory on dengue occurrence, which can improve the accuracy of future dengue forecasts in neighboring regions with similar climatic contexts.

IL-10 modified mRNA monotherapy prolongs survival after composite facial allografting through the induction of mixed chimerism.

Vascularized composite allotransplantation has great potential in face transplantation by supporting functional restoration following tissue grafting. However, the need for lifelong administration of immunosuppressive drugs still limits its wide use. Modified mRNA (modRNA) technology provides an efficient and safe method to directly produce protein in vivo. Nevertheless, the use of IL-10 modRNA-based protein replacement, which exhibits anti-inflammatory properties, has not been shown to prolong composite facial allograft survival. In this study, IL-10 modRNA was demonstrated to produce functional IL-10 protein in vitro, which inhibited pro-inflammatory cytokines and in vivo formation of an anti-inflammatory environments. We found that without any immunosuppression, C57BL/6J mice with fully major histocompatibility complex (MHC)-mismatched facial allografts and local injection of IL-10 modRNA had a significantly prolonged survival rate. Decreased lymphocyte infiltration and pro-inflammatory T helper 1 subsets and increased anti-inflammatory regulatory T cells (Tregs) were seen in IL-10 modRNA-treated mice. Moreover, IL-10 modRNA induced multilineage chimerism, especially the development of donor Treg chimerism, which protected allografts from destruction because of recipient alloimmunity. These results support the use of monotherapy based on immunomodulatory IL-10 cytokines encoded by modRNA, which inhibit acute rejection and prolong allograft survival through the induction of donor Treg chimerism.

How Spatial Epidemiology Helps Understand Infectious Human Disease Transmission.

Both directly and indirectly transmitted infectious diseases in humans are spatial-related. Spatial dimensions include: distances between susceptible humans and the environments shared by people, contaminated materials, and infectious animal species. Therefore, spatial concepts in managing and understanding emerging infectious diseases are crucial. Recently, due to the improvements in computing performance and statistical approaches, there are new possibilities regarding the visualization and analysis of disease spatial data. This review provides commonly used spatial or spatial-temporal approaches in managing infectious diseases. It covers four sections, namely: visualization, overall clustering, hot spot detection, and risk factor identification. The first three sections provide methods and epidemiological applications for both point data (i.e., individual data) and aggregate data (i.e., summaries of individual points). The last section focuses on the spatial regression methods adjusted for neighbour effects or spatial heterogeneity and their implementation. Understanding spatial-temporal variations in the spread of infectious diseases have three positive impacts on the management of diseases. These are: surveillance system improvements, the generation of hypotheses and approvals, and the establishment of prevention and control strategies. Notably, ethics and data quality have to be considered before applying spatial-temporal methods. Developing differential global positioning system methods and optimizing Bayesian estimations are future directions.

Modeling geographical invasions of Solenopsis invicta influenced by land-use patterns.

Research into geographical invasions of red imported fire ants (RIFAs) by anthropogenic disturbances has received much attention. However, little is known about how land-use change and the characteristics of roads with different land-use types are associated with the risk of RIFA successful invasion or remaining at the highest level of invasion (RIFA SIRH). Furthermore, it was often assumed in prior studies that the risk of RIFA SIRH had a linear association with the independent variables. However, a linear relationship may not reflect the actual circumstances. In this study, we applied linear and nonlinear approaches to assess how land-use types, distance from the nearest road, different land-use types, and spatial factors affect the risk of RIFA SIRH. The results showed that agricultural land, land for transportation usage, and areas that had undergone land-use change from 2014 to 2017 had greater odds of RIFA invasion than natural land cover. We also identified land for transportation usage and the area of land-use change from 2014 to 2017, had more than 60% of RIFA SIRH within 350 m and 150 m from the nearest road. This study provided important insights into RIFA invasions in an isolated island and the areas of control strategies implemented.

State-of-the-Art Capability of Convolutional Neural Networks to Distinguish the Signal in the Ionosphere.

Recovering and distinguishing different ionospheric layers and signals usually requires slow and complicated procedures. In this work, we construct and train five convolutional neural network (CNN) models: DeepLab, fully convolutional DenseNet24 (FC-DenseNet24), deep watershed transform (DWT), Mask R-CNN, and spatial attention-UNet (SA-UNet) for the recovery of ionograms. The performance of the models is evaluated by intersection over union (IoU). We collect and manually label 6131 ionograms, which are acquired from a low-latitude ionosonde in Taiwan. These ionograms are contaminated by strong quasi-static noise, with an average signal-to-noise ratio (SNR) equal to 1.4. Applying the five models to these noisy ionograms, we show that the models can recover useful signals with IoU > 0.6. The highest accuracy is achieved by SA-UNet. For signals with less than 15% of samples in the data set, they can be recovered by Mask R-CNN to some degree (IoU > 0.2). In addition to the number of samples, we identify and examine the effects of three factors: (1) SNR, (2) shape of signal, (3) overlapping of signals on the recovery accuracy of different models. Our results indicate that FC-DenseNet24, DWT, Mask R-CNN and SA-UNet are capable of identifying signals from very noisy ionograms (SNR < 1.4), overlapping signals can be well identified by DWT, Mask R-CNN and SA-UNet, and that more elongated signals are better identified by all models.

The Mandible Ameliorates Facial Allograft Rejection and Is Associated with the Development of Regulatory T Cells and Mixed Chimerism.

Vascularized composite allografts contain various tissue components and possess relative antigenicity, eliciting different degrees of alloimmune responses. To investigate the strategies for achieving facial allograft tolerance, we established a mouse hemiface transplant model, including the skin, muscle, mandible, mucosa, and vessels. However, the immunomodulatory effects of the mandible on facial allografts remain unclear. To understand the effects of the mandible on facial allograft survival, we compared the diversities of different facial allograft-elicited alloimmunity between a facial osteomyocutaneous allograft (OMC), including skin, muscle, oral mucosa, and vessels, and especially the mandible, and a myocutaneous allograft (MC) including the skin, muscle, oral mucosa, and vessels, but not the mandible. The different facial allografts of a BALB/c donor were transplanted into a heterotopic neck defect on fully major histocompatibility complex-mismatched C57BL/6 mice. The allogeneic OMC (Allo-OMC) group exhibited significant prolongation of facial allograft survival compared to the allogeneic MC group, both in the presence and absence of FK506 immunosuppressive drugs. With the use of FK506 monotherapy (2 mg/kg) for 21 days, the allo-OMC group, including the mandible, showed prolongation of facial allograft survival of up to 65 days, whereas the myocutaneous allograft, without the mandible, only survived for 34 days. The Allo-OMC group also displayed decreased lymphocyte infiltration into the facial allograft. Both groups showed similar percentages of B cells, T cells, natural killer cells, macrophages, and dendritic cells in the blood, spleen, and lymph nodes. However, a decrease in pro-inflammatory T helper 1 cells and an increase in anti-inflammatory regulatory T cells were observed in the blood and lymph nodes of the Allo-OMC group. Significantly increased percentages of donor immune cells were also observed in three lymphoid organs of the Allo-OMC group, suggesting mixed chimerism induction. These results indicated that the mandible has the potential to induce anti-inflammatory effects and mixed chimerism for prolonging facial allograft survival. The immunomodulatory understanding of the mandible could contribute to reducing the use of immunosuppressive regimens in clinical face allotransplantation including the mandible.

Recovery of Ionospheric Signals Using Fully Convolutional DenseNet and Its Challenges.

The technique of active ionospheric sounding by ionosondes requires sophisticated methods for the recovery of experimental data on ionograms. In this work, we applied an advanced algorithm of deep learning for the identification and classification of signals from different ionospheric layers. We collected a dataset of 6131 manually labeled ionograms acquired from low-latitude ionosondes in Taiwan. In the ionograms, we distinguished 11 different classes of the signals according to their ionospheric layers. We developed an artificial neural network, FC-DenseNet24, based on the FC-DenseNet convolutional neural network. We also developed a double-filtering algorithm to reduce incorrectly classified signals. That made it possible to successfully recover the sporadic E layer and the F2 layer from highly noise-contaminated ionograms whose mean signal-to-noise ratio was low, SNR = 1.43. The Intersection over Union (IoU) of the recovery of these two signal classes was greater than 0.6, which was higher than the previous models reported. We also identified three factors that can lower the recovery accuracy: (1) smaller statistics of samples; (2) mixing and overlapping of different signals; (3) the compact shape of signals.

Nanoporous Silver Telluride for Active Hydrogen Evolution.

Silver-based nanomaterials have been versatile building blocks of various photoassisted energy applications; however, they have demonstrated poor electrochemical catalytic performance and stability, in particular, in acidic environments. Here we report a stable and high-performance electrochemical catalyst of silver telluride (AgTe) for the hydrogen evolution reaction (HER), which was synthesized with a nanoporous structure by an electrochemical synthesis method. X-ray spectroscopy techniques on the nanometer scale and high-resolution transmission electron microscopy revealed an orthorhombic structure of nanoporous AgTe with precise lattice constants. First-principles calculations show that the AgTe surface possesses highly active catalytic sites for the HER with an optimized Gibbs free energy change of hydrogen adsorption (-0.005 eV). Our nanoporous AgTe demonstrates exceptional stability and performance for the HER, an overpotential of 27 mV, and a Tafel slope of 33 mV/dec. As a stable catalyst for hydrogen production, AgTe is comparable to platinum-based catalysts and provides a breakthrough for high-performance electrochemical catalysts.

Elucidating how the red imported fire ant (Solenopsis invicta) diffused spatiotemporally among different landscapes in north Taiwan, 2008-2015.

Solenopsis invicta Buren, also known as the red imported fire ant (RIFA), has had a large negative impact on human and livestock health. However, few studies have further investigated the influence of human land use, which is an important factor affecting the habitats of insects, on the expansion of RIFAs. In addition, there is a lack of knowledge of the empirical associations between RIFA diffusion and land use within countries. Therefore, the objectives of this study were to provide an approach to delineate the areas of RIFA infestations and explore how land use influences the spatiotemporal diffusion of S. invicta. We used RIFA data from 2008 to 2015 from the RIFA surveillance system, which was conducted by the National RIFA Control Center in Taiwan. Two regions in Taiwan with different RIFA infestation levels were investigated. The ordinary kriging method was applied to show the spatial intensity of RIFAs, and the extreme distance estimator method was applied to determine the critical dispersal distances, which showed the distance of the highest probability of RIFAs in two consecutive years. In addition, network analyses were used to identify RIFA invasion routes between land-use types. Finally, bivariate local indicators of spatial association were used to capture the invasion process in time and space. The results showed, paddy fields, main roads, and warehouses were identified as the top three land-use types of diffusion sources. On average, the critical RIFA dispersal distances were 600 and 650 m in two consecutive years in high- and low-infestation regions, respectively. Finally, RIFAs were likely to diffuse between main roads and warehouses in the low-infestation region. Therefore, it is suggested that RIFA control activities be implemented at least 600 m from the observed spot. Additionally, control activities should be conducted on the identified three land-use types of diffusion sources in the high-infestation region, and the roadsides between main roads and warehouses in the low-infestation region to prevent the accidental spread of RIFAs.

Low-Valent, Multiply Bonded, Trigonal-Planar Sb Complex: Rational Syntheses, Dual Acidic/Basic Properties, and Unexpected Semiconducting Characteristics.

A 4-center, 6π-conjugated, multiply bonded trigonal-planar complex, [Sb{Cr(CO)5}3]- (1), was synthesized via the hydride abstraction of [HSb{Cr(CO)5}3]2- (1-H) with HBF4·H2O, with the release of high yields of H2. The oxidation state of the Sb atom in [Et4N][1] was well-defined as 0, which was evidenced by X-ray photoelectron spectroscopy and X-ray absorption near-edge structure. The distinct color-structure relationship of this low-valent Sb complex 1 toward a wide range of organic solvents was demonstrated, as interpreted by time-dependent density functional theory calculations, allowing the trigonal-planar 1 and the tetrahedral solvent adducts to be probed, revealing the dual acid/base properties of the Sb center. In addition, 1 showed pronounced electrophilicity toward anionic and neutral nucleophiles, even with solvent molecules, to produce tetrahedral complexes [(Nu)Sb{Cr(CO)5}3]n- [1-Nu; n = 2, Nu = H, F, Cl, Br, I, OH; n = 1, Nu = PEt3, PPh3, N,N-dimethylformamide (DMF), acetonitrile (MeCN)]. On the contrary, the Fe/Cr hydride complex [HSb{Fe(CO)4}{Cr(CO)5}2]2- (2-H) was obtained by treating 1 with [HFe(CO)4]-. Upon hydride abstraction of 2-H with HBF4·H2O or [CPh3][BF4], a multiply bonded Fe/Cr trigonal-planar complex, [Sb{Fe(CO)4}{Cr(CO)5}2]- (2), was produced in which the oxidation coupling Sb2-containing complexes [Sb2Cr4Fe2(CO)28]2- (3-Cr) and [HSb2Cr3Fe2(CO)23]- (3-H) were yielded as final products. Complex 3-Cr exhibited dual Lewis acid/base properties via hydridation and protonation reactions, to form 2-H or 3-H, respectively. Surprisingly, [Et4N][1] possessed a low energy gap of 1.13 eV with an electrical conductivity in the range of (1.10-2.77) × 10-6 S·cm-1, showing that [Et4N][1] was a low-energy-gap semiconductor. The crystal packing, crystal indexing, and density of states results of [Et4N][1] further confirmed the efficient through-space conduction pathway via the intermolecular Sb···O(carbonyl) and O(carbonyl)···O(carbonyl) interactions of the 1D anionic zigzag chain of 1.

Human Wharton's Jelly Mesenchymal Stem Cell-Mediated Sciatic Nerve Recovery Is Associated with the Upregulation of Regulatory T Cells.

The acceleration of peripheral nerve regeneration is crucial for functional nerve recovery. Our previous study demonstrated that human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSC) promote sciatic nerve recovery and regeneration via the direct upregulation and release of neurotrophic factors. However, the immunomodulatory role of hWJ-MSC in sciatic nerve recovery remains unclear. The effects of hWJ-MSC on innate immunity, represented by macrophages, natural killer cells, and dendritic cells, as well as on adaptive immunity, represented by CD4+ T, CD8+ T, B, and regulatory T cells (Tregs), were examined using flow cytometry. Interestingly, a significantly increased level of Tregs was detected in blood, lymph nodes (LNs), and nerve-infiltrating cells on POD7, 15, 21, and 35. Anti-inflammatory cytokines, such as IL-4 and IL-10, were significantly upregulated in the LNs and nerves of hWJ-MSC-treated mice. Treg depletion neutralized the improved effects of hWJ-MSC on sciatic nerve recovery. In contrast, Treg administration promoted the functional recovery of five-toe spread and gait stance. hWJ-MSC also expressed high levels of the anti-inflammatory cytokines TGF-ß and IL-35. This study indicated that hWJ-MSC induce Treg development to modulate the balance between pro- and anti-inflammation at the injured sciatic nerve by secreting higher levels of anti-inflammatory cytokines.

Nanoprobing of MoS2 by Synchrotron Radiation When van der Waals Epitaxy Is Locally Invalid.

In this work, we demonstrated nano-scaled Laue diffractions by a focused polychromatic synchrotron radiation beam to discover what happens in MoS2 when van der Waals epitaxy is locally invalid. A stronger exciton recombination with a local charge depletion in the density of 1 × 1013 cm-2, extrapolated by Raman scattering and photoluminescence, occurs in grains, which exhibits a preferred orientation of 30° rotation with respect to the c-plane of a sapphire substrate. Else, the charge doping and trion recombination dominate instead. In addition to the breakthrough in extrapolating mesoscopic crystallographic characteristics, this work opens the feasibility to manipulate charge density by the selection of the substrate-induced disturbances without external treatment and doping. Practically, the 30° rotated orientation in bilayer MoS2 films is promoted on inclined facets in the patterned sapphire substrate, which exhibits a periodic array of charge depletion of about 1.65 × 1013 cm-2. The built-in manipulation of carrier concentrations could be a potential candidate to lateral and large-area electronics based on 2D materials.

Increased GABAergic inhibitory function against ischemic long-term potentiation in the CA1 region of the hippocampus.

Potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory synaptic plasticity around 1 h after brief exposure to anoxia/aglycemia is called ischemic long-term potentiation (iLTP), which is considered a pathological form of synaptic response during the early phase of ischemic stroke. It is known that GABAergic inhibitory transmission is also an important molecular process involved in synaptic plasticity and learning memory. However, whether GABAergic transmission is involved in iLTP and early-phase plasticity in ischemic stroke remains unknown. In this study, iLTP was found to be induced in the hippocampal Schaffer-collateral pathway by exposure to oxygen glucose deprivation (OGD). Western blot analysis was conducted to analyze excitatory synaptic receptors and inhibitory synaptic receptors following OGD. The ß3 subunit of the GABAA receptor (GABAAR) was markedly reduced, whereas the GluN2B subunit of the NMDAR was increased in the hippocampal area in the OGD group. Using extracellular recording, we demonstrated that application of GABAAR agonist midazolam could abolish the hippocampal iLTP. Moreover, midazolam had no significant effect on the increase in NMDAR subunit GluN2B, but ameliorated the reduction in the ß3 subunit of GABAAR after OGD. In summary, our results indicated that hippocampal GABAAR reduction promoted synaptic potentiation after OGD. Activation of GABAergic inhibitory transmission function could inhibit iLTP; thus, modulation of GABAergic function is a protective treatment method in the acute phase of synaptic plasticity in ischemic stroke.

Temporal Pattern of Mutations in the Knockdown Resistance (kdr) Gene of Aedes aegypti Mosquitoes Sampled from Southern Taiwan.

Aedes mosquitoes are the principal dengue vector in Taiwan, where the use of insecticides is a key element in the national control strategy. However, control efforts are constrained by the development of resistance to most insecticides, including pyrethroids. In this study, mutations in the voltage-gated sodium channel (VGSC) gene resulting in knockdown resistance (kdr) were examined in Aedes aegypti. Fragments of the VGSC gene were polymerase chain reaction (PCR)-amplified followed by restriction fragment length polymorphism analysis in samples from various settings in Southern Taiwan covering dry and wet seasons from 2013 to 2015. Three kdr mutations were identified: V1023G, D1794Y, and F1534C, with observed frequencies of 0.36, 0.55, and 0.33, respectively, in the dry season of 2013-2014. Exploring for temporal changes, the most important observation was the 1534C allele frequency increment in the following season to 0.60 (P < 0.05). This study suggests that continued insecticide pressure is driving the mutational changes, although the selection is ambiguous in the mosquito population.

Location, seasonal and functional characteristics of water-holding containers with juvenile Aedes albopictus in urban southern Taiwan: a cross-sectional study.

BACKGROUND: Urban Kaohsiung City (KC), in southern Taiwan, has experienced annual dengue epidemics for decades despite considerable vector control efforts. Substantial research has been undertaken to characterize Aedes aegypti breeding habitats, but no systematic assessment has been completed for Aedes albopictus present in KC. METHODS: A cross-sectional survey was conducted from 2013 to 2015 in a predefined area of KC. Each identified container was characterised by season, location, ownership, function and number of juvenile A. aegypti. Negative binomial hurdle analyses were applied to evaluate the association between the number of juvenile A. albopictus and the characteristics of each identified container. RESULTS: For all containers, high numbers of A. albopictus were significantly predicted by containers identified during the wet season (vs dry), located on government (vs private) property and classified as a discarded item (vs water storage). For outdoor containers, more A. albopictus were significantly predicted by wet season (vs dry) and discarded item (vs container in use). CONCLUSIONS: In order to improve dengue prevention in KC, we propose that vector control efforts be expanded to include A. albopictus through an increased focus during the wet season on discarded containers that are located outdoors and on government property.

Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer.

BACKGROUND: The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of this methyltransferase have been identified to date. METHODS: The clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. The PRMT3 protein level of human pancreatic tumors was detected by immunoblotting and immunohistochemical staining. PRMT3-associated proteins and the methylation sites on the proteins were investigated using mass spectrometry. Seahorse Bioscience analyzed the metabolic reprogramming. Combination index analysis and xenograft animal model were conducted to explore the effects of combination of inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidative phosphorylation on tumor growth. RESULTS: We found that the expression of PRMT3 is upregulated in pancreatic cancer, and its expression is associated with poor survival. We identified GAPDH as a PRMT3-binding protein and demonstrated that GAPDH is methylated at R248 by PRMT3 in vivo. The methylation of GAPDH by PRMT3 enhanced its catalytic activity while the mutation of R248 abolished the effect. In cells, PRMT3 overexpression triggered metabolic reprogramming and enhanced glycolysis and mitochondrial respiration simultaneously in a GAPDH-dependent manner. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induced a synergistic inhibition on cellular growth in vitro and in vivo. CONCLUSION: Our results suggest that PRMT3 mediates metabolic reprogramming and cellular proliferation through methylating R248 of GAPDH, and double blockade of GAPDH and mitochondrial respiration could be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer.

Location, seasonal, and functional characteristics of water holding containers with juvenile and pupal Aedes aegypti in Southern Taiwan: A cross-sectional study using hurdle model analyses.

BACKGROUND: Aedes aegypti carries several viruses of public health importance, including the dengue virus. Dengue is the most rapidly spreading mosquito-borne viral disease in the world. Prevention and control of dengue mainly rely on mosquito control as there is no antiviral treatment or a WHO-approved vaccine. To reduce the Ae. aegypti population, studying the characteristics of their habitats is necessary. Aedes aegypti prefer breeding in artificial water holding containers in peridomestic or domestic settings. Their juveniles (1st - 4th instar larvae and pupae) have a tendency to cluster in certain types of containers. To inform control strategies, it is important to assess whether the pupae subgroup has a distinct distribution by container type as compared to the overall group of juveniles. The objective of this study was to assess for distinct predictors (location, season, and function) of Ae. aegypti juveniles and pupae numbers in water holding containers by applying hurdle model analyses. METHODOLOGY: The field component of this study was carried out from November 2013 to July 2015 in Southern Taiwan where annual autochthonous dengue has been reported for decades. Water holding containers with stagnant water were identified in a predefined urban area in Kaohsiung City (KH) and a rural area in Pingtung County. Given that mosquito survey data often include many containers with zero Ae. aegypti, a negative binomial hurdle model was applied to model the association between location, seasonal and functional characteristics of the water holding containers and the number of Ae. aegypti in each container. RESULTS: The results showed that Ae. aegypti were almost exclusively present in the urban area. In this area, the negative binomial hurdle model predicted significantly more juveniles as well as pupae Ae. aegypti in water holding containers during the wet season when compared to the dry season. Notably, the model predicted more juveniles in containers located on private property compared to those on government property, irrespective of season. As for pupae, the model predicted higher amounts in indoor containers used for water storage compared to outdoor water storage containers, irrespective of season. However, for the specific category 'other water receptacle', higher amounts of pupae were predicted in outdoor compared to indoor in water receptacles, such as flower pot saucers and water catchment buckets. CONCLUSIONS: The difference in predictors for juveniles and the pupae subgroup was identified and it may be of importance to the control strategies of the authorities in KH. At present the authorities focus control activities on all water holding containers found on government property. To improve the ongoing control efforts in KH, the focus of control activities maintained by the KH authorities should be expanded to indoor water storage containers and outdoor water receptacles on both private and government properties to adequately address habitats harboring greater numbers of pupae. In addition, it is proposed to increase community engagement in managing water in all types of water holding containers located on privately owned properties (indoor and outdoor), especially during wet season.

Manual acupuncture relieves bile acid-induced itch in mice: the role of microglia and TNF-α.

Pruritus, or itch, is a frequent complaint amongst patients with cholestatic hepatobiliary disease and is difficult to manage, with many patients refractory to currently available antipruritic treatments. In this study, we examined whether manual acupuncture (MA) at particular acupoints represses deoxycholic acid (DCA)-induced scratching behavior and microglial activation and compared these effects with those induced by another pruritogen, 5'-guanidinonaltrindole (GNTI, a kappa opioid receptor antagonist). MA at Hegu (LI4) and Quchi (LI11) acupoints significantly attenuated DCA- and GNTI-induced scratching, whereas no such effects were observed at the bilateral Zusanli acupoints (ST36). Interestingly, GNTI-induced scratching was reduced similarly by both MA and electroacupuncture (EA) at the LI4 and LI11 acupoints. MA at non-acupoints did not affect scratching behavior. Intraperitoneal injection of minocycline (a microglial inhibitor) reduced GNTI- and DCA-induced scratching behavior. In Western blot analysis, subcutaneous DCA injection to the back of the neck increased spinal cord expression of ionized calcium-binding adapter molecule 1 (Iba1) and tumor necrosis factor-alpha (TNF-α) as compared with saline injection, while MA at LI4 and LI11 reduced these DCA-induced changes. Immunofluorescence confocal microcopy revealed that DCA-induced Iba1-positive cells with thicker processes emanated from the enlarged cell bodies, while this effect was attenuated by pretreatment with MA. It is concluded that microglia and TNF-α play important roles in the itching sensation and MA reduces DCA-induced scratching behavior by alleviating spinal microglial activation. MA may be an effective treatment for cholestatic pruritus.