Bone Marrow-Derived Microglia-Based Neurturin Delivery Protects Against Dopaminergic Neurodegeneration in a Mouse Model of Parkinson\u27s Disease

Although neurotrophic factors have long been recognized as potent agents for protecting against neuronal degeneration, clinical success in treating Parkinson\u27s disease and other neurodegenerative disorders has been hindered by difficulties in delivery of trophic factors across the blood brain barrier (BBB). Bone marrow hematopoietic stem cell-based gene therapy is emerging as a promising tool for overcoming drug delivery problems, as myeloid cells can cross the BBB and are recruited in large numbers to sites of neurodegeneration, where they become activated microglia that can secrete trophic factors. We tested the efficacy of bone marrow-derived microglial delivery of neurturin (NTN) in protecting dopaminergic neurons against neurotoxin-induced death in mice. Bone marrow cells were transduced ex vivo with lentivirus expressing the NTN gene driven by a synthetic macrophage-specific promoter. Infected bone marrow cells were then collected and transplanted into recipient animals. Eight weeks after transplantation, the mice were injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropuridine (MPTP) for seven days to induce dopaminergic neurodegeneration. Microglia-mediated NTN delivery dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and their terminals in the striatum. Microglia-mediated NTN delivery also induced significant recovery of synaptic marker staining in the striatum of MPTP-treated animals. Functionally, NTN treatment restored MPTP-induced decline in general activity, rearing behavior, and food intake. Thus, bone marrow-derived microglia can serve as cellular vehicles for sustained delivery of neurotrophic factors capable of mitigating dopaminergic injury

Population Conflicts and Tropical Cyclones: Relationship with Birthweight and Stunting in Low and Middle-Income Countries

Population conflicts and tropical cyclones represent significant public health threats, particularly in low and middle-income countries, disrupting societies and profoundly impacting child health outcomes. Birthweight and stunting are key measures for assessing impacts of environmental, nutritional, and social stressors during early development. Although existing research suggests that conflicts and cyclones adversely affect birthweight and childhood stunting, most studies focus on single countries or events. Large-scale studies across multiple countries and extended periods are scarce. This dissertation combines geo-referenced data from various independent sources to examine the impacts of conflicts and cyclones on birthweight and stunting across multiple countries over time. Causal inference methods were used to evaluate potential interventions to mitigate these adversities.First, the impact of population conflicts on birthweight and stunting was investigated in Sub-Saharan African countries, using data from the 1990-2020 DHS and UCDP GED. Fixed effect regression models compared children in conflict-affected regions to those in unaffected areas, considering conflict intensity and duration. Results showed reduced birthweight and increased stunting odds for children exposed to conflicts, particularly girls in rural areas with less educated mothers and no healthcare autonomy. Second, the impact of tropical cyclones on birthweight and stunting was examined in Southern and Southeastern Asia using data from the 2000-2018 DHS and EM-DAT. Similar regression models were used. In-utero exposure to cyclones in the Philippines reduced birthweight, especially for children in rural areas. In Bangladesh and India, cyclones increased stunting odds, with more pronounced effects in girls and rural children with less educated mothers. No interactions between cyclones and conflicts were found. Lastly, hypothetical interventions were estimated using causal inference methods. Results indicated that preventing exposure to conflicts and cyclones could significantly increase birthweight and reduce stunting prevalence. In summary, these studies provide evidence of the adverse impacts of population conflicts and tropical cyclones on child growth and development, highlighting the need for effective prevention and adaptation strategies in low and middle-income countries. Addressing these issues aligns with the SDGs and offers insights for global public health interventions to mitigate environmental and social disruptions for vulnerable children

Neuroprotective Effects of dl-3-n-Butylphthalide against Doxorubicin-Induced Neuroinflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Behavioral Changes

Doxorubicin (DOX) is a broad-spectrum antitumor drug while its use is limited due to its neurobiological side effects associated with depression. We investigated the neuroprotective efficacy of dl-3-n-butylphthalide (dl-NBP) against DOX-induced anxiety- and depression-like behaviors in rats. dl-NBP was given (30 mg/kg) daily by gavage over three weeks starting seven days before DOX administration. Elevated plus maze (EPM) test, forced swimming test (FST), and sucrose preference test (SPT) were performed to assess anxiety- and depression-like behaviors. Our study showed that the supplementation of dl-NBP significantly mitigated the behavioral changes induced by DOX. To further explore the mechanism of neuroprotection induced by dl-NBP, several biomarkers including oxidative stress markers, endoplasmic reticulum (ER) stress markers, and neuroinflammatory cytokines in the hippocampus were quantified. The results showed that dl-NBP treatment alleviated DOX-induced neural apoptosis. Meanwhile, DOX-induced oxidative stress and ER stress in the hippocampus were significantly ameliorated in dl-NBP pretreatment group. Our study found that dl-NBP alleviated the upregulation of malondialdehyde (MDA), nitric oxide (NO), CHOP, glucose-regulated protein 78 kD (GRP-78), and caspase-12 and increased the levels of reduced glutathione (GSH) and activities of catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) in the hippocampus of rats exposed to DOX. Additionally, the gene expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) and protein levels of inducible nitric oxide synthase (iNOS) were significantly increased in DOX-treated group, whereas DOX-induced neuroinflammation was significantly attenuated in dl-NBP supplementation group. In conclusion, dl-NBP could alleviate DOX-induced anxiety- and depression-like behaviors via attenuating oxidative stress, ER stress, inflammatory reaction, and neural apoptosis, providing a basis as a therapeutic potential against DOX-induced neurotoxicity

Estimating Surface Soil Heat Flux in Permafrost Regions Using Remote Sensing-Based Models on the Northern Qinghai-Tibetan Plateau under Clear-Sky Conditions

The ground surface soil heat flux (G0) quantifies the energy transfer between the atmosphere and the ground through the land surface. However; it is difficult to obtain the spatial distribution of G0 in permafrost regions because of the limitation of in situ observation and complication of ground surface conditions. This study aims at developing an improved G0 parameterization scheme applicable to permafrost regions of the Qinghai-Tibet Plateau under clear-sky conditions. We validated several existing remote sensing-based models to estimate G0 by analyzing in situ measurement data. Based on the validation of previous models on G0; we added the solar time angle to the G0 parameterization scheme; which considered the phase difference problem. The maximum values of RMSE and MAE between “measured G0„ and simulated G0 using the improved parameterization scheme and in situ data were calculated to be 6.102 W/m2 and 5.382 W/m2; respectively. When the error of the remotely sensed land surface temperature is less than 1 K and the surface albedo measured is less than 0.02; the accuracy of estimates based on remote sensing data for G0 will be less than 5%. MODIS data (surface reflectance; land surface temperature; and emissivity) were used to calculate G0 in a 10 x 10 km region around Tanggula site; which is located in the continuous permafrost region with long-term records of meteorological and permafrost parameters. The results obtained by the improved scheme and MODIS data were consistent with the observation. This study enhances our understanding of the impacts of climate change on the ground thermal regime of permafrost and the land surface processes between atmosphere and ground surface in cold regions

Integrated metabolomics, transcriptomics, and proteomics analyses reveal co-exposure effects of polycyclic aromatic hydrocarbons and cadmium on ryegrass (Lolium perenne L.)

Cadmium (Cd) and polycyclic aromatic hydrocarbons (PAHs) are prominent soil contaminants found in industrial sites, and their combined effects on plants are not yet fully understood. To investigate the mechanisms underlying the co-exposure of Cd and PAHs and identify key biomarkers for their co-effects, an integrated analysis of metabolomics, transcriptomics, and proteomics was conducted on ryegrass leaves cultivated in soil. In nontarget metabolomics analysis, nine differentially expressed metabolites that were specifically induced by the compound exposure were identified. When combined with the analysis of differentially expressed genes and proteins, it was determined that the major pathways involved in the response to the co-stress of Cd and PAHs were linoleic acid metabolism and phenylpropanoid biosynthesis. The upregulation of 12,13-dihydroxy-9Z-octadecenoic acid and the downregulation of sinapyl alcohol were identified as typical biomarkers, respectively. Compared to scenarios of single exposures, the compound exposure to Cd and PAHs disrupted the oxidation of linoleic acid, leading to alterations in the profiles of linoleate metabolites. Additionally, it intensified hydroxylation, carboxylation, and methylation processes, and interfered with reactions involving coenzyme A, thus inhibiting lignin production. As a result, oxidative stress was elevated, and the cell wall defense system in ryegrass was weakened. The findings of this study highlight the ecological risks associated with unique biological responses in plants co-exposed to Cd and PAHs in polluted soils

Assessment of Different Complementary-Relationship-Based Models for Estimating Actual Terrestrial Evapotranspiration in the Frozen Ground Regions of the Qinghai-Tibet Plateau

Actual evapotranspiration (ETa) is important since it is an important link to water, energy, and carbon cycles. Approximately 96% of the Qinghai-Tibet Plateau (QTP) is underlain by frozen ground, however, the ground observations of ETa are particularly sparse–which is especially true in the permafrost regions–leading to great challenge for the accurate estimation of ETa. Due to the impacts of freeze-thaw cycles and permafrost degradation on the regional ET process, it is therefore urgent and important to find a reasonable approach for ETa estimation in the regions. The complementary relationship (CR) approach is a potential method since it needs only routine meteorological variables to estimate ETa. The CR approach, including the modified advection-aridity model by Kahler (K2006), polynomial generalized complementary function by Brutsaert (B2015) and its improved versions by Szilagyi (S2017) and Crago (C2018), and sigmoid generalized complementary function by Han (H2018) in the present study, were assessed against in situ measured ETa at four observation sites in the frozen ground regions. The results indicate that five CR-based models are generally capable of simulating variations in ETa, whether default and calibrated parameter values are employed during the warm season compared with those of the cold season. On a daily basis, the C2018 model performed better than other CR-based models, as indicated by the highest Nash-Sutcliffe efficiency (NSE) and lowest root mean square error (RMSE) values at each site. On a monthly basis, no model uniformly performed best in a specific month. On an annual basis, CR-based models estimating ETa with biases ranging from −94.2 to 28.3 mm year−1, and the H2018 model overall performed best with the smallest bias within 15 mm year−1. Parameter sensitivity analysis demonstrated the relatively small influence of each parameter varying within regular fluctuation magnitude on the accuracy of the corresponding model

Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. Neurosci Lett 535

Abstract Although neurotrophic factors have long been recognized as potent agents for protecting against neuronal degeneration, clinical success in treating Parkinson's disease and other neurodegenerative disorders has been hindered by difficulties in delivery of trophic factors across the blood brain barrier (BBB). Bone marrow hematopoietic stem cell-based gene therapy is emerging as a promising tool for overcoming drug delivery problems, as myeloid cells can cross the BBB and are recruited in large numbers to sites of neurodegeneration, where they become activated microglia that can secrete trophic factors. We tested the efficacy of bone marrow-derived microglial delivery of neurturin (NTN) in protecting dopaminergic neurons against neurotoxininduced death in mice. Bone marrow cells were transduced ex vivo with lentivirus expressing the NTN gene driven by a synthetic macrophage-specific promoter. Infected bone marrow cells were then collected and transplanted into recipient animals. Eight weeks after transplantation, the mice were injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropuridine (MPTP) for seven days to induce dopaminergic neurodegeneration. Microglia-mediated NTN delivery dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and their terminals in the striatum. Microglia-mediated NTN delivery also induced significant recovery of synaptic marker staining in the striatum of MPTP-treated animals. Functionally, NTN treatment restored MPTP-induced decline in general activity, rearing behavior