Antibiotic resistance is a pervasive global health threat. To combat the spread of resistance, it is necessary to consider all possible sources and understand the pathways and mechanisms by which ...resistance disseminates. Best management practices are urgently needed to provide barriers to the spread of resistance and maximize the lifespan of antibiotics as a precious resource. Herein we advise upon the need for coordinated national and international strategies, highlighting three essential components: (1) Monitoring, (2) Risk Assessment, and (3) Mitigation of antibiotic resistance. Central to all three components is What exactly to monitor, assess, and mitigate? We address this question within an environmental framework, drawing from fundamental microbial ecological processes driving the spread of resistance.
Chemotherapy-induced cognitive impairment, also known as “chemobrain,” is a common side effect. The purpose of this study was to examine whether resveratrol, a natural polyphenol that has nootropic ...effects, could prevent chemobrain and its underlying mechanisms. Mice received three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination, a common chemotherapy regimen, at two-day intervals within one week. Resveratrol (50 and 100 mg/kg per day) was orally administered for three weeks, beginning one week before the DAC treatment. Water maze test and manganese-enhanced magnetic resonance imaging were used to evaluate animals' cognitive performance and brain neuronal activity, respectively. Blood and brain tissues were collected for measurement of cytokines, cytokine regulators, and biomarkers for neuroplasticity. DAC treatment produced a striking cognitive impairment. Cotreatment with 100 mg/kg resveratrol ameliorated DAC-induced cognitive impairment and decreases in prefrontal and hippocampal neuronal activity. Mice co-treated with both doses of resveratrol displayed significantly lower levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but markedly higher levels of the anti-inflammatory cytokines IL-4 and IL-10 in several sera and brain tissues than those co-treated with vehicle. Resveratrol modulated the cytokine-regulating pathway peroxisome proliferator activated receptor (PPAR)-γ/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and protected against DAC-induced decreases in the expression of the neuroplasticity biomarkers, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), amino acid neurotransmitter receptors, and calmodulin-dependent protein kinase II (CaMKII). These results demonstrate the efficacy of resveratrol in preventing chemobrain and its association with cytokine modulation and neuroprotection.
•Chemotherapy-induced cognitive impairment (chemobrain) is a common side effect.•Resveratrol has nootropic, neuroprotective, and immunomodulatory effects.•Resveratrol prevented cognitive decline in mice treated with chemotherapy.•This preventive effect is related to cytokine modulation and neuroprotection.•Resveratrol is an effective agent in preventing chemobrain in cancer patients.
Drug development and biological discovery require effective strategies to map existing genetic associations to causal genes. To approach this problem, we selected 12 common diseases and quantitative ...traits for which highly powered genome-wide association studies (GWAS) were available. For each disease or trait, we systematically curated positive control gene sets from Mendelian forms of the disease and from targets of medicines used for disease treatment. We found that these positive control genes were highly enriched in proximity of GWAS-associated single-nucleotide variants (SNVs). We then performed quantitative assessment of the contribution of commonly used genomic features, including open chromatin maps, expression quantitative trait loci (eQTL), and chromatin conformation data. Using these features, we trained and validated an Effector Index (
Ei
), to map target genes for these 12 common diseases and traits.
Ei
demonstrated high predictive performance, both with cross-validation on the training set, and an independently derived set for type 2 diabetes. Key predictive features included coding or transcript-altering SNVs, distance to gene, and open chromatin-based metrics. This work outlines a simple, understandable approach to prioritize genes at GWAS loci for functional follow-up and drug development, and provides a systematic strategy for prioritization of GWAS target genes.
Chemotherapy-induced cognitive impairment, also known as “chemobrain,” is a common side effect. The purpose of this study was to examine whether ginsenoside Rg1, a ginseng-derived compound, could ...prevent chemobrain and its underlying mechanisms. A mouse model of chemobrain was developed with three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination at a 2-day interval. Rg1 (5 and 10 mg/kg daily) was given 1 week prior to DAC regimen for 3 weeks. An amount of 10 mg/kg Rg1 significantly improved chemobrain-like behavior in water maze test. In vivo neuroimaging revealed that Rg1 co-treatment reversed DAC-induced decreases in prefrontal and hippocampal neuronal activity and ameliorated cortical neuronal dendritic spine elimination. It normalized DAC-caused abnormalities in the expression of multiple neuroplasticity biomarkers in the two brain regions. Rg1 suppressed DAC-induced elevation of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but increased levels of the anti-inflammatory cytokines IL-4 and IL-10 in multiple sera and brain tissues. Rg1 also modulated cytokine mediators and inhibited DAC-induced microglial polarization from M2 to M1 phenotypes. In in vitro experiments, while impaired viability of PC12 neuroblastic cells and hyperactivation of BV-2 microglial cells, a model of neuroinflammation, were observed in the presence of DAC, Rg1 co-treatment strikingly reduced DAC’s neurotoxic effects and neuroinflammatory response. These results indicate that Rg1 exerts its anti-chemobrain effect in an association with the inhibition of neuroinflammation by modulating microglia-mediated cytokines and the related upstream mediators, protecting neuronal activity and promoting neuroplasticity in particular brain regions associated with cognition processing.
Chemotherapy-induced cognitive impairment, often referred to as “chemobrain,” is a common side effect. In this study, mice received three intraperitoneal injections of a combination of docetaxel, ...adriamycin, and cyclophosphamide (DAC) at 2-day intervals. A water maze test was used to examine cognitive performance, and manganese-enhanced magnetic resonance imaging (MEMRI) was used to examine hippocampal neuronal activity. The whole brain, prefrontal cortex, hippocampus, and blood samples were then collected for cytokine measurement. The DAC-treated mice displayed a significantly shorter duration spent in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In a separate experiment using in vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines without changing the rate of spine formation, leading to a striking loss of spines in the medial prefrontal cortex. DAC treatment resulted in significant elevations in the levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) and in significant decreases in the levels of the anti-inflammatory cytokines IL-4 and IL-10 in most of the sera and brain tissues examined. The IL-6 and TNF-α levels of several sera and brain tissues showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain.
Erythrophagocytosis by reparative monocyte-derived macrophage contributes to hematoma clearance and neurological recovery after intracerebral hemorrhage (ICH). Vitamin D (VitD) is a neuroprotective ...hormone and regulates the differentiation of monocyte-derived macrophage from monocytes. In this study, we examined the effects of VitD supplementation on monocyte-derived macrophage and hematoma clearance in rodent with ICH.
Neurobehavioral functions and hematoma volume were assessed using a collagenase injection model in both young- and middle-aged mice with or without VitD treatment given 2 hours post-ICH induction. We used flow cytometry to analyze CD36 expression and macrophage and undifferentiated monocyte cell numbers during in vivo erythrophagocytosis in collagenase and autologous blood injection models. Western blot analysis and immunofluorescence were used to assess the expression levels of the PPAR-γ (peroxisome proliferator-activated receptor γ)-CD36 axis and CD206. A macrophage differentiation study was conducted on murine bone marrow-derived monocytes.
VitD promoted neurological recovery and facilitated hematoma clearance in both young- and middle-aged mice after ICH. Within the perihematomal region, mature macrophages, rather than undifferentiated monocytes, expressed higher levels of CD36 in driving erythrocyte clearance. VitD increased the macrophage number but decreased the monocyte number and elevated the levels of CD36 and PPAR-γ in the brain. In vitro, VitD accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes.
VitD promotes reparative macrophage differentiation, facilitates hematoma clearance, and improves neurobehavioral performance in mice with ICH, suggesting that VitD should be further examined as a potentially promising treatment for ICH.
Brain possesses a complex spatiotemporal architecture for efficient information processing and computing. However, it remains unknown how neural signal propagates to its intended targets brain-wide. ...Using optogenetics and functional MRI, we arbitrarily initiated various discrete neural activity pulse trains with different temporal patterns and revealed their distinct long-range propagation targets within the well-defined, topographically organized somatosensory thalamo-cortical circuit. We further observed that such neural activity propagation over long range could modulate brain-wide sensory functions. Electrophysiological analysis indicated that distinct propagation pathways arose from system level neural adaptation and facilitation in response to the neural activity temporal characteristics. Together, our findings provide fundamental insights into the long-range information transfer and processing. They directly support that temporal coding underpins the whole brain functional architecture in presence of the vast and relatively static anatomical architecture.
Blood oxygen level-dependent functional MRI (fMRI) constitutes a powerful neuroimaging technology to map brain-wide functions in response to specific sensory or cognitive tasks. However, fMRI mapping ...of the vestibular system, which is pivotal for our sense of balance, poses significant challenges. Physical constraints limit a subject’s ability to perform motion- and balance-related tasks inside the scanner, and current stimulation techniques within the scanner are nonspecific to delineate complex vestibular nucleus (VN) pathways. Using fMRI, we examined brain-wide neural activity patterns elicited by optogenetically stimulating excitatory neurons of a major vestibular nucleus, the ipsilateral medial VN (MVN). We demonstrated robust optogenetically evoked fMRI activations bilaterally at sensorimotor cortices and their associated thalamic nuclei (auditory, visual, somatosensory, and motor), high-order cortices (cingulate, retrosplenial, temporal association, and parietal), and hippocampal formations (dentate gyrus, entorhinal cortex, and subiculum). We then examined the modulatory effects of the vestibular system on sensory processing using auditory and visual stimulation in combination with optogenetic excitation of the MVN. We found enhanced responses to sound in the auditory cortex, thalamus, and inferior colliculus ipsilateral to the stimulated MVN. In the visual pathway, we observed enhanced responses to visual stimuli in the ipsilateral visual cortex, thalamus, and contralateral superior colliculus. Taken together, our imaging findings reveal multiple brain-wide central vestibular pathways. We demonstrate large-scale modulatory effects of the vestibular system on sensory processing.
Metal-organic frameworks (MOFs) are attracting increasing interests as photocatalysts for solar-driven hydrogen production from water. This paper reports on a comparative study of using either acetic ...acid (AA) or trifluoroacetic acid (TFA) as the representative UiO-66 organic modulators for synthesizing visible light responsive UiO-66(Zr)-X (X: NH
2
or NO
2
) photocatalysts for water splitting. The results show that photocatalytic hydrogen generation from a water/methanol mixture can be improved by varying the nature and amount of the modulator employed to prepare the different UiO-66(Zr)-X (X: NH
2
or NO
2
) solid derivatives. UiO-66(Zr)-NH
2
was the most active photocatalyst, followed by UiO-66(Zr)-NO
2
, both prepared with 12 equivalents of AA with respect to the organic ligand. This UiO-66(Zr)-NH
2
solid was more active than the parent MOF in photocatalytic overall water splitting (OWS) (H
2
and O
2
production of 450 and 160 µmol·g
−1
, respectively, in 5 h; apparent quantum yield (AQY) at 400 nm of 0.06%) in the absence of methanol and compares favourably with analogous reports. Information on the photocatalytic activity of the most active solids of both series was obtained by means of a series of techniques, including ultraviolet–visible (UV–vis) diffuse reflectance, X-ray photoelectron spectroscopy (XPS), laser flash photolysis (LFP), electron spin resonance (ESR), photoluminescence and photoelectrochemical measurements together with density functional theory (DFT) calculations. The results showed that organic acid modulators can be used to enhance the photocatalytic activity of missing linker UiO-66 defective materials in solar-powered water splitting.
Altered cerebral glucose uptake is one of the hallmarks of Alzheimer's disease (AD). A dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) approach was developed to simultaneously monitor ...d-glucose uptake and clearance in both brain parenchyma and cerebrospinal fluid (CSF). We observed substantially higher uptake in parenchyma of young (6 months) transgenic AD mice compared to age-matched wild-type (WT) mice. Notably lower uptakes were observed in parenchyma and CSF of old (16 months) AD mice. Both young and old AD mice had an obviously slower CSF clearance than age-matched WT mice. This resembles recent reports of the hampered CSF clearance that leads to protein accumulation in the brain. These findings suggest that DGE MRI can identify altered glucose uptake and clearance in young AD mice upon the emergence of amyloid plaques. DGE MRI of brain parenchyma and CSF has potential for early AD stratification, especially at 3T clinical field strength MRI.
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