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Ischemic stroke remains a leading cause of death and long-term disability, yet effective treatments that promote recovery beyond the acute phase are lacking. Neuregulin-1 (NRG-1) has shown potent neuroprotective and anti-inflammatory properties in preclinical stroke models, with evidence of enhanced neuronal regeneration when administered after injury. To investigate the spatial mechanisms underlying its neuroregenerative therapeutic effects, we examined brain proteomic responses to post-ischemic NRG-1 treatment in mice using NanoString Digital Spatial Profiling (DSP). Adult C57BL/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and treated with NRG-1β (5 μg/kg/day) or vehicle at 24- and 48-h post-stroke. Brains were collected at 3 days post-ischemia for spatial proteomic analysis of 68 neural proteins across the ischemic core, peri-infarct tissue, and peri-infarct normal tissue (PiNT). While NRG-1 did not significantly alter overall neuronal death, it markedly reshaped the neuroregenerative milieu, upregulating myelin basic protein (MBP) and synaptophysin and attenuating inflammatory mediators (SPP1, P2RX7, and CD39). NRG-1 also enhanced expression of autophagy and mitophagy markers (ULK1, LC3B, ATG5, PINK1, and Park7), suggesting restoration of cellular clearance and mitochondrial quality control. Pathway and network analyses revealed activation of neuroregeneration, autophagy, and lysosomal biogenesis pathways, while suppressing neuroinflammatory signaling. These findings demonstrate that delayed NRG-1 therapy, even when initiated 24 h after stroke, induces early molecular programs that prime an anti-inflammatory and neuroregenerative environment. The results support further development of NRG-1 as a clinically translatable, multimodal therapy for extending the post-stroke treatment window and promoting functional recovery.

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

Stroke is ranked as the fifth leading cause of death and the leading cause of adult disability in the USA. The progression of neuronal damage after stroke is recognized to be a complex integration of glia, neurons, and the surrounding extracellular matrix, therefore potential treatments must target the detrimental effects created by these interactions. In this study, we examined the spatial cellular and neuroinflammatory mechanisms occurring early after ischemic stroke utilizing Nanostring Digital Spatial Profiling (DSP) technology. Male C57bl/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and sacrificed at 3 days post-ischemia. Spatial distinction of the ipsilateral hemisphere was studied according to the regions of interest: the ischemic core, peri-infarct tissues, and peri-infarct normal tissue (PiNT) in comparison to the contralateral hemisphere. We demonstrated that the ipsilateral hemisphere initiates distinct spatial regulatory proteomic profiles with DSP technology that can be identified consistently with the immunohistochemical markers, FJB, GFAP, and Iba-1. The core border profile demonstrated an induction of neuronal death, apoptosis, autophagy, immunoreactivity, and early degenerative proteins. Most notably, the core border resulted in a decrease of the neuronal proteins Map2 and NeuN; an increase in the autophagy proteins BAG3 and CTSD; an increase in the microglial and peripheral immune invasion proteins Iba1, CD45, CD11b, and CD39; and an increase in the neurodegenerative proteins BACE1, APP, amyloid β 1–42, ApoE, and hyperphosphorylated tau protein S-199. The peri-infarct region demonstrated increased astrocytic, immunoreactivity, apoptotic, and neurodegenerative proteomic profiles, with an increase in BAG3, GFAP, and hyperphosphorylated tau protein S-199. The PiNT region displayed minimal changes compared to the contralateral cortex with only an increase in GFAP. In this study, we showed that mechanisms known to be associated with stroke, such as apoptosis and inflammation, occur in distinct spatial domains of the injured brain following ischemia. We also demonstrated the dysregulation of specific autophagic pathways that may lead to neurodegeneration in peri-infarct brain tissues. Taken together, these data suggest that identifying post-ischemic mechanisms occurring in a spatiotemporal manner may lead to more precise targets for successful therapeutic interventions to treat stroke.

Identifying novel neuroprotectants that can halt or reverse the neurological effects of stroke is of interest to both clinicians and scientists. We and others previously showed the pre-clinical neuroprotective efficacy of neuregulin-1 (NRG-1) in rats following focal brain ischemia. In this study, we examined neuroprotection by exogenous and endogenous NRG-1 using a mouse model of ischemic stroke. C57BL6 mice were subjected to middle cerebral artery occlusion (MCAO) followed by reperfusion. NRG-1 or vehicle was infused intra-arterially (i.a.) or intravenously (i.v.) after MCAO and before the onset of reperfusion. NRG-1 treatment (16 μg/kg; i.a.) reduced cerebral cortical infarct volume by 72% in mice when delivered post-ischemia. NRG-1 also inhibited neuronal injury as measured by Fluoro Jade B labeling and rescued NeuN immunoreactivity in neurons. Neuroprotection by NRG-1 was also observed in mice when administered i.v. (100 μg/kg) in both male and female mice. We investigated whether endogenous NRG-1 was neuroprotective using male and female heterozygous NRG-1 knockout mice (NRG-1+/−) compared with wild-type mice (WT) littermates. NRG-1+/− and WT mice were subjected to MCAO for 45 min, and infarct size was measured 24 h following MCAO. NRG-1+/− mice displayed a sixfold increase in cortical infarct size compared with WT mice. These results demonstrate that NRG-1 treatment mitigates neuronal damage following cerebral ischemia. We further showed that reduced endogenous NRG-1 results in exacerbated neuronal injury in vivo. These findings suggest that NRG-1 represents a promising therapy to treat stroke in human patients.

Stroke is ranked as the fifth leading cause of death and the leading cause of adult disability. Unfortunately, Tissue Plasminogen Activator is the only FDA approved stroke treatment but does not address acute injury or cerebral recovery. Neuregulin-1 (NRG-1) has demonstrated promise as an acute neuroprotective, anti-inflammatory, and neuroregenerative agent in animal stroke models. In this dissertation, we examined the spatial cellular and inflammatory mechanisms occurring early after ischemic stroke and with NRG-1 treatment. Exogenous NRG-1 treatment administered to C57bl/6 male and female mice via intra-arterial or intravenous routes significantly reduced cerebral cortical infarct volume, inhibited neuronal injury, and reduced apoptosis at 24-hours after MCAO. Neuroprotection by endogenous NRG-1 was also seen as male and female heterozygous NRG-1 (NRG-1 +/-) knockout mice demonstrated a sixfold increase in cortical infarct size compared to wild-type mice. Immunohistochemistry and Nanostring Digital Spatial Profiling (DSP) were then utilized to characterize the spatial mechanisms occurring early after ischemia and determine if NRG-1 plays a therapeutic role in a similar spatial manner. Male C57bl/6 mice were given a photothrombotic MCAO and sacrificed at three-days post-ischemia. We demonstrated that the ipsilateral hemisphere initiates distinct spatial regulatory proteomic profiles that can be identified consistently with the immunohistochemical markers, FJB, GFAP, and Iba-1. DSP defined the core border profile as inducing neuronal death, apoptosis, immunoreactivity, and early degenerative proteins. The peri-infarct induced astrocytic immunoreactivity, autophagy, and neurodegenerative proteins, while the peri-infarct normal tissue demonstrated minimal changes. These profiles were then analyzed after daily NRG-1 treatment beginning at 24-hours after ischemic onset. We found no difference in FJB, Iba-1, or GFAP expression between treatment groups. However, delayed daily NRG-1 treatment induced proteomic changes indicating restoration of autophagy and mitophagy within neurons and myeloid cells within the ischemic core border and peri-infarct regions as early as three days post-ischemia, suggesting neuronal resistance to apoptosis and priming for an anti-inflammatory and neuroregenerative niche. Therefore, we identify NRG-1 as a potent ischemic therapeutic capable of inducing immediate and late neuroprotection, early neuroregeneration, and extending the therapeutic treatment window.

Stroke is ranked as the fifth leading cause of death and the leading cause of adult disability. The progression of neuronal damage after stroke is recognized to be a complex integration of glia, neurons, and the surrounding extracellular matrix, therefore potential treatments must target the detrimental effects created by these interactions. In this study, we examined the spatial cellular and neuroinflammatory mechanisms occurring early after ischemic stroke utilizing Nanostring Digital Spatial Profiling (DSP) technology. Male C57bl/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and sacrificed at three-days post-ischemia. Spatial distinction of the ipsilateral hemisphere was studied according to the regions of interest: the ischemic core, peri-infarct tissues, and peri-infarct normal tissue (PiNT) in comparison to the contralateral hemisphere. We demonstrated that the ipsilateral hemisphere initiates distinct spatial regulatory proteomic profiles with DSP technology that can be identified consistently with the immunohistochemical markers, FJB, GFAP, and Iba-1. The core border profile demonstrated an induction of neuronal death, apoptosis, autophagy, immunoreactivity, and early degenerative proteins. Most notably, the core border resulted in a decrease of the neuronal proteins Map2 and NeuN, an increase in the autophagy proteins BAG3 and CTSD, an increase in the microglial and peripheral immune invasion proteins Iba1, CD45, CD11b, and CD39, and an increase in the neurodegenerative proteins BACE1, APP, αβ 1-42, ApoE, and hyperphosphorylated tau protein S-199. The peri-infarct region demonstrated increased astrocytic immunoreactivity, apoptotic, and neurodegenerative proteomic profile, with an increase in BAG3, GFAP, and hyperphosphorylated tau protein S-199. The PiNT region displayed minimal changes compared to the contralateral cortex with only an increase in GFAP. Overall, our data highlight the importance of identifying ischemic mechanisms in a spatial manner to understand the complex, dynamic interactions throughout ischemic progression and repair as well to introduce potential targets for successful therapeutic interventions.

We present observations obtained with the Near Infrared Spectrograph on JWST of the five Jupiter Trojans that will be visited by the Lucy spacecraft—the Patroclus–Menoetius binary, Eurybates, Orus, Leucus, and Polymele. The measured 1.7–5.3 μm reflectance spectra, which provide increased wavelength coverage, spatial resolution, and signal-to-noise ratio over previous ground-based spectroscopy, reveal several distinct absorption features. We detect a broad OH band centered at 3 μm that is most prominent on the less-red objects Eurybates, Patroclus–Menoetius, and Polymele. An additional absorption feature at 3.3–3.6 μm, indicative of aliphatic organics, is systematically deeper on the red objects Orus and Leucus. The collisional fragment Eurybates is unique in displaying an absorption band at 4.25 μm that we attribute to bound or trapped CO2. Comparisons with other solar system small bodies reveal broad similarities in the 2.7–3.6 μm bands with analogous features on Centaurs, Kuiper Belt objects (KBOs), and the active asteroid 238P. In the context of recent solar system evolution models, which posit that the Trojans initially formed in the outer solar system, the significant attenuation of the 2.7–3.6 μm absorption features on Trojans relative to KBOs may be the result of secondary thermal processing of the Trojans’ surfaces at the higher temperatures of the Jupiter region. The CO2 band manifested on the surface of Eurybates suggests that CO2 may be a major constituent in the bulk composition of Trojans, but resides in the subsurface or deeper interior and is largely obscured by refractory material that formed from the thermophysical processes that were activated during their inward migration.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused more than 760 million cases and over 6.8 million deaths as of March 2023. Vaccination has been the main strategy used to contain the spread of the virus and to prevent hospitalizations and deaths. Currently, two mRNA-based vaccines and one adenovirus-vectored vaccine have been approved and are available for use in the U.S. population. The versatility, low cost, and rapid production of DNA vaccines provide important advantages over other platforms. Additionally, DNA vaccines efficiently induce both B- and T-cell responses by expressing the antigen within transfected host cells, and the antigen, after being processed into peptides, can associate with MHC class I or II of antigen-presenting cells (APCs) to stimulate different T cell responses. However, the efficiency of DNA vaccination needs to be improved for use in humans. Importantly, in vivo DNA delivery combined with electroporation (EP) has been used successfully in the field of veterinary oncology, resulting in high rates of response after electrochemotherapy. Here, we evaluate the safety, immunogenicity, and protective efficacy of a novel linear SARS-CoV-2 DNA vaccine candidate delivered by intramuscular injection followed by electroporation (Vet-ePorator™) in ferrets. The linear SARS-CoV-2 DNA vaccine candidate did not cause unexpected side effects. Additionally, the vaccine elicited neutralizing antibodies and T cell responses on day 42 post-immunization using a low dose of the linear DNA construct in a prime-boost regimen. Most importantly, vaccination significantly reduced shedding of infectious SARS-CoV-2 through oral and nasal secretions in a ferret model.

The last decades of neuroscience research have produced immense progress in the methods available to understand brain structure and function. Social, cognitive, clinical, affective, economic, communication, and developmental neurosciences have begun to map the relationships between neuro-psychological processes and behavioral outcomes, yielding a new understanding of human behavior and promising interventions. However, a limitation of this fast moving research is that most findings are based on small samples of convenience. Furthermore, our understanding of individual differences may be distorted by unrepresentative samples, undermining findings regarding brain–behavior mechanisms. These limitations are issues that social demographers, epidemiologists, and other population scientists have tackled, with solutions that can be applied to neuroscience. By contrast, nearly all social science disciplines, including social demography, sociology, political science, economics, communication science, and psychology, make assumptions about processes that involve the brain, but have incorporated neural measures to differing, and often limited, degrees; many still treat the brain as a black box. In this article, we describe and promote a perspective—population neuroscience—that leverages interdisciplinary expertise to (i) emphasize the importance of sampling to more clearly define the relevant populations and sampling strategies needed when using neuroscience methods to address such questions; and (ii) deepen understanding of mechanisms within population science by providing insight regarding underlying neural mechanisms. Doing so will increase our confidence in the generalizability of the findings. We provide examples to illustrate the population neuroscience approach for specific types of research questions and discuss the potential for theoretical and applied advances from this approach across areas.

We estimated the reactive nitrogen (Nr) lost per unit food Nr consumed for organic food production in the United States and compared it to conventional production. We used a nitrogen footprint model approach, which accounts for both differences in Nr losses as well as differences in productivity of the two systems. Additionally, we quantified the types of Nr inputs (new versus recycled) that are used in both production systems. We estimated Nr losses from organic crop and animal production to be of comparable magnitude to conventional production losses, with the exception of beef. While Nr losses from organic vegetables are possibly higher (+37%), Nr losses from organic grains, starchy roots, legumes are likely of similar magnitude to conventional production (+7%, +6%, −12%, respectively). Nr losses from organic poultry, pigmeat, and dairy production are also likely comparable to conventional production (+9%, +10%, +12%, respectively), while Nr losses from organic beef production were estimated to be higher (+124%). Due to the high variability and high uncertainty in Nr efficiency in both systems we cannot make conclusions yet on the statistical significance of these potential differences. Conventional production relies heavily on the creation of new Nr (70%-90% of inputs are from new Nr sources like synthetic fertilizer), whereas organic production primarily utilizes already existing Nr (0%-50% of organic inputs are from new Nr sources like leguminous N fixation). Consuming organically produced foods has little impact on an individual's food N footprint but changes the percentage of new versus recycled Nr in the footprint. With the exception of beef, Nr losses from organic production per unit N in product are comparable to conventional production. However, organic production requires the creation of less new Nr, which could reduce global Nr pollution.