For the continuation and evolution of life, primitive membranes formed from prebiotically available components must have fulfilled certain essential requirements. Candidate amphiphiles, such as ...straight-chain fatty acids, that can self-assemble into cell-like structures have been shown to be capable of performing many life-like functions. However, obstacles that preclude a cohesive description of the evolution of modern-day cells from the origins of primitive membranes remain. Terpenoids are uniquely placed in terms of their derivation and chemical motifs to play an important role in primitive membranes, as they do in extant cells. Here, we discuss the principles behind primitive membrane formation and offer a biophysics perspective regarding the potential role of terpenoids in membrane function. By doing so, we identify opportunities in the realm of protocell research.
•A tight-fitting helmet-shape receive array with a single transmit loop for anesthetized macaque brain MRI at 7T was fabricated with four openings constructed to accommodate multimodal neuroimaging ...and neurostimulation devices.•The coil provides satisfactory transmit efficiency / homogeneity, signal coverage and SNR over the macaque brain.•Promising results obtained by combining fMRI with infrared neural stimulation, focused ultrasound stimulation, or transcranial direct current stimulation.•This pilot study reveals the opportunity for brain investigation at multiple spatiotemporal scales, which may advance our understanding in dynamic brain networks.
Blood-oxygen-level-dependent functional MRI allows to investigte neural activities and connectivity. While the non-human primate plays an essential role in neuroscience research, multimodal methods combining functional MRI with other neuroimaging and neuromodulation enable us to understand the brain network at multiple scales.
In this study, a tight-fitting helmet-shape receive array with a single transmit loop for anesthetized macaque brain MRI at 7T was fabricated with four openings constructed in the coil housing to accommodate multimodal devices, and the coil performance was quantitatively evaluated and compared to a commercial knee coil. In addition, experiments over three macaques with infrared neural stimulation (INS), focused ultrasound stimulation (FUS), and transcranial direct current stimulation (tDCS) were conducted.
The RF coil showed higher transmit efficiency, comparable homogeneity, improved SNR and enlarged signal coverage over the macaque brain. Infrared neural stimulation was applied to the amygdala in deep brain region, and activations in stimulation sites and connected sites were detected, with the connectivity consistent with anatomical information. Focused ultrasound stimulation was applied to the left visual cortex, and activations were acquired along the ultrasound traveling path, with all time course curves consistent with pre-designed paradigms. The existence of transcranial direct current stimulation electrodes brought no interference to the RF system, as evidenced through high-resolution MPRAGE structure images.
This pilot study reveals the feasibility for brain investigation at multiple spatiotemporal scales, which may advance our understanding in dynamic brain networks.
An Australian estuarine isolate of Penicillium sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide ...opioid agonists, we elucidated that they were weak (K
i low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist (K
i 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit β-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting β-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.
To map in vivo cortical circuitry at the mesoscale, we applied a novel approach to map interareal functional connectivity. Electrical intracortical microstimulation (ICMS) in conjunction with optical ...imaging of intrinsic signals (OIS) was used map functional connections in somatosensory cortical areas in anesthetized squirrel monkeys. ICMS produced activations that were focal and that displayed responses which were stimulation intensity dependent. ICMS in supragranular layers of Brodmann Areas 3b, 1, 2, 3a, and M1 evoked interareal activation patterns that were topographically appropriate and appeared consistent with known anatomical connectivity. Specifically, ICMS revealed Area 3b connections with Area 1; Area 1 connections with Areas 2 and 3a; Area 2 connections with Areas 1, 3a, and M1; Area 3a connections with Areas M1, 1, and 2; and M1 connections with Areas 3a, 1, and 2. These somatosensory connectivity patterns were reminiscent of feedforward patterns observed anatomically, although feedback contributions are also likely present. Further consistent with anatomical connectivity, intra‐areal and intra‐areal patterns of activation were patchy with patch sizes of 200–300 μm. In summary, ICMS with OIS is a novel approach for mapping interareal and intra‐areal connections in vivo. Comparisons with feedforward and feedback anatomical connectivity are discussed.
By combining intracortical electrical microstimulation (ICMS) with intrinsic optical imaging, we find that focal ICMS at single digit locations in monkey cortex (Areas 3a, 3b, 1, 2, and M1) reveals known anatomical connections. This novel method of studying cortical connections is in vivo, rapid, targeted, and mesoscale.
The retina is known to have a local renin-angiotensin system (RAS) and dysfunction in the RAS is often associated with diseases of the retinal vasculature that cause irreversible vision loss. ...Regulation of the retinal vasculature to meet the metabolic needs of the tissues occurs through a mechanism called neurovascular coupling, which is critical for maintaining homeostatic function and support for neurons. Neurovascular coupling is the process by which support cells, including glia, regulate blood vessel calibre and blood flow in response to neural activity. In retinal vascular diseases, this coupling mechanism is often disrupted. However, the role that angiotensin II (Ang II), the main effector peptide of the RAS, has in regulating both the retinal vasculature and neurovascular coupling is not fully understood. As components of the RAS are located on the principal neurons, glia and blood vessels of the retina, it is possible that Ang II has a role in regulating communication and function between these three cell types, and therefore the capacity to regulate neurovascular coupling. This review focuses on components of the RAS located on the retinal neurovascular unit, and the potential of this system to contribute to blood flow modulation in the healthy and compromised retina.
•The retina has its own independent renin-angiotensin system.•Regulation of the vasculature by glia may involve the renin-angiotensin system.•Microglia are immune cells that may be involved in modulation of the renin-angiotensin system.•Retinal vascular diseases are associated with anomalies in renin-angiotensin signalling.
•Both CUMS and chronic CORT treatment induced depressive-like behavior and comorbid hyperalgesia.•Both treatments resulted in similar changes of plasma hormone and cytokine levels.•Two treatments ...resulted in different immune responds in the different brain regions.
Recent studies have indicated that inflammatory pathways and hypothalamic-pituitary-adrenal (HPA) axis function may be responsible for the interaction between pain and depression.
Animals were examined for depressive and painful behavior following exposure to chronic unpredictable mild stress (CUMS) and chronic corticosterone (CORT) treatment. Subsequently, serum cytokines, adrenocorticotropic hormone (ACTH) and CORT were measured by enzyme-linked immunosorbent assay (ELISA). mRNA expression of cytokines in the brain were measured by quantitative PCR (qPCR).
The present study found that both CUMS and chronic CORT treatment induced behavioral changes of depression comorbid hyperalgesia. Moreover, both the treatments increased levels of serum ACTH, CORT, and cytokines including tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL1ß), interleukin 6 (IL6), and Caspase 1 (CASP1). Following CUMS, Il1ß levels were found to be elevated in all examined regions, including the raphe nuclei, thalamus, hippocampus, prefrontal cortex, and pituitary. In the raphe nuclei particularly, CUMS elevated all examined cytokine levels. Chronic CORT treatment, however, produced Il1ß elevation in the hippocampus and the pituitary, with showing elevated levels in all examined cytokines.
To clarify the causal relationship between behavioral changes and altered cytokine levels via either antidepressant treatment or blockage of pre-inflammatory cytokine production, further studies should be conducted.
Despite similar behavioral consequences, hypercortisolism and peripheral inflammation, CUMS and chronic CORT treatment seem to produce differing inflammatory brain responses.
Abstract Cutting edge advances in electrical visual cortical prosthetics have evoked perception of shapes, motion, and letters in the blind. Here, we present an alternative optical approach using ...pulsed infrared neural stimulation. To interface with dense arrays of cortical columns with submillimeter spatial precision, both linear array and 100-fiber bundle array optical fiber interfaces were devised. We deliver infrared stimulation through these arrays in anesthetized cat visual cortex and monitor effects by optical imaging in contralateral visual cortex. Infrared neural stimulation modulation of response to ongoing visual oriented gratings produce enhanced responses in orientation-matched domains and suppressed responses in non-matched domains, consistent with a known higher order integration mediated by callosal inputs. Controls include dynamically applied speeds, directions and patterns of multipoint stimulation. This provides groundwork for a distinct type of prosthetic targeted to maps of visual cortical columns.
Self-assembling single-chain amphiphiles available in the prebiotic environment likely played a fundamental role in the advent of primitive cell cycles. However, the instability of prebiotic fatty ...acid-based membranes to temperature and pH seems to suggest that primitive cells could only host prebiotically relevant processes in a narrow range of nonfluctuating environmental conditions. Here we propose that membrane phase transitions, driven by environmental fluctuations, enabled the generation of daughter protocells with reshuffled content. A reversible membrane-to-oil phase transition accounts for the dissolution of fatty acid-based vesicles at high temperatures and the concomitant release of protocellular content. At low temperatures, fatty acid bilayers reassemble and encapsulate reshuffled material in a new cohort of protocells. Notably, we find that our disassembly/reassembly cycle drives the emergence of functional RNA-containing primitive cells from parent nonfunctional compartments. Thus, by exploiting the intrinsic instability of prebiotic fatty acid vesicles, our results point at an environmentally driven tunable prebiotic process, which supports the release and reshuffling of oligonucleotides and membrane components, potentially leading to a new generation of protocells with superior traits. In the absence of protocellular transport machinery, the environmentally driven disassembly/assembly cycle proposed herein would have plausibly supported protocellular content reshuffling transmitted to primitive cell progeny, hinting at a potential mechanism important to initiate Darwinian evolution of early life forms.
Radiotherapy (RT) has become one of the most widely used treatments for malignant tumors in clinics. Developing a novel radiosensitizer for the integration of precise diagnosis and effective ...radiotherapy against hypoxic tumors is desirable but remains a great challenge. Herein, protein sulfenic acid reactive gold nanoparticles as effective radiosensitizers were for the first time reported for enhanced X-ray computed tomography (CT) imaging and radiotherapy of tumors in vivo. The gold nanoparticles were decorated with biocompatible poly(ethylene glycol), folic acid (FA), and sulfenic acid reactive groups 1,3-cyclohexanedione (CHD). Such a nanostructure enables on-site immobilization within tumors under oxidative stress through the specific reaction between CHD and endogenous protein sulfenic acids resulting in enhanced accumulation and retention of gold nanoparticles within tumors, which remarkably improves the sensitivity of CT imaging and the radiotherapeutic efficacy of tumors in living mice. This study thus is the first to demonstrate that protein sulfenic acid reactive gold nanoparticles with a tumor anchoring function may serve as effective radiosensitizers for clinical X-ray theranostic application in the future.
Recent studies have highlighted the importance of understanding the architecture and function of microvasculature, and dysfunction of these microvessels may underlie neurodegenerative disease. Here, ...we utilize a high-precision ultrafast laser-induced photothrombosis (PLP) method to occlude single capillaries and then quantitatively study the effects on vasodynamics and surrounding neurons. Analysis of the microvascular architecture and hemodynamics after single-capillary occlusion reveals distinct changes upstream vs. downstream branches, which shows rapid regional flow redistribution and local downstream blood-brain barrier (BBB) leakage. Focal ischemia via capillary occlusions surrounding labeled target neurons induces dramatic and rapid lamina-specific changes in neuronal dendritic architecture. Further, we find that micro-occlusion at two different depths within the same vascular arbor results in distinct effects on flow profiles in layers 2/3 vs layer 4. The current results reveal laminar-scale regulation distinctions in microinfarct response and raise the possibility that relatively greater impacts on microvascular function contribute to cognitive decline in neurodegenerative disease.
Display omitted
•Single-capillary occlusion leads to rapid regional blood flow autoregulation•Focal capillary occlusions induce signs of neuronal degenerative change•Microvessel occlusions produce lamina-specific microvascular flow vasodynamics
Zhu et al. utilize a precision photothrombosis technique to produce depth-targeted single capillary occlusions and reveal regional hemodynamic alternation, neurodegenerative change, and laminar-scale regulation distinctions induced by microvessel occlusion. This finding raises the possibility that microvascular dysfunction contributes to cognitive decline in neurodegenerative disease.
PDF
