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Abstract The classical properties of thermal light fields were instrumental in shaping our early understanding of light. Before the invention of the laser, thermal light was used to investigate the wave-particle duality of light. The subsequent formulation of the quantum theory of electromagnetic radiation later confirmed the classical nature of thermal light fields. Here, we fragment a pseudothermal field into its multiparticle constituents to demonstrate that it can host multiphoton dynamics mediated by either classical or quantum properties of coherence. This is shown in a forty-particle system through a process of scattering mediated by twisted paths endowed with orbital angular momentum. This platform enables accurate projections of the scattered pseudothermal system into isolated multiphoton subsystems governed by quantum dynamics. Interestingly, the isolated multiphoton subsystems exhibiting quantum coherence produce interference patterns previously attributed to entangled optical systems. As such, our work unveils novel mechanisms to isolate quantum systems from classical fields. This possibility opens new paradigms in quantum physics with enormous implications for the development of robust quantum technologies.

Preclinical studies of pro-remyelinating therapies for multiple sclerosis tend to neglect the effect of the disease-relevant inflammatory milieu. Interferon-gamma (IFN-γ) is known to suppress oligodendrocyte progenitor cell (OPC) differentiation and induce a recently described immune OPC (iOPC) phenotype characterized by expression of major histocompatibility complex (MHC) molecules. We tested the effects of cladribine (CDB), dimethylfumarate (DMF), and interferon-beta (IFN-β), existing anti-inflammatory therapies for MS, on the IFN-γ-induced iOPC formation and OPC differentiation block. In line with previous reports, we demonstrate that IFN-β and DMF inhibit OPC proliferation, while CDB had no effect. None of the drugs exhibited cytotoxic effects at the physiological concentrations tested in vitro. In a differentiation assay, none of the drugs were able to promote differentiation, under inflammatory or basal conditions. To study drug effects on iOPCs, we monitored MHC expression in vitro with live cell imaging using cells isolated from MHC reporter mice. IFN-β suppressed induction of MHC class II, and DMF led to suppression of both class I and II. CDB had no effect on MHC induction. We conclude that promoting proliferation and differentiation and suppressing iOPC induction under inflammatory conditions may require separate therapeutic strategies and must be balanced for maximal repair. Our in vitro MHC screening assay can be leveraged across cell types to test the effects of drug candidates and disease-related stimuli.

Abstract During the “decade on restoration,” we must understand how to reliably re‐establish native plant populations. When establishing populations through seed addition, practitioners often prioritize obtaining seed from locations geographically near the restoration site (i.e. “local seed sourcing”). They are assumed to be under similar environmental conditions to the restoration site and should establish more robust plant populations and preserve local biotic interactions better than seeds sourced from further away. However, this assumption remains virtually untested in realistic restoration settings and the importance of seed sourcing, relative to other factors such as seeding rate and management regimes, is unclear. To determine if seed sourcing decision impacts plant establishment, abundance and phenology, we developed a partnership between university‐researchers and a native seed producer that kept records on where their seed was sourced from and where it was planted. At each site, we recorded the abundance and phenological stage of five commonly used tallgrass prairie restoration species seeded at 24 sites undergoing restoration across Michigan. We considered two measures of seed source locality: geographic distance (seeds were sourced from locations 6–750 km away from their respective restoration sites) and environmental distance. We also obtained data on the seeding rate and post‐seeding management at each site. We found that no measure of seed source locality predicted the likelihood of plant establishment or abundance at restoration sites. However, sites sown with seed from further away, or from cooler and wetter climates, had a greater proportion of flowering individuals earlier in the season. Finally, sites with higher seeding rates had greater plant abundance, and post‐seeding management of the restoration site increased the likelihood a species would establish by 36%. Overall, these results support that seed sourcing decisions did not impact plant establishment or abundance in our system. However, using less‐local seed sources may alter flowering phenology. Our results suggest that tallgrass prairie restoration efforts should prioritize higher seeding rates, post‐seeding management, and might expand the region seed sources are considered “local”, though this may impact flowering phenology. Future research leveraging native seed producer records can help answer critical questions about restoration seed sourcing.

Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury, and disease.

The majority of natural products utilized to treat a diverse array of human conditions and diseases are derived from terrestrial sources. In recent years, marine ecosystems have proven to be a valuable resource of diverse natural products that are generated to defend and support their growth. Such marine sources offer a large opportunity for the identification of novel compounds that may guide the future development of new drugs and therapies. Using the National Oceanic and Atmospheric Administration (NOAA) portal, we explore deep-sea coral and sponge species inhabiting a segment of the U.S. Exclusive Economic Zone, specifically off the western coast of Florida. This area spans ~100,000 km2, containing coral and sponge species at sea depths up to 3000 m. Utilizing PubMed, we uncovered current knowledge on and gaps across a subset of these sessile organisms with regards to their natural products and mechanisms of altering cytoskeleton, protein trafficking, and signaling pathways. Since the exploitation of such marine organisms could disrupt the marine ecosystem leading to supply issues that would limit the quantities of bioactive compounds, we surveyed methods and technological advances that are necessary for sustaining the drug discovery pipeline including in vitro aquaculture systems and preserving our natural ecological community in the future. Collectively, our efforts establish the foundation for supporting future research on the identification of marine-based natural products and their mechanism of action to develop novel drugs and therapies for improving treatment regimens of human conditions and diseases.

Abstract Background The integrity of microtubule filament networks is essential for the roles in diverse cellular functions, and disruption of its structure or dynamics has been explored as a therapeutic approach to tackle diseases such as cancer. Microtubule-interacting drugs, sometimes referred to as antimitotics, are used in cancer therapy to target and disrupt microtubules. However, due to associated side effects on healthy cells, there is a need to develop safer drug regimens that still retain clinical efficacy. Currently, many questions remain open regarding the extent of effects on cellular physiology of microtubule-interacting drugs at clinically relevant and low doses. Here, we use super-resolution microscopies (single-molecule localization and optical fluctuation based) to reveal the initial microtubule dysfunctions caused by nanomolar concentrations of colcemid. Results We identify previously undetected microtubule (MT) damage caused by clinically relevant doses of colcemid. Short exposure to 30–80 nM colcemid results in aberrant microtubule curvature, with a trend of increased curvature associated to increased doses, and curvatures greater than 2 rad/μm, a value associated with MT breakage. Microtubule fragmentation was detected upon treatment with ≥ 100 nM colcemid. Remarkably, lower doses (

Traumatic joint injuries are common, leading to progressive tissue degeneration and the development of osteoarthritis. The post-traumatic joint experiences a pro-inflammatory milieu, initiating a subtle but deteriorative process in cartilage tissue. To prevent or even reverse this process, our group previously developed a tissue-penetrating methacrylated hyaluronic acid (MeHA) hydrogel system, crosslinked within cartilage to restore and/or protect the tissue. In the current study, we further optimized this approach by investigating the impact of biomaterial molecular weight (MW; 20, 75, 100 kDa) on its integration within and reinforcement of cartilage, as well as its ability to protect tissue degradation in a catabolic state. Indeed, the low MW MeHA integrated and reinforced cartilage tissue better than the high MW counterparts. Furthermore, in a 2 week IL-1β explant culture model, the 20 kDa MeHA demonstrated the most protection from biphasic mechanical loss, best retention of proteoglycans (Safranin O staining), and least aggrecan breakdown (NITEGE). Thus, the lower MW MeHA gels integrated better into the tissue and provided the greatest protection of the cartilage matrix. Future work will test this formulation in a preclinical model, with the goal of translating this therapeutic approach for cartilage preservation.

Abstract Serine proteases catalyze a multi-step covalent catalytic mechanism of peptide bond cleavage. It has long been assumed that serine proteases including thrombin carry-out catalysis without significant conformational rearrangement of their stable two-β-barrel structure. We present nuclear magnetic resonance (NMR) and hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments on the thrombin-thrombomodulin (TM) complex. Thrombin promotes procoagulative fibrinogen cleavage when fibrinogen engages both the anion binding exosite 1 (ABE1) and the active site. It is thought that TM promotes cleavage of protein C by engaging ABE1 in a similar manner as fibrinogen. Thus, the thrombin-TM complex may represent the catalytically active, ABE1-engaged thrombin. Compared to apo- and active site inhibited-thrombin, we show that thrombin-TM has reduced μs-ms dynamics in the substrate binding (S1) pocket consistent with its known acceleration of protein C binding. Thrombin-TM has increased μs-ms dynamics in a β-strand connecting the TM binding site to the catalytic aspartate. Finally, thrombin-TM had doublet peaks indicative of dynamics that are slow on the NMR timescale in residues along the interface between the two β-barrels. Such dynamics may be responsible for facilitating the N-terminal product release and water molecule entry that are required for hydrolysis of the acyl-enzyme intermediate.

Alzheimer’s disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aβ) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aβ oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer’s disease, by targeting both neuroinflammation and neurodegeneration.

Serine proteases catalyze a multi-step covalent catalytic mechanism of peptide bond cleavage. It has long been assumed that serine proteases including thrombin carry-out catalysis without significant conformational rearrangement of their stable two-β-barrel structure. We present nuclear magnetic resonance (NMR) and hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments on the thrombin-thrombomodulin (TM) complex. Thrombin promotes procoagulative fibrinogen cleavage when fibrinogen engages both the anion binding exosite 1 (ABE1) and the active site. It is thought that TM promotes cleavage of protein C by engaging ABE1 in a similar manner as fibrinogen. Thus, the thrombin-TM complex may represent the catalytically active, ABE1-engaged thrombin. Compared to apo- and active site inhibited-thrombin, we show that thrombin-TM has reduced μs-ms dynamics in the substrate binding (S1) pocket consistent with its known acceleration of protein C binding. Thrombin-TM has increased μs-ms dynamics in a β-strand connecting the TM binding site to the catalytic aspartate. Finally, thrombin-TM had doublet peaks indicative of dynamics that are slow on the NMR timescale in residues along the interface between the two β-barrels. Such dynamics may be responsible for facilitating the N-terminal product release and water molecule entry that are required for hydrolysis of the acyl-enzyme intermediate.

Amide hydrogen/deuterium exchange mass spectrometry (HDXMS) of proteins has become extremely popular for identifying ligand-binding sites, protein-protein interactions, intrinsic disorder, and allosteric changes upon protein modification. Such phenomena are revealed when amide exchange is measured in the fast limit, that is, within a few minutes of exchange in deuterated buffer. The HDXMS data have a resolution of the length of peptides and are difficult to interpret because many different phenomena lead to changes in hydrogen/deuterium exchange. We present a quantitative analysis of accelerated molecular dynamics simulations that provides impressive agreement with peptide-length HDXMS data. Comparative analysis of thrombin and a single-point mutant reveals that the simulation analysis can distinguish the subtle differences in exchange due to mutation. In addition, the results provide a deeper understanding of the underlying changes in dynamics revealed by the HDXMS that extend far from the site of mutation.

The classical properties of thermal light fields were instrumental in shaping our early understanding of light. Before the invention of the laser, thermal light was used to investigate the wave-particle duality of light. The subsequent formulation of the quantum theory of electromagnetic radiation later confirmed the classical nature of thermal light fields. Here, we fragment a pseudothermal field into its multiparticle constituents to demonstrate that it can host multiphoton dynamics mediated by either classical or quantum properties of coherence. This is shown in a forty-particle system through a process of scattering mediated by twisted paths endowed with orbital angular momentum. This platform enables accurate projections of the scattered pseudothermal system into isolated multiphoton subsystems governed by quantum dynamics. Interestingly, the isolated multiphoton subsystems exhibiting quantum coherence produce interference patterns previously attributed to entangled optical systems. As such, our work unveils novel mechanisms to isolate quantum systems from classical fields. This possibility opens new paradigms in quantum physics with enormous implications for the development of robust quantum technologies. [ABSTRACT FROM AUTHOR]

Background. People living with HIV continue to face laws, policies, and practices that impact their potential for travel and migration. These laws include: mandatory HIV testing and involuntary disclosure of HIV; lack of access to affordable HIV-related health care, treatment and counselling during the migration process; deportation of foreign nationals living with HIV; and restrictions on the length of stays. Methods. HIV migration laws were the topic of a half-day community forum held as part of the 12th International AIDS Society Conference on HIV Science held in Brisbane, Australia, in July 2023. Over 150 delegates attended and, after a series of presentations, delegates were invited to participate in structured, facilitated conversations about issues related to policy, health and law concerning migration of people living with HIV. In this paper, we report on key themes from those discussions and identify areas for ongoing investigation. Results. Advocates recommended the removal of unfair and unjust migration laws and policies that contribute to HIV stigma and discrimination; updated migration policies that reflect the current context and cost of biomedical approaches to HIV management and prevention; expanded and equitable access to HIV-related care regardless of migration or residency status; and the development of advocacy networks to promote changes to migration policies. Conclusions. Laws limiting the migration of people living with HIV actively discourage individuals from seeking HIV testing, treatment and care. Ultimately, restrictive migration laws and policies undermine global efforts to end AIDS as a public health concern and to virtually eliminate HIV transmission by 2030. [ABSTRACT FROM AUTHOR]