Protic ruthenium complexes using the dihydroxybipyridine (dhbp) ligand combined with a spectator ligand (N,N = bpy, phen, dop, Bphen) have been studied for their potential activity vs. cancer cells ...and their photophysical luminescent properties. These complexes vary in the extent of π expansion and the use of proximal (6,6'-dhbp) or distal (4,4'-dhbp) hydroxy groups. Eight complexes are studied herein as the acidic (OH bearing) form, (N,N)
Ru(
'-dhbp)Cl
, or as the doubly deprotonated (O
bearing) form. Thus, the presence of these two protonation states gives 16 complexes that have been isolated and studied. Complex
, (dop)
Ru(4,4'-dhbp)Cl
, has been recently synthesized and characterized spectroscopically and by X-ray crystallography. The deprotonated forms of three complexes are also reported herein for the first time. The other complexes studied have been synthesized previously. Three complexes are light-activated and exhibit photocytotoxicity. The log(D
) values of the complexes are used herein to correlate photocytotoxicity with improved cellular uptake. For Ru complexes
-
bearing the 6,6'-dhbp ligand, photoluminescence studies (all in deaerated acetonitrile) have revealed that steric strain leads to photodissociation which tends to reduce photoluminescent lifetimes and quantum yields in both protonation states. For Ru complexes
-
bearing the 4,4'-dhbp ligand, the deprotonated Ru complexes (
-
) have low photoluminescent lifetimes and quantum yields due to quenching that is proposed to involve the
LLCT excited state and charge transfer from the O
-bpy
ligand to the N,N spectator ligand. The protonated OH bearing 4,4'-dhbp Ru complexes (
-
) have long luminescence lifetimes which increase with increasing π expansion on the N,N spectator ligand. The Bphen complex,
, has the longest lifetime of the series at 3.45 μs and a photoluminescence quantum yield of 18.7%. This Ru complex also exhibits the best photocytotoxicity of the series. A long luminescence lifetime is correlated with greater singlet oxygen quantum yields because the triplet excited state is presumably long-lived enough to interact with
O
to yield
O
.
Laser wakefield accelerators (LWFAs) have electric fields that are orders of magnitude larger than those of conventional accelerators, promising an attractive, small-scale alternative for ...next-generation light sources and lepton colliders. The maximum energy gain in a single-stage LWFA is limited by dephasing, which occurs when the trapped particles outrun the accelerating phase of the wakefield. Here, we demonstrate that a single space-time structured laser pulse can be used for ionization injection and electron acceleration over many dephasing lengths in the bubble regime. Simulations of a dephasingless laser wakefield accelerator driven by a 6.2-J laser pulse show 25 pC of injected charge accelerated over 20 dephasing lengths (1.3 cm) to a maximum energy of 2.1 GeV. The space-time structured laser pulse features an ultrashort, programmable-trajectory focus. Accelerating the focus, reducing the focused spot-size variation, and mitigating unwanted self-focusing stabilize the electron acceleration, which improves beam quality and leads to projected energy gains of 125 GeV in a single, sub-meter stage driven by a 500-J pulse.
Senescence is a cellular defense mechanism that helps cells prevent acquired damage, but chronic senescence, as in aging, can contribute to the development of age-related tissue dysfunction and ...disease. Previous studies clearly show that removal of senescent cells can help prevent tissue dysfunction and extend healthspan during aging. Senescence increases with age in the skeletal system, and selective depletion of senescent cells or inhibition of their senescence-associated secretory phenotype (SASP) has been reported to maintain or improve bone mass in aged mice. This suggests that promoting the selective removal of senescent cells, via the use of senolytic agents, can be beneficial in the treatment of aging-related bone loss and osteoporosis. Navitoclax (also known as ABT-263) is a chemotherapeutic drug reported to effectively clear senescent hematopoietic stem cells, muscle stem cells, and mesenchymal stromal cells in previous studies, but its
in vivo
effects on bone mass had not yet been reported. Therefore, the purpose of this study was to assess the effects of short-term navitoclax treatment on bone mass and osteoprogenitor function in old mice. Aged (24 month old) male and female mice were treated with navitoclax (50 mg/kg body mass daily) for 2 weeks. Surprisingly, despite decreasing senescent cell burden, navitoclax treatment decreased trabecular bone volume fraction in aged female and male mice (−60.1% females, −45.6% males), and BMSC-derived osteoblasts from the navitoclax treated mice were impaired in their ability to produce a mineralized matrix (−88% females, −83% males). Moreover,
in vitro
administration of navitoclax decreased BMSC colony formation and calcified matrix production by aged BMSC-derived osteoblasts, similar to effects seen with the primary BMSC from the animals treated
in vivo
. Navitoclax also significantly increased metrics of cytotoxicity in both male and female osteogenic cultures (+1.0 to +11.3 fold). Taken together, these results suggest a potentially harmful effect of navitoclax on skeletal-lineage cells that should be explored further to definitively assess navitoclax’s potential (or risk) as a therapeutic agent for combatting age-related musculoskeletal dysfunction and bone loss.
Fibrodysplasia ossificans progressiva (FOP) is a debilitating rare disease known for episodic endochondral heterotopic ossification (HO) caused by gain-of-function mutations in ACVR1/ALK2. However, ...disease severity varies among patients with identical mutations suggesting disease-modifying factors, including diet, may have therapeutic implications. The roles of vitamin D
in calcium metabolism and chondrogenesis are known, but its effects on BMP signaling and chondrogenesis are less studied. This review attempts to assess the possibility of vitamin D's effects in FOP by exploring relevant intersections of VD
with mechanisms of FOP flares.
In vitro and in vivo studies suggest vitamin D suppresses inflammation, while clinical studies suggest that vitamin D
protects against arteriosclerosis and inversely correlates with non-genetic intramuscular HO. However, the enhancement of chondrogenesis, BMP signaling, and possibly Activin A expression by vitamin D may be more relevant in FOP. There appears to be little potential for vitamin D to reduce HO in FOP, but testing the potential for excess vitamin D to promote HO may be warranted.
Although much work has linked the human microbiome to specific phenotypes and lifestyle variables, data from different projects have been challenging to integrate and the extent of microbial and ...molecular diversity in human stool remains unknown. Using standardized protocols from the Earth Microbiome Project and sample contributions from over 10,000 citizen-scientists, together with an open research network, we compare human microbiome specimens primarily from the United States, United Kingdom, and Australia to one another and to environmental samples. Our results show an unexpected range of beta-diversity in human stool microbiomes compared to environmental samples; demonstrate the utility of procedures for removing the effects of overgrowth during room-temperature shipping for revealing phenotype correlations; uncover new molecules and kinds of molecular communities in the human stool metabolome; and examine emergent associations among the microbiome, metabolome, and the diversity of plants that are consumed (rather than relying on reductive categorical variables such as veganism, which have little or no explanatory power). We also demonstrate the utility of the living data resource and cross-cohort comparison to confirm existing associations between the microbiome and psychiatric illness and to reveal the extent of microbiome change within one individual during surgery, providing a paradigm for open microbiome research and education.
We show that a citizen science, self-selected cohort shipping samples through the mail at room temperature recaptures many known microbiome results from clinically collected cohorts and reveals new ones. Of particular interest is integrating
= 1 study data with the population data, showing that the extent of microbiome change after events such as surgery can exceed differences between distinct environmental biomes, and the effect of diverse plants in the diet, which we confirm with untargeted metabolomics on hundreds of samples.
Purpose of Review
Fibrodysplasia ossificans progressiva (FOP) is a debilitating rare disease known for episodic endochondral heterotopic ossification (HO) caused by gain-of-function mutations in
...ACVR1
/ALK2. However, disease severity varies among patients with identical mutations suggesting disease-modifying factors, including diet, may have therapeutic implications. The roles of vitamin D
3
in calcium metabolism and chondrogenesis are known, but its effects on BMP signaling and chondrogenesis are less studied. This review attempts to assess the possibility of vitamin D’s effects in FOP by exploring relevant intersections of VD
3
with mechanisms of FOP flares.
Recent Findings
In vitro and in vivo studies suggest vitamin D suppresses inflammation, while clinical studies suggest that vitamin D
3
protects against arteriosclerosis and inversely correlates with non-genetic intramuscular HO. However, the enhancement of chondrogenesis, BMP signaling, and possibly Activin A expression by vitamin D may be more relevant in FOP.
Summary
There appears to be little potential for vitamin D to reduce HO in FOP, but testing the potential for excess vitamin D to promote HO may be warranted.
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