Sulfate Reduction in Sediments Produces High Levels of Chromophoric Dissolved Organic Matter

Sulfate reduction plays an important role in altering dissolved organic matter (DOM) in estuarine and coastal sediments, although its role in the production of optically active chromophoric DOM (CDOM) and a subset of fluorescent DOM (FDOM) has not been previously investigated in detail. Freshwater sediment slurries were incubated anaerobically with added sulfate and acetate to promote sulfate-reducing bacteria. Ultraviolet visible (UV-Vis) absorbance and 3-dimensional excitation emission matrix (EEM) fluorescence spectra were measured over a five weeks anaerobic dark incubation period. Parallel Factor Analysis (PARAFAC) of FDOM determined components that increased significantly during dark and anaerobic incubation matching three components previously considered of terrestrially-derived or humic-like origin published in the OpenFluor database. The observed FDOM increase was strongly correlated (R2 = 0.96) with the reduction of sulfate. These results show a direct experimental link between sulfate reduction and FDOM production, which impacts our understanding of coastal FDOM sources and early sediment diagenesis. As 3D fluorescence techniques are commonly applied to diverse systems, these results provide increasing support that FDOM can have many diverse sources not consistently captured by common classifications such as “humic-like” fluorescence

Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease

Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, which induces an anti-inflammatory shift in microglia and macrophages. This targeted anti-inflammatory agent improves physical deficits in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we sought to determine whether tuftsin is also effective in combination with benztropine, an FDA-approved drug that stimulates remyelination, in both EAE and in the cuprizone model of demyelination. We show that combining these two agents to promote anti-inflammatory and remyelinating mechanisms alleviates symptoms in EAE and lessens pathological hallmarks in both MS models. Importantly, tuftsin is required to transform the inflammatory CNS environment normally present in EAE/MS into one of an anti-inflammatory nature, and benztropine is required in the cuprizone model to improve remyelination. Our data further support tuftsin's beneficial immunomodulatory activity in the context of EAE, and show that when studying remyelination in the absence of an autoimmune insult, tuftsin still activated microglia toward an anti-inflammatory fate, but benztropine was necessary for significant repair of the damaged myelin. Overall, tuftsin effectively combined with benztropine to significantly improve MS-like pathologies in both models

Osteocyte specific responses to soluble and mechanical stimuli in a stem cell derived culture model

Studying osteocyte behavior in culture has proven difficult because these embedded cells require spatially coordinated interactions with the matrix and surrounding cells to achieve the osteocyte phenotype. Using an easily attainable source of bone marrow mesenchymal stem cells, we generated cells with the osteocyte phenotype within two weeks. These “stem cell derived-osteocytes” (SCD-O) displayed stellate morphology and lacunocanalicular ultrastructure. Osteocytic genes Sost, Dmp1, E11, and Fgf23 were maximally expressed at 15 days and responded to PTH and 1,25(OH)2D3. Production of sclerostin mRNA and protein, within 15 days of culture makes the SCD-O model ideal for elucidating regulatory mechanisms. We found sclerostin to be regulated by mechanical factors, where low intensity vibration significantly reduced Sost expression. Additionally, this model recapitulates sclerostin production in response to osteoactive hormones, as PTH or LIV repressed secretion of sclerostin, significantly impacting Wnt-mediated Axin2 expression, via β-catenin signaling. In summary, SCD-O cells produce abundant matrix, rapidly attain the osteocyte phenotype, and secrete functional factors including sclerostin under non-immortalized conditions. This culture model enables ex vivo observations of osteocyte behavior while preserving an organ-like environment. Furthermore, as marrow-derived mesenchymal stem cells can be obtained from transgenic animals; our model enables study of genetic control of osteocyte behaviors

Mechanically Activated Fyn Utilizes mTORC2 to Regulate RhoA and Adipogenesis in Mesenchymal Stem Cells

Mechanical strain provides an anti-adipogenic, pro-osteogenic stimulus to mesenchymal stem cells (MSC) through generating intracellular signals and via cytoskeletal restructuring. Recently, mTORC2 has been shown to be a novel mechanical target critical for the anti-adipogenic signal leading to preservation of β-catenin. As mechanical activation of mTORC2 requires focal adhesions (FAs), we asked whether proximal signaling involved Src and FAK, which are early responders to integrin-FA engagement. Application of mechanical strain to marrow-derived MSCs was unable to activate mTORC2 when Src family kinases were inhibited. Fyn, but not Src, was specifically required for mechanical activation of mTORC2 and was recruited to FAs after strain. Activation of mTORC2 was further diminished following FAK inhibition, and as FAK phosphorylation (Tyr-397) required Fyn activity, provided evidence of Fyn/FAK cooperativity. Inhibition of Fyn also prevented mechanical activation of RhoA as well as mechanically induced actin stress fiber formation. We thus asked whether RhoA activation by strain was dependent on mTORC2 downstream of Fyn. Inhibition of mTORC2 or its downstream substrate, Akt, both prevented mechanical RhoA activation, indicating that Fyn/FAK affects cytoskeletal structure via mTORC2. We then sought to ascertain whether this Fyn-initiated signal pathway modulated MSC lineage decisions. siRNA knockdown of Fyn, but not Src, led to rapid attainment of adipogenic phenotype with significant increases in adipocyte protein 2, peroxisome proliferator-activated receptor gamma, adiponectin, and perilipin. As such, Fyn expression in mdMSCs contributes to basal cytoskeletal architecture and, when associated with FAs, functions as a proximal mechanical effector for environmental signals that influence MSC lineage allocation

Concert recording 2017-04-27

[Track 1]. Adoramus te, Christe / Giovanni Pierluigi da Palestrina -- [Track 2]. Ubi caritas / Maurice Duruflé -- [Track 3]. Three Hungarian folk songs. I. The handsome butcher II. Apple, apple III. The old woman / Matyas Seiber -- [Track 4]. He watching over Israel from Elijah / Felix Mendelssohn Bartholdy -- [Track 5]. Ain\u27t got time to die / Hall Johnson

Metformin for treatment of cytopenias in children and young adults with Fanconi anemia

Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824

The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity

Autoimmune diseases of the central nervous system (CNS) involve inflammatory components and result in neurodegenerative processes. Microglia, the resident macrophages of the CNS, are the first responders after insults to the CNS and comprise a major link between the inflammation and neurodegeneration. Here, we will focus on the roles of microglia in two autoimmune diseases: the prevalent condition of multiple sclerosis (MS) and the much rarer Rasmussen’s encephalitis (RE). Although there is an abundance of evidence that microglia actively contribute to neuronal damage in pathological states such as MS and RE, there is also evidence of important reparative functions. As current research supports a more complex and diverse array of functions and phenotypes that microglia can assume, it is an especially interesting time to examine what is known about both the damaging and restorative roles that microglia can play in the inflammatory CNS setting. We will also discuss the pharmacological approaches to modulating microglia towards a more neuroprotective state

Soundscapes of a marine community before and during Covid-19 lockdowns

Noise from human activities in the ocean have increased by about 3.3 dB per decade. Given that many marine species rely on sound for several biologically important activities (e.g., feeding, reproduction, navigation) scientists are concern about the impact of an increasingly noisy ocean. The Covid-19 lockdowns have provided a unique opportunity to study the impact of anthropogenic noise on marine communities. This study uses data from passive acoustic monitoring in two nearby locations within the Archipelago of Chiriquí in Panama from August 2017 and 2020 to study changes in boat and biological noise levels before and during the Covid-19 lockdowns. We predict that the Covid-19 lockdowns resulted in a reduced presence of boats and an increase in biological noises. This study can provide an alternative to marine community health assessments which can improve preservation of ecosystem function

When Is an Adolescent an Adult? Assessing Cognitive Control in Emotional and Nonemotional Contexts

An individual is typically considered an adult at age 18, although the age of adulthood varies for different legal and social policies. A key question is how cognitive capacities relevant to these policies change with development. The current study used an emotional go/no-go paradigm and functional neuroimaging to assess cognitive control under sustained states of negative and positive arousal in a community sample of one hundred ten 13- to 25-year-olds from New York City and Los Angeles. The results showed diminished cognitive performance under brief and prolonged negative emotional arousal in 18- to 21-year-olds relative to adults over 21. This reduction in performance was paralleled by decreased activity in fronto-parietal circuitry, implicated in cognitive control, and increased sustained activity in the ventromedial prefrontal cortex, involved in emotional processes. The findings suggest a developmental shift in cognitive capacity in emotional situations that coincides with dynamic changes in prefrontal circuitry. These findings may inform age-related social policies