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Diabetes is a chronic health condition that has reached global epidemic proportions and continues to increase with every passing year. There are two major types of diabetes: type 1 and type 2 diabetes (T2D); 90 percent of those living with this health condition have T2D. These individuals suffer from high blood glucose levels, which induces insulin resistance and eventual organ failure that leads to death. Current therapeutic approaches to alleviate high glucose levels are limited to dieting, personally administered insulin injections, devices that release insulin, and blood glucose lowering pharmacological agents. We believe that glycocalyx remodeling could be a potential therapeutic to improve glucose homeostasis in individuals with T2D. We have generated evidence that heparan sulfate mimetics will alter the differentiation program of pre-adipocytes by modulating Wnt signaling. This results in adipocytes with increased glucose uptake and utilization independent of insulin secretion. In this current study, we aim to identify a targetable pre-adipocyte marker to selectively deliver our heparan sulfate mimetic. This marker will then be utilized to demonstrate that heparan sulfate mimetic addition during adipogenesis does not alter cell identity and function.

A course to provide a common introductory experience for both majors and non-majors is described. The topics and concepts taught in the quantum mechanics segment of the course are discussed. (DT)

Objective To compare the gut microbiome composition and serum metabolome profile among individuals with spinal cord injury (SCI) and normal glucose tolerance (NGT) or prediabetes/type 2 diabetes (preDM/T2D). Design Cross-sectional design. Setting Research university. Participants A total of 25 adults (N=25) with SCI were included in the analysis and categorized as NGT (n=16) or preDM/T2D (n=9) based on their glucose concentration at minute 120 during a 75-g oral glucose tolerance test. The American Diabetes Association diagnosis guideline was used for grouping participants. Interventions Not applicable. Main Outcome Measures A stool sample was collected and used to assess the gut microbiome composition (alpha and beta diversity, microbial abundance) via the 16s ribosomal RNA sequencing technique. A fasting serum sample was used for liquid chromatography–mass spectrometry–based untargeted metabolomics analysis, the results from which reflect the relative quantity of metabolites detected and identified. Gut microbiome and metabolomics data were analyzed by the Quantitative Insights into Microbial Ecology 2 and Metaboanalyst platforms, respectively. Results Gut microbiome alpha diversity (Pielou's evenness index, Shannon's index) and beta diversity (weighted UniFrac distances) differed between groups. Compared with participants with NGT, participants with preDM/T2D had less evenness in microbial communities. In particular, those with preDM/T2D had a lower abundance of the Clostridiales order and higher abundance of the Akkermansia genus, as well as higher serum levels of gut-derived metabolites, including indoxyl sulfate and phenylacetylglutamine (P Conclusions Our results provide evidence for altered gut microbiome composition and dysregulation of gut-derived metabolites in participants with SCI and preDM/T2D. Both indoxyl sulfate and phenylacetylglutamine have been implicated in the development of cardiovascular diseases in the able-bodied population. These findings may inform future investigations in the field of SCI and cardiometabolic health.

The molecular titanium-oxo cluster [Ti6O6((OPr)-Pr-i)(6)((O2CBu)-Bu-t)(6)] (1) can be photoactivated by UV light, resulting in a deeply coloured mixed valent (photoreduced) Ti (iii/iv) cluster, alongside alcohol and ketone (photooxidised) organic products. Mechanistic studies indicate that a two-electron (not free-radical) mechanism occurs in this process, which utilises the cluster structure to facilitate multielectron reactions. The photoreduced products [Ti6O6((OPr)-Pr-i)(4)((O2CBu)-Bu-t)(6)(sol)(2)], sol = (PrOH)-Pr-i (2) or pyridine (3), can be isolated in good yield and are structurally characterized, each with two, uniquely arranged, antiferromagnetically coupled d-electrons. 2 and 3 undergo onward oxidation under air, with 3 cleanly transforming into peroxide complex, [Ti6O6((OPr)-Pr-i)(4)((O2CBu)-Bu-t)(6)(py)(O-2)] (5). 5 reacts with isopropanol to regenerate the initial cluster (1) completing a closed cycle, and suggesting opportunities for the deployment of these easily made and tuneable clusters for sustainable photocatalytic processes using air and light. The redox reactivity described here is only possible in a cluster with multiple Ti sites, which can perform multi-electron processes and can adjust its shape to accommodate changes in electron density.

The understanding of the solvation of electrons and their degree of delocalisation in that state have been of fundamental interest ever since first discovered in alkali metal ammonia solutions. Neutral, alkali metal-doped clusters serve as ideal model systems to study solvated electrons in their size-dependent properties. The presented work focuses on the characterisation of electronic properties via angle-resolved photoelectron spectroscopy and of their magnetic properties by Stern-Gerlach deflection. The combination of both experimantal techniques reveals information on the solvated electron binding energy, electron orbital and spin angular momenta as well as the cluster rotational angular momentum. We report measurements of electron binding energies and photoelectron anisotropies in angle-dependent photoelectron spectra of lithium-doped dimethyl ether clusters as a function of cluster size distribution. Neutral singly doped lithium clusters are studied in the range from bare lithium atom to an average cluster size of 63 dimethyl ether molecules. We explain trends in electron binding energies and photoemission anisotropies on the bases of density functional calculations of LiCH3OCH3 clusters. The results of lithium-doped clusters are compared to a previous study performed in our group on NaCH3OCH3 clusters. The comparison reveals similar trends of electron binding energies and photoemission anisotropies with increasing cluster size. Yet, structural and electronic differences arise from the alkali metal substitution. In highly symmetric clusters, the highest occupied molecular orbital can delocalize over an extended region and form a symmetric charge distribution of mainly s-character, resulting in a pronounced photoemission anisotropy. The photoelectron angular distributions of Li(CH3OCH3)n reveal pronounced s-character at n=4, 5 and 6. These cluster sizes are refered to as magic clusters for the photoelectron anisotropy. Photoelectron studies of cluster size distributions are limited in their details of cluster size-resolved photoelectron contributions. Size-resolved measurements of electron binding energies and photoemission anisotropies of neutral Na(NH3)n clusters are achieved with photoelectron-photoion-coincidence-spectroscopy, for photon energies in the range of 5.5 eV - 9.9 eV. Photoelectron kinetic energy spectra in combination with ab initio calculations show three distinct ionisation pathways of the single solvated electron, each of the pathways is dominant in a certain photon energy range. One of the ionisation pathways occurs via an autoionisation process after resonant excitation of the neutral state. The excitation process is proposed to be characterised by an electron transfer of an NH3 molecule lone pair to the singly occupied molecular orbital. This excited state is characterised by a doubly occupied orbital, the so called solvated dielectron. The excited, solvated dielectron subsequently decays by electron transfer processes with the emission of low kinetic energy electrons. Besides studying the electronic states of the clusters, we exploit their magnetic character due to the unpaired electron in magnetic deflection experiments on molecular beams. The paramagnetic propeties of sodium-doped clusters with ammonia, water, methanol and dimethyl ether for cluster sizes n=1-4 are characterised by their deflection behaviour when traversing a magnetic field gradient. The spatial deflection is compared to molecular dynamics simulations based on the Zeeman interaction of a spin 1/2 system. The comparison of experiment and simulation reveals unperturbed magnetic properties of a spin 1/2 system for the smallest clusters NaNH3 and NaH2O. All larger clusters, in contrast show reduced deflection compared to simulations of a spin 1/2 system. Deviations from a spin 1/2 deflection behavior are attributed to a reduction of magnetic moment due to intracluster spin-relaxation processes. Determining effective magnetic moments for these clusters allows us to identify trends in their paramagnetic properties. The observed trends are discussed in terms of spin and rotational angular momentum interactions of the thermally accessible rovibrational density of states. We used density functional methods to determine the lowest energy cluster geometries and the rovibrational states with the harmonic oscillator and rigid rotor approximation. With this approach we find that the dominant mechanism of intracluster spin-relaxation processes in sodium-doped clusters is governed by the thermal population of spin-rotational coupled Zeeman states.

High-fat diets are linked with obesity and changes in dopamine neurotransmission. Mounting evidence shows that saturated fat impacts dopamine neurons and their terminal fields, but little is known about the effect a diet high in unsaturated fat has on the dopamine system. This study sought to determine whether fat type, saturated vs. unsaturated, differentially affected body weight, blood glucose regulation, locomotor behavior, and control of dopamine release and uptake at dopamine neuron terminals in the nucleus accumbens (NAc). C57BL/6 mice were fed a control diet or a nutrient-matched diet high in saturated fat (SF), unsaturated flaxseed oil (Flax) or a blend of the two fats. After 6-weeks, mice from each high-fat diet group gained significantly more weight than Controls, but the group fed Flax gained less weight than the SF group and had fasting blood glucose levels similar to Controls. Ex-vivo fast scan cyclic voltammetry revealed the SF group also had significantly slower synaptic dopamine clearance and a reduced capacity for phasic dopamine release in the nucleus accumbens (NAc), but the Flax and Blend groups resembled Controls. These data show that different types of dietary fat have substantially different effects on metabolic phenotype and influence how dopamine terminals in the NAc regulate dopamine neurotransmission. Our data also suggests that a diet high in unsaturated fat may preserve normal metabolic and behavioral parameters as well as dopamine signaling in the NAc.

Proton exchange membrane (PEM) fuel cells offer an alternative as an efficient power source with low environmental impact. The heart of the fuel cell is the membrane, which conducts protons through an aqueous channel network. Proton transport is critically tied to the channel connectivity – disconnected channels do not participate in the overall electrochemical activity of the cell. Nafion, the current benchmark PEM, is a random statistical copolymer, characterized by a percolating network of cylindrical channels. In previous work, conductive-probe atomic force microscopy (cp-AFM) was used to image the conductance of Nafion. Although cp-AFM provides relevant information on which channels are connected, it provides no information on the disconnected “dead-end” channels at the surface. Electrostatic Force Microscopy (EFM) was used to analyze the structure and frequency of the “dead-end” channels. Applying a simple parallel plate model allowed us to assign differences in the EFM signal to particular channel shapes: connected cylindrical channels, “dead-end” cylinder channels, and bottle-neck channels. Anion exchange membranes (AEMs), which conduct hydroxide, have attracted recent interest due to improved reaction kinetics in alkaline media, yet suffer from low conductivity and easily degrade. To this end, our AFM methodology was applied to analyze the channel connectivity of a commercial FumaTech AEM was investigated in its hydroxide form over a wide range of relative humidity (RH) by combining phase imaging and cp-AFM. At high RH, our AFM data indicates significant surface swelling. Lastly, we investigated a class of phosphonium-containing diblock copolymer AEMs that formed ordered morphologies. Although channels were observed to be well-connected in the bulk by TEM, channels aligned parallel at the surface leading to many “dead-end” channels shown by EFM. Correlating these findings with bulk measurements could offer insight toward AEMs with improved conductivity and chemical stability.

Many gastropod species will not cross copper barriers; thus, copper has been used to manipulate their movements and minimize caging artifacts. However, as the reason for copper barrier avoidance is unknown, it is difficult to predict experimental artifacts that might result from its use. Copper can be toxic to gastropods, resulting in behavioral alterations or death, but there is little evidence copper barriers can cause these effects. In this study, we assessed whether copper mobilizes from copper barriers in water and alters gastropod behavior, using periwinkle snails Littoraria irrorata. Snails were placed in containers with and without copper tape and in copper solutions (0, 0.1, 0.2, 1.0, and 2.0 ppm) created by soaking copper tape in seawater. We measured the number of snails that climbed out of the water and the ability of snails to emerge and right themselves. Snails in 1.0, 2.0 ppm, and copper tape treatments were immobilized and did not climb out of the water or emerge from their shells. Snails in lower concentrations were more likely to climb out of the water. Low copper concentrations also reduced the number of snails emerging and righting, but those that did emerge did so in less time. When exposed snails were moved to clean water, snails previously immobilized by copper were quicker to crawl out of the water. Our results demonstrate that copper can mobilize from copper barriers resulting in alterations to snail behavior. To avoid experimental artifacts, we suggest the use of copper barriers be avoided in future experiments.

The Nova-Bollinger Ni-Cu sulfide ore deposit is the first economic Ni-Cu-Co sulfide deposit to have been discovered in the Albany-Fraser orogen in Western Australia. The host rocks are mafic-ultramafic intrusive cumulates subdivided into two connected intrusions, designated Upper and Lower. The Upper Intrusion is bowl-shaped and modally layered with alternating peridotite and norite mesocumulate layers, with a Basal Series of dominantly orthocumulate mafic lithologies. The Lower Intrusion is a much thinner, semiconformable chonolith (flattened tube-shaped intrusion) consisting of mostly unlayered mafic to ultramafic orthocumulates. The Lower Intrusion hosts all the high-grade mineralization and most of the disseminated ores. A distinctive plagioclase-bearing lherzolite containing both orthopyroxene and olivine as cumulus phases is a characteristic of the Lower Intrusion and the Basal Series of the Upper. The intrusions differ slightly in olivine and spinel chemistry, the differences being largely attributable to the more orthocumulate character of the Lower Intrusion. Sector zoning in Cr content of pyroxenes is observed in the Lower Intrusion and in the lower marginal zone of the Upper and is attributed to crystallization under supercooled conditions. Symplectite pyroxene-spinel-amphibole coronas at olivine-plagioclase contacts are ubiquitous and are attributed to near-solidus peritectic reaction between olivine, plagioclase, and liquid during and after high-pressure emplacement, consistent with high Al contents in igneous pyroxenes and estimates of the peak regional metamorphism. Original cumulus olivines had compositions around Fo86 and were variably Ni depleted, interpreted as the result of preintrusion equilibration with sulfide liquid. The Upper and Lower Intrusion rocks represent cumulates from a similar parental magma, a high-Al tholeiite with MgO between 10 and 12%, low TiO2 (0.5–0.6%), and high Al2O3 (14–17%). Modeling using alphaMELTS indicates a primary water content of around 2 wt %. The cumulates of both intrusions were derived via multiple magma pulses of liquid-olivine-sulfide slurries with variable amounts of orthopyroxene emplaced into the deep crust at pressures of around 0.7 GPa during the peak of regional metamorphism. The intrusions developed initially as a bifurcating sill, the lower arm developing into the ore-bearing Lower Intrusion chonolith and the upper arm inflating into the cyclically layered Upper Intrusion.

Promoting a senescent phenotype to supress tumour progression may present an alternative strategy for treating cancer and encourages the development of positron emission tomography (PET) imaging biomarkers for assessing response to treatment. The accumulation of lipofuscin deposits in senescent cells are visualised using the pathology stain Sudan Black B (SBB) and is an emerging biomarker of senescence. We describe the design, synthesis and evaluation of [18F]fluoroethyltriazole-SBB ([18F]FET-SBB), a fluorine-18 radiolabelled derivative of SBB. The in vitro uptake of [18F]FET-SBB in a senescent cell line corelated with lipofuscin deposits; in vivo PET imaging and metabolite analysis confirms a favourable pharmacokinetic and metabolic profile for futher studies of in vivo models of senescence.

Recombinant adeno-associated virus (rAAV) has emerged as an important gene therapy vector with many clinical trials currently in progress. Analytical characterization and quantitation of particle content remain challenges in both the development and production of rAAV vectors. In this study, charge detection mass spectrometry (CDMS) and gel electrophoresis are used to characterize the DNA content of recombinant AAV8 (rAAV8) vectors with a wide range of target genome sizes. We show that the differences between the masses of empty particles and particles with the genome of interest (GOI) are correlated with the expected genome mass. A small systematic deviation (around 2%) is attributed to the packaging of counterions along with the DNA. In addition to the GOI, a broad distribution of heterogeneous DNA is packaged. The distribution peaks are close to the packaging capacity of the rAAV8 vectors. There is also evidence for the co-packaging of small DNA fragments along with the GOI. Finally, we present evidence that incubation at an elevated temperature can reduce the heterogeneity of the packaged DNA. Taken together, these results show that CDMS is a viable tool for characterization of the packaged genome., Graphical abstract, Charge detection mass spectrometry and gel electrophoresis are used to characterize the DNA content of rAAV8 vectors. In addition to the genome of interest, there is a broad distribution of heterogeneous DNA that peaks near the packaging capacity and evidence for the co-packaging of small DNA fragments.

Summary Background We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. Methods This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2–8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8–24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [ clinicaltrials.gov ( NCT03824483 ). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. Findings Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52–70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0–27·3), 33 (89%) of 37 patients (95% CI 75–97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8–12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0–18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. Interpretation BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. Funding Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Assessment of neurocognitive function (NCF) is important in brain tumor clinical trials, however there are varying methodologies available. We used the Cogstate computerized NCF testing battery and the mini-mental state examination (MMSE) to prospectively assess cognition in adult patients with recurrent glioblastoma (GBM) enrolled in the CABARET randomized phase II clinical trial of bevacizumab versus bevacizumab plus carboplatin chemotherapy. We determined completion rates; compared NCF results between trial arms; and assessed baseline NCF as a predictor of survival outcome. 93 of 103 eligible patients completed baseline Cogstate NCF testing. Completion rates were between 60 and 100% across each timepoint, and 38% at disease progression. There was no evidence of difference between arms in time to deterioration in NCF using either test. Prior to disease progression, deterioration on the Cogstate tests was substantially more common (90%) than deterioration on the MMSE (37%), and decline in the Cogstate composite score within the first 8 weeks was associated with shorter overall survival. This testing methodology may be useful when determining net clinical benefit for therapies in patients with recurrent GBM.

We conducted a petrologic study of apatite within eight unbrecciated, non-cumulate eucrites and two monomict, non-cumulate eucrites. These data were combined with previously published data to quantify the abundances of F, Cl, and H2O in the bulk silicate portion of asteroid 4 Vesta (BSV). Using a combination of apatite-based melt hygrometry/chlorometry and appropriately paired volatile/refractory element ratios, we determined that BSV has 3.0–7.2 ppm F, 0.39–1.8 ppm Cl, and 3.6–22 ppm H2O. The abundances of F and H2O are depleted in BSV relative to CI chondrites to a similar degree as F and H2O in the bulk silicate portion of the Moon. This degree of volatile depletion in BSV is similar to what has been determined previously for many moderately volatile elements in 4 Vesta (e.g., Na, K, Zn, Rb, Cs, and Pb). In contrast, Cl is depleted in 4 Vesta by a greater degree than what is recorded in samples from Earth or the Moon. Based on the Cl-isotopic compositions of eucrites and the bulk rock Cl/F ratios determined in this study, the eucrites likely formed through serial magmatism of a mantle with heterogeneous δ37Cl and Cl/F, not as extracts from a partially crystallized global magma ocean. Furthermore, the volatile depletion and Cl-isotopic heterogeneity recorded in eucrites is likely inherited, at least in part, from the precursor materials that accreted to form 4 Vesta and is unlikely to have resulted solely from degassing of a global magma ocean, magmatic degassing of eucrite melts, and/or volatile loss during thermal metamorphism. Although our results can be reconciled with the past presence of wide-scale melting on 4 Vesta (i.e., a partial magma ocean), any future models for eucrite petrogenesis involving a global magma ocean would need to account for the preservation of a heterogeneous eucrite source with respect to Cl/F ratios and Cl isotopes.

Human norovirus (HuNoV) is the leading causative agent of foodborne outbreaks and is associated with the second most prevalent cause of waterborne infections in the United States. The goal of this research was to investigate the antiviral activity of chitosan microparticles (CM) against HuNoV GII.4 Sydney and its cultivable surrogate, Tulane virus (TuV), in suspensions mimicking fecally-contaminated water. CM was prepared by crosslinking chitosan molecules with sodium sulfate, and then its anti-noroviral activity was assessed using infectivity assay on TuV and RT-qPCR on TuV and HuNoV. A 3% CM suspension in PBS (pH 7.2) showed binding to TuV particles but with a negligible impact on virus infectivity (p>0.05). TuV and HuNoV suspended in fecal suspensions showed a 1.5-log10 reduction in genomic copies per ml following a 10-min contact time (p

Within the growing field of amino acid metabolism, tryptophan (Trp) catabolism is an area of increasing interest. Trp is essential for protein synthesis, and its metabolism gives rise to biologically active catabolites including serotonin and numerous metabolites in the kynurenine (Kyn) pathway. In normal tissues, the production of Trp metabolites is directly regulated by the tissue-specific expression of Trp-metabolizing enzymes. Alterations of these enzymes in cancers can shift the balance and lead to an increased production of specific byproducts that can function as oncometabolites. For example, increased expression of the enzyme indoleamine 2,3-dioxygenase, which converts Trp into Kyn, leads to an increase in Kyn levels in numerous cancers. Kyn functions as an oncometabolite in cancer cells by promoting the activity of the transcription factor aryl hydrocarbon receptor, which regulates progrowth genes. Moreover, Kyn also inhibits T-cell activity and thus allows cancer cells to evade clearance by the immune system. Therefore, targeting the Kyn pathway has become a therapeutic focus as a novel means to abrogate tumor growth and immune resistance. This review summarizes the biological role and regulation of Trp metabolism and its catabolites with an emphasis on tumor cell growth and immune evasion and outlines areas for future research focus.

This paper describes the testing and pulse performance analysis of a 45 N thruster, designated A45, using a 19.78% monomethylhydrazine–80.22% hydrazine fuel blend with mixed oxides of nitrogen cont...

Experiments involving the irradiation of water contained within magnesium hydroxide and alumina nanoparticle sludges were conducted and culminated in observations of an increased yield of molecular hydrogen when compared to the yield from the irradiation of bulk water. We show that there is a relationship linking this increased yield to the direct nanoscale ionization mechanism in the nanoparticles, indicating that electron emission from the nanoparticles drives new radiative pathways in the water. Because the chemical changes in these sludges are introduced by irradiation only, we have a genuinely unstirred system. This feature allows us to determine the diffusivity of the dissolved gas. Using the measured gas production rate, we have developed a method for modelling when hydrogen bubble formation will occur within the nanoparticle sludges. This model facilitates the determination of a consistent radiolytic consumption rate coinciding with the observations of bubble formation. Thus, we demonstrate a nanoscale radiation effect directly influencing the formation of molecular hydrogen.

Global warming is causing significant losses of marine ice around the polar regions. In Antarctica, the retreat of tidewater glaciers is opening up novel, low-energy habitats (fjords) that have the potential to provide a negative feedback loop to climate change. These fjords are being colonized by organisms on and within the sediment and act as a sink for particulate matter. So far, blue carbon potential in Antarctic habitats has mainly been estimated using epifaunal megazoobenthos (although some studies have also considered macrozoobenthos). We investigated two further pathways of carbon storage and potential sequestration by measuring the concentration of carbon of infaunal macrozoobenthos and total organic carbon (TOC) deposited in the sediment. We took samples along a temporal gradient since time of last glacier ice cover (1–1000 years) at three fjords along the West Antarctic Peninsula. We tested the hypothesis that seabed carbon standing stock would be mainly driven by time since last glacier covered. However, results showed this to be much more complex. Infauna were highly variable over this temporal gradient and showed similar total mass of carbon standing stock per m2 as literature estimates of Antarctic epifauna. TOC mass in the sediment, however, was an order of magnitude greater than stocks of infaunal and epifaunal carbon and increased with time since last ice cover. Thus, blue carbon stocks and recent gains around Antarctica are likely much higher than previously estimated as is their negative feedback on climate change.

Background This study examines cobalt levels and pseudotumor characteristics in a non-recalled modular femoral prosthesis. We sought to determine relationships between serum cobalt levels and pseudotumors following modular and metal-on-metal (MoM) total hip arthroplasty (THA), the location and size of pseudotumors, and changes to pseudotumor grade over time. Methods We retrospectively evaluated a cohort of 190 primary THAs implanted with a dual-modular femoral stem by one surgeon from 2005 to 2013. One hundred seventeen THAs used a cobalt-chromium modular neck (CoCrMN) component and non-MoM articulation, 63 THAs had a titanium neck component and MoM articulation, and 10 had a titanium neck component and polyethylene liner. Serum ion levels were recorded for all patients. Pseudotumor grade and location were measured by musculoskeletal-trained radiologists. Results Cobalt levels did not correlate to time after index arthroplasty. In the CoCrMN group, cobalt levels were elevated in 11 of 19 (57.9%) patients with pseudotumor compared to 14 of 19 (73.7%) in the MoM group. Pseudotumors were more often located lateral to the hip joint in the CoCrMN group compared to anteromedial following MoM arthroplasty. In CoCrMN THAs, pseudotumors were visualized in 12 of 51 (23.5%) initial MARS MRIs within 40 months compared to 5 of 66 (7.6%) performed later (P = .02). Conclusion Pseudotumor characteristics differ between patients with CoCrMN designs vs those with an MoM articulation. Normal serum cobalt levels did not exclude the presence of a pseudotumor and routine MARS MRI should be included in follow-up of patients with this CoCrMN prostheses.

Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.)

BACKGROUND AND PURPOSE Nitrous oxide misuse is a recognized issue worldwide. Prolonged misuse inactivates vitamin B12, causing a myeloneuropathy. METHODS Twenty patients presenting between 2016 and 2020 to tertiary hospitals in Sydney with myeloneuropathy due to nitrous oxide misuse were reviewed. RESULTS The average age was 24 years, and mean canister consumption was 148 per day for 9 months. At presentation, paresthesias and gait unsteadiness were common, and seven patients were bedbound. Mean serum B12 was normal (258 pmol/L, normal range [NR] = 140-750) as was active B12 (87 pmol/L, normal > 35). In contrast, mean serum homocysteine was high (51 μmol/L, NR = 5-15). Spinal magnetic resonance imaging (MRI) showed characteristic dorsal column T2 hyperintensities in all 20 patients. Nerve conduction studies showed a predominantly axonal sensorimotor neuropathy (n = 5). Patients were treated with intramuscular vitamin B12, with variable functional recovery. Three of the seven patients who were bedbound at presentation were able to walk again with an aid at discharge. Of eight patients with follow-up data, most had persistent paresthesias and/or sensory ataxia. Mobility scores at admission and discharge were not significantly correlated with the serum total and active B12 levels or cumulative nitrous oxide use. There were no significant trends between serum active B12 level and cumulative nitrous oxide use (Spearman rho = -0.331, p = 0.195). CONCLUSIONS Nitrous oxide misuse can cause a severe but potentially reversible subacute myeloneuropathy. Serum and active B12 can be normal, while elevated homocysteine and dorsal column high T2 signal on MRI strongly suggest the diagnosis. Neurological deficits can improve with abstinence and B12 supplementation, even in the most severely affected patients.

PURPOSE: PGF(2α) analogs are commonly used to treat glaucoma and are associated with higher rates of meibomian gland dysfunction (MGD). The purpose of this study was to evaluate the physiological effects of PGF(2α) and PGE(2) on immortalized human meibomian gland epithelial cells (HMGECs). METHODS: HMGECs were immunostained for the four PGE(2) receptors (EP1, EP2, EP3, EP4) and the one PGF(2α) receptor (FP) and imaged. Rosiglitazone-differentiated HMGECs were exposed to PGF(2α) and PGE(2) (10(−9) to 10(−6) M) for three hours. Cell viability was assessed by an ATP-based luminescent assay, and lipid extracts were analyzed for cholesteryl esters (CEs), wax esters (WEs), and triacylglycerols (TAGs) by ESI-MSMS(ALL) in positive ion mode by a Triple TOF 5600 Mass Spectrometer using SCIEX LipidView 1.3. RESULTS: HMGECs express three PGE(2) receptors (EP1, EP2, EP4) and the one PGF(2α) receptor (FP). Neither PGE(2) nor PGF(2α) showed signs of cytotoxicity at any of the concentrations tested. WEs were not detected from any of the samples, but CEs and TAGs both exhibited a diverse and dynamic profile. PGE(2) suppressed select CEs (CE 22:1, CE 26:0, CE 28:1, CE 30:1). PGF(2α) dose dependently increased several CEs (CE 20:2, CE 20:1, CE 22:1, CE 24:0) yet decreased others. Both prostaglandins led to nonspecific TAG remodeling. CONCLUSION: PGE(2) and PGF(2α) have minimal effect on HMGEC viability. PGF(2α) influences lipid expression greater than PGE(2) and may do so by interfering with meibocyte differentiation. This work may provide insight into the mechanism of MGD development in glaucoma patients treated with PGF(2α) analogs.

OBJECTIVE Previous work indicates that African-American adolescents are at high risk for concurrent alcohol and cannabis use. The present study examines the associations of traditional ecological predictors of substance use with concurrent alcohol and cannabis use among African-American adolescents. It also examines whether racial identity, a culturally relevant factor, is associated with concurrent use beyond the influence of traditional factors. METHOD Secondary analyses were conducted based on a large survey of high school adolescents. Responses on self-report measures of substance use and psychosocial determinants of health were examined for those respondents in grades 9-12 who identified as African American (N = 465; 59.8% female). RESULTS Findings demonstrated that traditional risk and resilience factors, including externalizing symptoms and substance use beliefs, were related to alcohol and cannabis co-use relative to other patterns of use among African-American adolescents. Racial identity dimensions were also associated with alcohol and cannabis co-use beyond the influence of traditional factors. However, the direction of these associations varied by dimension. CONCLUSIONS Findings from the present study assist in advancing the current knowledge base by identifying potential risk and protective factors for alcohol and cannabis co-use among African-American youth, who face increasing rates of this substance use pattern. They also underscore the importance of accounting for cultural variability in models of adolescent substance use among this population. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Radix Pueraria (the root of kudzu Pueraria lobota) is a popular traditional Chinese medicine used in dietary supplements in Western markets and has potential health benefits. Kudzu roots are rich in isoflavones C‐ and O‐glycosides, of which puerarin (daidzein 8‐C‐glucoside) is the most abundant isoflavone. Puerarin is a unique isoflavone that it is resistant to intestinal hydrolysis and has a wide range of effects in preventing metabolic diseases. Our previous studies indicate that chronic exposure to a diet enriched in puerarin significantly reduces serum total cholesterol, arterial blood pressure, insulin resistance and hyperglycemia in ovariectomized, stroke‐prone spontaneously hypertensive rats (SP‐SHR), a model of metabolic syndrome. Further, our studies demonstrate that puerarin is absorbed as the intact glucoside and acutely improves glucose tolerance, indicating that it has potential for the prevention and treatment of diabetes. This paper reviews recent progress in the understanding of biological activities and metabolism and in the analysis of puerarin in kudzu root extracts or supplements.

The way molecules absorb, transfer, and emit light can be modified by coupling them to optical cavities. The extent of the modification is often defined by the cavity-molecule coupling strength, which depends on the number of coupled molecules. We experimentally and numerically study the evolution of photoemission from a thin layered J-aggregated molecular material strongly coupled to a Fabry-Perot microcavity as a function of the number of coupled layers. We unveil an important difference between the strong coupling signatures obtained from reflection spectroscopy and from polariton assisted photoluminescence. We also study the effect of the vibrational modes supported by the molecular material on the polariton assisted emission both for a focused laser beam and for normally incident excitation, for two different excitation wavelengths: a laser in resonance with the lower polariton branch, and a laser not in resonance. We found that Raman scattered photons appear to play an important role in populating the lower polariton branch, especially when the system was excited with a laser in resonance with the lower polariton branch. We also found that the polariton assisted photoemission depends on the extent of modification of the molecular absorption induced by the molecule-cavity coupling., Nanoscale, 13 (34), ISSN:2040-3364, ISSN:2040-3372

Combretastatin A‐4 (CA4) is a potent anti‐mitotic and vascular disrupting agent. Organic chemists have been working to optimize the synthesis of CA4 for the past 3 decades, with methods requiring hazardous solvents and harsh reaction conditions. Here, we report the synthesis of CA4 and a variety of stilbenes in an aqueous Wittig system. Potassium carbonate or lithium hydroxide were used as base in this Wittig reaction to give excellent yields of mixtures of E‐ and Z‐stilbenes. The synthesis of CA4 was achieved using tetrahydropyran (THP) or silyl protected phenolic aldehydes. The THP groups were removed using dilute acid whilst the silyl groups fortuitously fell off during work up.

G-protein coupled receptors (GPCRs) sense a wide variety of stimuli, including lipids, and transduce signals to the intracellular environment to exert various physiological responses. However, the structural features of GPCRs responsible for detecting and triggering responses to distinct lipid ligands have only recently begun to be revealed. 14,15-epoxyeicosatrienoic acid (14,15-EET) is one such lipid mediator that plays an essential role in the vascular system, displaying both vasodilatory and anti-inflammatory properties. We recently reported multiple low-affinity 14,15-EET-binding GPCRs, but the mechanism by which these receptors sense 14,15-EET remains unclear. Here, we have taken a combined computational and experimental approach to identify and confirm critical residues and properties within the lipid-binding pocket. Furthermore, we generated mutants to engineer selected GPCR-predicted binding sites to either confer or abolish 14,15-EET-induced signaling. Our structure-function analyses indicate that hydrophobic and positively charged residues of the receptor-binding pocket are prerequisites for recognizing lipid ligands such as 14,15-EET and possibly other eicosanoids.

The spread of SARS-CoV-2 has led to a devastating pandemic, with infections resulting in a range of symptoms collectively known as COVID-19. The full repertoire of human tissues and organs susceptible to infection is an area of active investigation, and some studies have implicated the reproductive system. The effects of COVID-19 on human reproduction remain poorly understood, and particularly the impact on early embryogenesis and establishment of a pregnancy are not known. In this work, we explore the susceptibility of early human embryos to SARS-CoV-2 infection. By using RNA-seq and immunofluorescence, we note that ACE2 and TMPRSS2, two canonical cell entry factors for SARS-CoV-2, are co-expressed in cells of the trophectoderm in blastocyst-stage preimplantation embryos. For the purpose of viral entry studies, we used fluorescent reporter virions pseudotyped with Spike (S) glycoprotein from SARS-CoV-2, and we observe robust infection of trophectoderm cells. This permissiveness could be attenuated with blocking antibodies targeting S or ACE2. When exposing human blastocysts to the live, fully infectious SARS-CoV-2, we detected cases of infection that compromised embryo health. Therefore, we identify a new human target tissue for SARS-CoV-2 with potential medical implications for reproductive health during the COVID-19 pandemic and its aftermath.

Background: Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit-safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods: A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings: Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit-safety balances remain better than those of the noncannabinoid drugs. Interpretation: The benefit-safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.

This Tutorial Account aims to be a useful educational resource which describes how to automate fluorine-18 positron emission tomography (PET) radiochemistry using cassette-based automated radiosynthesis platforms.

To evaluate the effects of water hardness on survival to hatch of eyed rainbow trout Oncorhynchus mykiss eggs during iodophor disinfection, hard (300 mg/L CaCl2) and soft water (20 mg/L CaCl2) solutions were used in combination with iodophor treatments of 0, 100, 200, 400, 800, and 1600 mg/L. Water hardness did not significantly influence egg survival-to-hatch. In addition, there was no significant interaction between water hardness and iodine concentration on egg survival. However, significant differences in egg survival due to iodine concentration were observed. Egg survival significantly decreased at 800 mg/L, with near complete mortality occurring at 1,600 mg/L. Rainbow trout eyed egg disinfection using iodine concentrations of 800 mg/L or greater are not recommended, regardless of water hardness (calcium) concentrations. Keywords: Eyed eggs, iodophor, disinfection, rainbow trout, water hardness, mortality.

Objectives: The objective of this study was to describe the real-world use and effectiveness of dolutegravir-based regimens (DBRs) in routine clinical practice in the United Kingdom. Methods: Retrospective analysis was conducted using data from four National Health Service trusts using Climate-HIV, an electronic case record system. Eligible patients were aged ≥18 years with HIV-1 infection who were prescribed a DBR from December 2012 to March 2018. Outcome measurements were accessed at DBR initiation and at weeks 24, 48 and 96 and the last recorded visit up to the extraction date (last measurement). The primary endpoint was the proportion of patients with HIV-1 RNA Results: The study cohort included 934 patients; 337 (36%) were female, 414 (47%) were white and 717 (77%) were treatment experienced (TE). The Kaplan–Meier estimated probability of achieving HIV-1 RNA Conclusions: High levels of virologic suppression and low rates of discontinuation of DBRs were seen in a large, diverse, UK-based population with HIV-1 infection. These findings are broadly consistent with efficacy data from phase III studies.

Background In plants, a large diversity of polysaccharides comprise the cell wall. Each major type of plant cell wall polysaccharide, including cellulose, hemicellulose, and pectin, has distinct structures and functions that contribute to wall mechanics and influence plant morphogenesis. In recent years, pectin valorization has attracted much attention due to its expanding roles in biomass deconstruction, food and material science, and environmental remediation. However, pectin utilization has been limited by our incomplete knowledge of its structure. Herein, we present a workflow of principles relevant for the characterization of polysaccharide primary structure using nature’s most complex polysaccharide, rhamnogalacturonan-II (RG-II), as a model. Results We outline how to isolate RG-II from celery and duckweed cell walls and from red wine using chemical or enzymatic treatments coupled with size-exclusion chromatography. From there, we applied mass spectrometry (MS)-based techniques to determine the glycosyl residue and linkage compositions of the intact RG-II and derived oligosaccharides including special considerations for labile monosaccharides. In doing so, we demonstrated that in the duckweed Wolffiella repanda the arabinopyranosyl (Arap) residue of side chain B is substituted at O-2 with rhamnose. We used electrospray-MS techniques to identify non-glycosyl modifications including methyl-ethers, methyl-esters, and acetyl-esters on RG-II-derived oligosaccharides. We then showed the utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) to investigate the structure of intact RG-II and to complement the RG-II dimerization studies performed using size-exclusion chromatography. Conclusions The complexity of pectic polysaccharide structures has hampered efforts aimed at their valorization. In this work, we used RG-II as a model to demonstrate the steps necessary to isolate and characterize polysaccharides using chromatographic, MS, and NMR techniques. The principles can be applied to the characterization of other saccharide structures and will help inform researchers on how saccharide structure relates to functional properties in the future.