Sulfobetaine Zwitterions with Embedded Fluorocarbons: Synthesis and Interfacial Properties.

We describe the preparation of a new set of fluorinated sulfobetaine (FSB) zwitterionic polymers in which fluorocarbon moieties are attached directly to the zwitterionic components. An efficient two-step modification to the conventional sulfobetaine methacrylate monomer synthesis gave access to a series of polymer zwitterions containing varying extents of fluorocarbon character. FSB methacrylates proved amenable to homo- and copolymerizations using reversible addition-fragmentation chain transfer (RAFT) conditions, affording polymers with molecular weights ranging from 5 to 20 kDa and with low molecular weight distributions. Thin films of FSB homopolymers on glass proved stable to aqueous environments and exhibited increasing hydrophobicity with fluorocarbon content, as well as remarkably large water contact angle hysteresis values that enable pinning of water droplets on hydrophobic surfaces, reminiscent of the "petal effect" found in nature. FSB-containing copolymers in aqueous media demonstrated markedly reduced oil-water interfacial tension values, even with moderate (20-50 mol %) FSB incorporation.

Exercise Preconditioning Preserves Cardiac Function and Enhances Cardiac Recovery Following Dobutamine Stimulation in Doxorubicin-Treated Rat Hearts.

Exercise preconditioning has been shown to protect against DOX-induced cardiac dysfunction when hearts are maintained under resting conditions. However, it is unclear whether this exercise-induced protective effect is maintained when the heart is challenged with the ß1-adrenergic receptor agonist dobutamine (DOB), which mimics acute exercise stress. Fischer 344 rats were randomly assigned to sedentary (SED) or voluntary wheel running (WR) groups for 10 weeks. At week 11, rats were treated with either 15 mg/kg DOX or saline (SAL). Five days later, ex vivo cardiac function was assessed using an isolating working heart model at baseline, during the infusion of 7.5 µg/kg/min DOB, and during recovery. DOB infusion significantly increased left ventricular developed pressure (LVDP), maximal (dP/dtmax) and minimal (dP/dtmin) rate of left ventricular pressure development, and heart rate in all groups (p<0.05). SED+DOX also showed a lower baseline and recovery LVDP than WR+DOX (83 ± 12 vs. 109 ± 6 mmHg baseline, 76 ± 11 vs. 100 ± 10 mmHg recovery, p<0.05). WR+DOX showed higher dP/dtmax and lower dP/dtmin when compared to SED+DOX during DOB infusion (7311 ± 1481 vs. 5167 ± 1436 mmHg/s and -4059 ± 1114 vs.-3158 ± 1176 mmHg/s, respectively). SED+DOX dP/dtmax was significantly lower during baseline and during recovery when compared to all other groups (p<0.05). These data suggest that exercise preconditioning preserved cardiac function after DOX exposure even when the heart is challenged with DOB, and it appeared to preserve the heart's ability to recover from this functional challenge.

Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression (CREATINE-52): a protocol for a double-blind randomized controlled trial.

BACKGROUND: Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). The backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC) is androgen deprivation therapy (ADT) with an androgen signaling inhibitor. ADT is an effective cancer treatment, but it facilitates significant declines in muscle mass and adverse health outcomes important to mCSPC survivors, such as fatigue, and reductions in physical function, independence, insulin sensitivity, and QoL. In non-metastatic CSPC survivors, resistance training (RT) preserves muscle mass and improves these related health outcomes, but the biggest barrier to RT in CSPC survivors of all stages is fatigue. Creatine monohydrate supplementation coupled with RT (Cr + RT) may address this barrier since creatine plays a critical role in energy metabolism. Cr + RT in cancer-free older adults and other clinical populations improves muscle mass and related health outcomes. Evidence also suggests that creatine supplementation can complement cancer treatment. Thus, Cr + RT is a strategy that addresses gaps in survivorship needs of people with mCSPC. The purpose of this parallel, double-blind randomized controlled trial is to test the effects of 52-weeks of Cr + RT compared with placebo (PLA) and RT (PLA + RT) on muscle mass, other related health outcomes, and markers of cancer progression. METHODS: We will carry out this trial with our team's established, effective, home-based, telehealth RT program in 200 mCSPC survivors receiving ADT, and evaluate outcomes at baseline, 24-, and 52-weeks. RT will occur twice weekly with elastic resistance bands, and an established creatine supplementation protocol will be used for supplementation delivery. Our approach addresses a major facilitator to RT in mCSPC survivors, a home-based RT program, while utilizing a supervised model for safety. DISCUSSION: Findings will improve delivery of comprehensive survivorship care by providing a multicomponent, patient-centered lifestyle strategy to preserve muscle mass, improve health outcomes, and complement cancer treatment (NCT06112990).

A single-centre, observational study to evaluate immune response to Covid-19 vaccines in immunocompromised patients with haematological disorders (COVAC-IC)

ObjectiveTo evaluate immunological response to Covid-19 vaccines in immunocompromised haematology patients and compare with immunocompetent healthy controls DesignWe compared total Anti-SARS-CoV-2 spike antibody and T cell response in 45 immunocompromised haematology patients with 30 healthy adults following 2 doses of Covid-19 vaccine for 3 -5 months at 30 day intervals SettingSingle Centre, University Hospital, United Kingdom, March 2021-December 2021 Main Outcome measuresPeak quantitative total spike-specific antibody and cellular responses ResultsWe found O_LINon - significant difference in T cell and total Anti-SARS-CoV-2 S antibody response between study and control group patients C_LIO_LISix (13%) study group participants did not have detectable Total Anti-SARS -Cov-2 S antibodies at any time point throughout the study monitoring period. C_LIO_LIThree (7%) of the study group participants had no response, even after additional booster doses of Covid-19 vaccine. C_LIO_LIAll (100%) of the control group had detectable Anti-SARS-Cov-2 S antibodies after 2 doses of Covid-19 vaccine. C_LIO_LINo participant died or was hospitalised due to severe Covid-19 infection during the study period. This included study group participants who had no antibody response at any time point. C_LI ConclusionsThough there was a non - significant difference in T cell and total Anti-SARS-CoV-2 S antibody response between immunocompromised patients and healthy controls this did not result in any severe infection or Covid-19 related mortality in our study cohort. We did not identify any patient-specific factor (age, gender), specific haematological condition or treatment as determinant of response. Covid-19 vaccination was well tolerated without major side effects in both groups. What was already known about this topicprior to starting this study there were no studies to confirm immunological response following Covid-19 vaccination in immunocompromised haematology patients. During the conduct of our study there have been publications from researchers confirming blunted serological response in 62-66% of immunocompromised haematology patients compared to 74-95% in healthy controls. What this study addsOur study did not identify a significant difference in serological or T cell response between immunocompromised and healthy groups. Though 13% of immunocompromised patients had no response to Covid-19 vaccination none of them suffered from severe Covid-19 infection. We believe T cell response to Covid-19 vaccination has an important role in providing protective efficacy against Covid-19.

T Cell Zone Resident Macrophages Silently Dispose of Apoptotic Cells in the Lymph Node.

In lymph nodes (LNs), dendritic cells (DCs) are thought to dispose of apoptotic cells, a function pertaining to macrophages in other tissues. We found that a population of CX3CR1+ MERTK+ cells located in the T cell zone of LNs, previously identified as DCs, are efferocytic macrophages. Lineage-tracing experiments and shield chimeras indicated that these T zone macrophages (TZM) are long-lived macrophages seeded in utero and slowly replaced by blood monocytes after birth. Imaging the LNs of mice in which TZM and DCs express different fluorescent proteins revealed that TZM-and not DCs-act as the only professional scavengers, clearing apoptotic cells in the LN T cell zone in a CX3CR1-dependent manner. Furthermore, similar to other macrophages, TZM appear inefficient in priming CD4 T cells. Thus, efferocytosis and T cell activation in the LN are uncoupled processes designated to macrophages and DCs, respectively, with implications to the maintenance of immune homeostasis.

Ferredoxin competes with bacterial frataxin in binding to the desulfurase IscS.

The bacterial iron-sulfur cluster (isc) operon is an essential machine that is highly conserved from bacteria to primates and responsible for iron-sulfur cluster biogenesis. Among its components are the genes for the desulfurase IscS that provides sulfur for cluster formation, and a specialized ferredoxin (Fdx) whose role is still unknown. Preliminary evidence suggests that IscS and Fdx interact but nothing is known about the binding site and the role of the interaction. Here, we have characterized the interaction using a combination of biophysical tools and mutagenesis. By modeling the Fdx·IscS complex based on experimental restraints we show that Fdx competes for the binding site of CyaY, the bacterial ortholog of frataxin and sits in a cavity close to the enzyme active site. By in vivo mutagenesis in bacteria we prove the importance of the surface of interaction for cluster formation. Our data provide the first structural insights into the role of Fdx in cluster assembly.