Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68⁺ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.

     

New antiarrhythmic drugs for atrial fibrillation: Focus on dronedarone and vernakalant

The prevalence of atrial fibrillation (AF) is forecast to rise to 2–5% of the general population by 2050. Of the two fundamental treatment strategies for AF management, rhythm control is the approach which is generally preferred for active, symptomatic, and/or younger patients, whereas rate control is all that is found necessary in the more elderly, sedentary, asymptomatic individual. In many cases, at neither extreme, there remains a genuine choice of therapy, and for those patients, antiarrhythmic strategies would be preferred if effective and safe antiarrhythmic medications were available. Many new antiarrhythmic agents exploiting new mechanisms of action or novel combinations of established antiarrhythmic activity are currently being investigated. Agents which selectively inhibit ion channels specifically involved in atrial repolarization, so-called atrial repolarization delaying agents, are widely acknowledged as potentially ideal antiarrhythmic treatments, as they will probably be both effective and safe, at the very least (free of pro-arrhythmic effects at the ventricular level). Modified analogues of traditional antiarrhythmic drugs with different combinations of ion channel and receptor blocking effects, novel mechanisms of action, and less complicated metabolic profiles are also under development. Completely innovative antiarrhythmic agents with new antiarrhythmic mechanisms, such as stretch receptor antagonism, sodium calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation are also being explored. In addition, there is increasing evidence in support of the antiarrhythmic action of non-antiarrhythmic drugs. Treatments with statins, omega-3 fatty acids, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and aldosterone antagonists are all potentially valuable, over and above any effect related to the treatment of underlying heart disease. Professor A. John Camm is a consultant to AstraZeneca, Cardiome, sanofi aventis, and Xention.     

Effects of Q/N-rich, polyQ, and non-polyQ amyloids on the de novo formation of the [PSI+] prion in yeast and aggregation of Sup35 in vitro

Prions are infectious protein conformations that are generally ordered protein aggregates. In the absence of prions, newly synthesized molecules of these same proteins usually maintain a conventional soluble conformation. However, prions occasionally arise even without a homologous prion template. The conformational switch that results in the de novo appearance of yeast prions with glutamine/aspargine (Q/N)-rich prion domains (e.g., [PSI+]), is promoted by heterologous prions with a similar domain (e.g., [RNQ+], also known as [PIN+]), or by overexpression of proteins with prion-like Q-, N-, or Q/N-rich domains. This finding led to the hypothesis that aggregates of heterologous proteins provide an imperfect template on which the new prion is seeded. Indeed, we show that newly forming Sup35 and preexisting Rnq1 aggregates always colocalize when [PSI+] appearance is facilitated by the [RNQ+] prion, and that Rnq1 fibers enhance the in vitro formation of fibers by the prion domain of Sup35 (NM). The proteins do not however form mixed, interdigitated aggregates. We also demonstrate that aggregating variants of the polyQ-containing domain of huntingtin promote the de novo conversion of Sup35 into [PSI+]; whereas nonaggregating variants of huntingtin and aggregates of non-polyQ amyloidogenic proteins, transthyretin, alpha-synuclein, and synphilin do not. Furthermore, transthyretin and alpha-synuclein amyloids do not facilitate NM aggregation in vitro, even though in [PSI+] cells NM and transthyretin aggregates also occasionally colocalize. Our data, especially the in vitro reproduction of the highly specific heterologous seeding effect, provide strong support for the hypothesis of cross-seeding in the spontaneous initiation of prion states.     

Energetics and Mechanism of Conformational Transitions of Protein‐Like NIPAM‐Sodium Styrene Sulfonate Copolymers in Aqueous Solutions

Protein‐like and random NIPAM‐sodium styrene sulfonate copolymers of similar composition have been prepared by radical polymerization in water at temperatures above and below the LCST of PNIPAM, respectively. Thermal transitions of the copolymers in aqueous solutions have been studied by means of dynamic light scattering, viscometry, and high‐sensitivity differential scanning calorimetry. The phase separation or cooperative conformational transitions without phase separation were observed for the random or the protein‐like copolymers, respectively. Transition temperature, enthalpy, and heat capacity increment of the protein‐like copolymer differed insignificantly from those of the random copolymer of similar composition. The transition heat capacity increments of the protein‐like copolymers revealed that only 10–20% of their NIPAM links participate in the formation of a dense water‐free globule core. The coil–globule transitions of the protein‐like copolymers were described by the thermodynamic three‐state model according to the scheme “random coil?condensed coil?globule”, which is known to simulate the folding mechanism of globular proteins.

     

Using Patient Feedback to Optimize the Design of a Certolizumab Pegol Electromechanical Self-Injection Device: Insights from Human Factors Studies

Introduction

We incorporated patient feedback from human factors studies (HFS) in the patient-centric design and validation of ava^®, an electromechanical device (e-Device) for self-injecting the anti-tumor necrosis factor certolizumab pegol (CZP).

Methods

Healthcare professionals, caregivers, healthy volunteers, and patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or Crohn’s disease participated in 11 formative HFS to optimize the e-Device design through intended user feedback; nine studies involved simulated injections. Formative participant questionnaire feedback was collected following e-Device prototype handling. Validation HFS (one EU study and one US study) assessed the safe and effective setup and use of the e-Device using 22 predefined critical tasks. Task outcomes were categorized as “failures” if participants did not succeed within three attempts.

Results

Two hundred eighty-three participants entered formative (163) and validation (120) HFS; 260 participants performed one or more simulated e-Device self-injections. Design changes following formative HFS included alterations to buttons and the graphical user interface screen. All validation HFS participants completed critical tasks necessary for CZP dose delivery, with minimal critical task failures (12 of 572 critical tasks, 2.1%, in the EU study, and 2 of 5310 critical tasks, less than 0.1%, in the US study).

Conclusion

CZP e-Device development was guided by intended user feedback through HFS, ensuring the final design addressed patients’ needs. In both validation studies, participants successfully performed all critical tasks, demonstrating safe and effective e-Device self-injections.

Funding

UCB Pharma.

Plain Language Summary

Plain language summary available on the journal website.