The Parker problem: existence of smooth force-free fields and coronal heating

Parker (Astrophys J 174:499, 1972) put forward a hypothesis regarding the fundamental nature of equilibrium magnetic fields in astrophysical plasmas. He proposed that if an equilibrium magnetic field is subjected to an arbitrary, small perturbation, then—under ideal plasma dynamics—the resulting magnetic field will in general not relax towards a smooth equilibrium, but rather, towards a state containing tangential magnetic field discontinuities. Even at astrophysical plasma parameters, as the singular state is approached dissipation must eventually become important, leading to the onset of rapid magnetic reconnection and energy dissipation. This topological dissipation mechanism remains a matter of debate, and is a key ingredient in the nanoflare model for coronal heating. We review the various theoretical and computational approaches that have sought to prove or disprove Parker’s hypothesis. We describe the hypothesis in the context of coronal heating, and discuss different approaches that have been taken to investigating whether braiding of magnetic field lines is responsible for maintaining the observed coronal temperatures. We discuss the many advances that have been made, and highlight outstanding open questions.

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10−11 M), but also shows improved safety with lower bystander toxicity (IC50: 10−9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.