Problems making proteins kills nerve cells: Neurodegeneration is associated with a variety of different diseases, but its cellular roots are often obscure. Ishimura et al. find that mutant mice whose brain cells start to die rapidly soon after birth have lost the function of two vital cellular components (see the Perspective by Darnell). The first is a protein that releases stalled ribosomes stuck on messenger RNA (mRNA); the second is a transfer RNA (tRNA), which reads the code for arginine in the mRNA. This tRNA is expressed predominantly in the central nervous system. The lack of the tRNA leads to increased ribosomal stalling at arginine codons, which, when left uncorrected, blocks protein synthesis and proves fatal. Science , this issue p. 455 ; see also p. 378

Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.

We study the dynamics of the passage of a polymer through a membrane pore (translocation), focusing on the scaling properties with the number of monomers N. The natural coordinate for translocation is the number of monomers on one side of the hole at a given time. Commonly used models that assume Brownian dynamics for this variable predict a mean (unforced) passage time $\tau$ that scales as $N^2,$ even in the presence of an entropic barrier. In particular, however, the time it takes for a free polymer to diffuse a distance of the order of its radius by Rouse dynamics scales with an exponent larger than two, and this should provide a lower bound to the translocation time. To resolve this discrepancy, we perform numerical simulations with Rouse dynamics for both phantom (in space dimensions $d=1\mathrm{}$ and 2), and self-avoiding (in $d=2)$ chains. The results indicate that for large N, translocation times scale in the same manner as diffusion times, but with a larger prefactor that depends on the size of the hole. Such scaling implies anomalous dynamics for the translocation process. In particular, the fluctuations in the monomer number at the hole are predicted to be nondiffusive at short times, while the average pulling velocity of the polymer in the presence of a chemical-potential difference is predicted to depend on N.

Michael A. Kiebish, Xianlin Han, Hua Cheng, Jeffrey H. Chuang, Thomas N. Seyfried

Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of C57BL/6J-Gtpbp2^nmf205-/- mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNA^Arg_UCU tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2α (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2α kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in C57BL/6J-Gtpbp2^nmf205-/- mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress.