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 N2, 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 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.

In higher eukaryotes, tRNAs with the same anticodon are encoded by multiple nuclear genes and little is known about how mutations in these genes affect translation and cellular homeostasis. Similarly, the surveillance systems that respond to such defects in higher eukaryotes are not clear. Here, we discover that loss of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, in mice with a mutation in a tRNA gene that is specifically expressed in the central nervous system causes ribosome stalling and widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes.

Otto Warburg first proposed that cancer originated from irreversible injury to mitochondrial respiration, but the structural basis for this injury has remained elusive. Cardiolipin (CL) is a complex phospholipid found almost exclusively in the inner mitochondrial membrane and is intimately involved in maintaining mitochondrial functionality and membrane integrity. Abnormalities in CL can impair mitochondrial function and bioenergetics. We used shotgun lipidomics to analyze CL content and composition in highly purified brain mitochondria from the C57BL/6J (B6) and VM/Dk (VM) inbred strains and from subcutaneously grown brain tumors derived from these strains to include an astrocytoma and ependymoblastoma (B6 tumors), a stem cell tumor, and two microgliomas (VM tumors). Major abnormalities in CL content or composition were found in all tumors. The compositional abnormalities involved an abundance of immature molecular species and deficiencies of mature molecular species, suggesting major defects in CL synthesis and remodeling. The tumor CL abnormalities were also associated with significant reductions in both individual and linked electron transport chain activities. A mathematical model was developed to facilitate data interpretation. Otto Warburg first proposed that the prime cause of cancer was impaired energy metabolism (1, 2). This impairment involved irreversible injury to cellular respiration that was followed in time by a gradual dependence on fermentation (glycolytic) energy to compensate for the energy lost from respiration. Cell viability requires a constant delta G′ of ATP hydrolysis of approximately 257 kJ/mol (3, 4). Most normal mammalian cells achieve this level of useable energy through respiration, whereas tumor cells achieve this level through a combination of respiration and glycolysis (2, 5). Indeed, elevated glycolysis is the metabolic hallmark of nearly all tumors, including brain tumors, and is the basis for tumor imaging using labeled glucose analogs (5-8). Much controversy has surrounded the Warburg theory, however, largely over issues regarding the Pasture effect and aerobic glycolysis (9-14). Numerous structural and biochemical abnormalities occur in tumor cell mitochondria that could compromise function, thus forcing a reliance on glycolysis for cell survival (5,6,9,(15)(16)(17). Although several prior studies have evaluated the lipid composition of tumor mitochondria (18)(19)(20)(21)(22)(23)(24)(25), no prior studies have evaluated both the content and the composition of cardiolipin (CL) in highly purified mitochondria isolated from brain tumors and from their orthotopic host tissue.CL (1,3-diphosphatidyl-sn -glycerol) is a complex mitochondrial-specific phospholipid that regulates numerous enzyme activities, especially those related to oxidative phosphorylation and coupled respiration (26-31). CL binds complexes I, III, IV, and V and stabilizes the super complexes (I/III/IV and II/III/IV), demonstrating an absolute requirement of CL for catalytic activity of these enzyme comp...

Molecular imprinting (MI) is a technique for preparing polymer scaffolds that function as synthetic receptors1 -3, and imprinted polymers that can selectively recognize organic compounds have been proven useful for sensor development2 -7. Although creating synthetic MI polymers (MIPs) that recognize proteins remains challenging8 -11, nanodevices and nanomaterials show promise for protein recognition into sensor architectures12 -14. Here, we show that arrays of carbon nanotube (nanotube) tips imprinted with a non-conducting polymer coating can recognize proteins with subpicogram per litre sensitivity using electrochemical impedance spectroscopy. We specifically developed MI sensors for human ferritin and human papillomavirus derived E7 protein. The MI-based nanosensor can also discriminate between Ca 2+ -induced conformational changes in calmodulin. This ultrasensitive, label-free electrochemical detection of proteins offers an alternative to biosensors based on biomolecule recognition.MI technology offers considerable potential as a cost-effective alternative to the use of biomolecule-based recognition in a variety of sensor applications [15][16][17] . MIPs afford the creation of specific recognition sites in synthetic polymers by a process that involves copolymerization of functional monomers and cross-linkers around template molecules. The molecules are removed from the polymer, rendering complementary binding sites capable of subsequent template molecule recognition 1-3. Although deposition of MIPs onto the surface * To whom correspondence should be addressed: caid@bc.edu . Author contributions D.C. contributed to the original nano-imprinting concept, overall experimental design, data analysis, manuscript preparation, and directed the measurements; L.R. was responsible for the EIS recordings and contributed to sensor fabrication; H.Z. fabricated the nanotube arrays; C.J.X. was responsible for protein preparation and purification; Y.Y. contributed to the PPn nanocoating; H.W. and Y.L. contributed to the high resolution transmission electron microscopy image; M.F.R. was responsible for the circular dichroism measurements; L.Z. and J.C. were responsible for computational analysis of the interaction between E7 protein and PPn; M.J.N. provided technical support for nanotube fabrication and assisted in manuscript editing; Z.F.R. contributed expertise for nanotube fabrication, experiment design for transmission electron microscopy evaluation of hFtn entrapment, and manuscript editing; and T.C. contributed to the design of experiments for demonstrating nanosensor selectivity and was responsible for writing and editing the revised manuscript. Additional InformationThe authors declare no competing financial interests in connection to this publication.Supplementary information accompanies this paper at www.nature.com/naturenanotechnology. Reprints and permission information is available online at http://npg.nature.com/reprintsandpermissions/. □Correspondence and requests for materials should be addressed to D.C.Summary ...

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.