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Cells must operate far from equilibrium, utilizing and dissipating energy continuously to maintain their organization and to avoid stasis and death. However, they must also avoid unnecessary waste of energy. Recent studies have revealed that molecular machines are extremely efficient thermodynamically compared with their macroscopic counterparts. However, the principles governing the efficient out-of-equilibrium operation of molecular machines remain a mystery. A theoretical framework has been recently formulated in which a generalized friction coefficient quantifies the energetic efficiency in nonequilibrium processes. Moreover, it posits that, to minimize energy dissipation, external control should drive the system along the reaction coordinate with a speed inversely proportional to the square root of that friction coefficient. Here, we demonstrate the utility of this theory for designing and understanding energetically efficient nonequilibrium processes through the unfolding and folding of single DNA hairpins.

Wearable devices have generally been rigid due to their reliance on silicon‐based technologies, while future wearables will utilize flexible components for example transistors within microprocessors to manage data. Two‐dimensional (2D) semiconducting flakes have yet to be investigated in fiber transistors but can offer a route toward high‐mobility, biocompatible, and flexible fiber‐based devices. Here, the electrochemical exfoliation of semiconducting 2D flakes of tungsten diselenide (WSe2) and molybdenum disulfide (MoS2) is shown to achieve homogeneous coatings onto the surface of polyester fibers. The high aspect ratio (>100) of the flake yields aligned and conformal flake‐to‐flake junctions on polyester fibers enabling transistors with mobilities μ ≈1 cm2 V−1 s−1 and a current on/off ratio, Ion/Ioff ≈102–104. Furthermore, the cytotoxic effects of the MoS2 and WSe2 flakes with human keratinocyte cells are investigated and found to be biocompatible. As an additional step, a unique transistor 'knot' architecture is created by leveraging the fiber diameter to establish the length of the transistor channel, facilitating a route to scale down transistor channel dimensions (≈100 µm) and utilize it to make a MoS2 fiber transistor with a human hair that achieves mobilities as high as μ ≈15 cm2 V−1 s−1. [ABSTRACT FROM AUTHOR]

Aim: For patients with locally advanced rectal cancer, previous STELLAR studies have shown that a new adjuvant treatment paradigm of short‐course radiotherapy followed by neoadjuvant chemotherapy can achieve pathological complete response rates superior to those of standard care; however, the 3‐year DFS is inferior to neoadjuvant concurrent radiotherapy. Recent studies have shown that immune checkpoint inhibitors may improve the prognosis of rectal cancer and have good synergy with radiotherapy. Therefore, neoadjuvant chemotherapy combined with immune checkpoint inhibitors after a short course of radiotherapy has the potential to further improve complete response rates and prognosis. Method: The STELLAR II study is a multicentre, open label, two‐arm randomized, phase II/III trial of short‐course radiotherapy followed by neoadjuvant chemotherapy concurrent with immunotherapy for locally advanced rectal cancer. A total of 588 patients with locally advanced rectal cancer (LARC) will be randomly assigned to the experimental and control groups. The experimental group will receive short‐course radiotherapy and neoadjuvant chemotherapy in combination with sindilizumab, while the control group will receive short‐course radiotherapy and neoadjuvant chemotherapy. Both groups will subsequently receive either total rectal mesenteric resection or a watch & wait (W&W) strategy. The phase II primary endpoint is the complete remission rate, and the secondary endpoints include grade 3–4 adverse events, perioperative complications, R0 resection rate, overall survival, local recurrence rate, distant metastasis rate and quality of life score. A seamless phase II/III randomized controlled design will be used to investigate the effectiveness and safety of the TNT strategy with the addition of immunotherapy. The trial opened, and the first patient was recruited on 31 August 2022. Trial registration number and date of registration: ClinicalTrials.govNCT05484024, 29 July 2022. Discussion: The STELLAR II trial will prospectively evaluate the efficacy of TNT treatment strategies that incorporate immune checkpoint inhibitors. The trial will yield important information to guide routine management of patients with local advanced rectal cancer. [ABSTRACT FROM AUTHOR]

Subunits in multimeric ring-shaped motors must coordinate their activities to ensure correct and efficient performance of their mechanical tasks. Here, we study WT and arginine finger mutants of the pentameric bacteriophage φ29 DNA packaging motor. Our results reveal the molecular interactions necessary for the coordination of ADP-ATP exchange and ATP hydrolysis of the motor's biphasic mechanochemical cycle. We show that two distinct regulatory mechanisms determine this coordination. In the first mechanism, the DNA up-regulates a single subunit's catalytic activity, transforming it into a global regulator that initiates the nucleotide exchange phase and the hydrolysis phase. In the second, an arginine finger in each subunit promotes ADP-ATP exchange and ATP hydrolysis of its neighbor. Accordingly, we suggest that the subunits perform the roles described for GDP exchange factors and GTPase-activating proteins observed in small GTPases. We propose that these mechanisms are fundamental to intersubunit coordination and are likely present in other ring ATPases.

This work formulates and investigates a steel grade design problem (SGDP) arising from a production process of steelmaking continuous casting. For the first time, we consider uncertain yield and demand in SGDP and construct a two-stage robust optimisation model accordingly. Then, we propose an enhanced column-and-constraint generation algorithm to obtain high-quality solutions. By exploiting the problem characteristics, we first use a Lagrangian relaxation method to decompose SGDP into multiple subproblems and then apply a standard column-and-constraint generation algorithm to solve the latter. At last, we test the proposed algorithm by extensive instances constructed based on actual production rules of a steelmaking shop. Numerical results show that it can effectively solve large-scale SGDPs. The obtained plan is better than those obtained by a commonly-used and standard column-and-constraint generation algorithm. [ABSTRACT FROM AUTHOR]