In many cell types, mitochondria undergo extensive fusion and fission to form dynamic, responsive network structures that contribute to a number of homeostatic, metabolic, and signaling functions. The relationship between the dynamic interactions of individual mitochondrial units and the cell-scale network architecture remains an open area of study. In this work, we use coarse-grained simulations and approximate analytic models to establish how the network morphology is governed by local mechanical and kinetic parameters. The transition between fragmented structures and extensive networks is controlled by local fusion-to-fission ratios, network density, and geometric constraints. Similar fusion rate constants are found to account for the very different structures formed by mammalian networks (poised at the percolation transition) and well-connected budding yeast networks. Over a broad parameter range, the simulated network structures can be described by effective mean-field association constants that exhibit a nonlinear dependence on the microscopic nonequilibrium fusion, fission, and transport rates. Intermediate fusion rate constants are shown to result in the highest rates of network remodeling, with mammalian mitochondrial networks situated in a regime of high turnover. This spatially resolved modeling and simulation framework helps elucidate the emergence of cellular scale network structures, and allows for the quantitative extraction of microscopic kinetic parameters from past and future experimental data. Published by the American Physical Society 2024

The dimer tiling problem asks in how many ways can the edges of a graph be covered by dimers so that each site is covered once. In the special case of a planar graph, this problem has a solution in terms of a free fermionic field theory. We rediscover and explore an expression for the number of coverings of an arbitrary graph by arbitrary objects in terms of an interacting fermionic field theory first proposed by Samuel. Generalizations of the dimer tiling problem, which we call “dimer piling problems,” demand that each site be covered N times by indistinguishable dimers. Our field theory provides a solution of these problems in the large-N limit. We give a similar path integral representation for certain lattice coloring problems. Published by the American Physical Society 2024

Transcription factors (TFs) regulate the differentiation of T cells into diverse states with distinct functionalities. To precisely program desired T cell states in viral infections and cancers, we generated a comprehensive transcriptional and epigenetic atlas of nine CD8 + T cell differentiation states for TF activity prediction. Our analysis catalogued TF activity fingerprints of each state, uncovering new regulatory mechanisms that govern selective cell state differentiation. Leveraging this platform, we focused on two critical T cell states in tumor and virus control: terminally exhausted T cells (TEX term ), which are dysfunctional, and tissue-resident memory T cells (T RM ), which are protective. Despite their functional differences, these states share significant transcriptional and anatomical similarities, making it both challenging and essential to engineer T cells that avoid TEX term differentiation while preserving beneficial T RM characteristics. Through in vivo CRISPR screening combined with single-cell RNA sequencing (Perturb-seq), we validated the specific TFs driving the TEX term state and confirmed the accuracy of TF specificity predictions. Importantly, we discovered novel TEX term -specific TFs such as ZSCAN20, JDP2, and ZFP324. The deletion of these TEX term -specific TFs in T cells enhanced tumor control and synergized with immune checkpoint blockade. Additionally, this study identified multi-state TFs like HIC1 and GFI1, which are vital for both TEX term and T RM states. Furthermore, our global TF community analysis and Perturb-seq experiments revealed how TFs differentially regulate key processes in T RM and TEX term cells, uncovering new biological pathways like protein catabolism that are specifically linked to TEX term differentiation. In summary, our platform systematically identifies TF programs across diverse T cell states, facilitating the engineering of specific T cell states to improve tumor control and providing insights into the cellular mechanisms underlying their functional disparities.

The recent discovery of high-temperature superconductivity in La_{3}Ni_{2}O_{7} offers a fresh platform for exploring unconventional pairing mechanisms. Starting with the basic argument that the electrons in d_{z^{2}} orbitals nearly form local moments, we examine the effect of the Hubbard interaction U on the binding strength of Cooper pairs based on a single-orbital bilayer model with intralayer hopping t_{∥} and interlayer superexchange J_{⊥}. By extensive density matrix renormalization group calculations, we observe a remarkable enhancement in binding energy as much as 10-20 times larger with U/t_{∥} increasing from 0 to 12 at J_{⊥}/t_{∥}∼1. We demonstrate that such a substantial enhancement stems from a kinetic-energy-driven mechanism. Specifically, a Z_{2} Berry phase will emerge at large U due to the Hilbert space restriction (Mottness), which strongly suppresses the mobility of single particle propagation as compared to U=0. However, the kinetic energy of the electrons (holes) can be greatly restored by forming an interlayer spin-singlet pairing, which naturally results in a superconducting state even for relatively small J_{⊥}. An effective hard-core bosonic model is further proposed to estimate the superconducting transition temperature at the mean-field level.

High-resolution measurements of the positronium formation cross sections for positron energies from threshold to 10eV are presented for aniline (C_{6}H_{5}NH_{2}), pyridine (C_{5}H_{5}N), and cyclopentane (C_{5}H_{10}). The data reveal that the measured energy dependence of the cross sections on the excess energy in the near-threshold region (1-2eV) is nearly identical to that of the corresponding photoionization cross sections. This similarity occurs despite the difference between the basic threshold laws for processes without and with a Coulomb interaction between the final-state particles. It is proposed here that the near-threshold behavior of these two different ionization processes is governed by the vibrational dynamics of the final-state cation. This is supported by comparison of the data with the calculated spectrum of vibronic intensities for the pyridine cation [Trofimov etal., J. Chem. Phys. 153, 164307 (2020)JCPSA60021-960610.1063/5.0024446].

Pelvic floor disorders are common and burdensome. Data on the effect of induction of labor on pelvic floor disorders are sparse and results are mixed. Our aim was to evaluate whether elective labor induction in nulliparous women increases the risks of symptomatic urinary incontinence (UI), anal incontinence (AI), or pelvic organ prolapse (POP) 4 years after delivery. In this single-site follow-up study of "A Randomized Trial of Induction Versus Expectant Management" (ARRIVE) that randomized low-risk nulliparous women with a singleton fetus to elective induction of labor versus expectant management, we compared pelvic floor symptoms between groups at a median of 4 years (interquartile range, 3.5-5.3) after first delivery using validated questionnaires. Seventy hundred sixty-six of 1,042 (74%) original participants responded, and 647 participants (62%) were included in the analysis after exclusions. The overall prevalence rates of symptomatic moderate to severe UI, AI, and POP were 21%, 14%, and 8%, respectively. There were no significant differences in any of the outcomes between women randomized to induction of labor and those to expectant management, either in unadjusted or adjusted analyses. There were also no differences in secondary outcomes, including subtypes of UI or flatal versus stool incontinence. In this single-site study, we found no significant differences in any UI, AI, and POP symptoms between nulliparous women randomized to elective induction of labor and to expectant management; however, for the least frequent outcome (POP), meaningful differences cannot be ruled out.

Medication utilization has been increasing in the U.S. year-over-year for several decades. As older adults take more medications, there is a higher risk of them being exposed to drug-drug or drug-disease interactions. The American Geriatrics Society in 2019 updated their Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults. The objective of this study was to assess the prevalence of utilization of medications included in the 2019 Beers Criteria. An analysis was conducted using the Medicare Part D Provider Utilization and Payment Data Public Use File for calendar-year 2020. Medications identified in the 2019 Beers Criteria were applied to the analysis. Two categories of medications were assessed: (1) "Avoid" and (2) "Use With Caution." In 2020, 56 million prescriptions were dispensed to Medicare patients 65 years and older that are recommended to be avoided without exception (4.7% of all prescriptions) totaling $957 million in medication costs. The most utilized medication classes in this category were benzodiazepines (25,949,994 prescriptions), "Z-drugs" (6,204,909 prescriptions), long-acting sulfonylureas (5,306,577 prescriptions), 1st-generation antihistamines (5,049,289 prescriptions), and tricyclic antidepressants (4,190,062 prescriptions). Additionally, 135 million prescriptions were dispensed to Medicare beneficiaries 65 years and older for medications which the Beers Criteria states to use caution (11.3% of all prescriptions) exceeding $2.85 billion in medication costs. The most utilized medications for this category were diuretics (74,599,126 prescriptions), selective serotonin reuptake inhibitors (30,033,121 prescriptions), serotonin and norepinephrine reuptake inhibitors (11,858,968 prescriptions), tramadol (11,450,878 prescriptions), and mirtazapine (5,737,304 prescriptions). Even with the existence of the AGS Beers Criteria for PIM Use in Older Adults and its continued updated versions, 16% of medications dispensed to Medicare Part D were potentially inappropriate. Future studies are needed to assess if this has led to worsened outcomes among older adults who utilized these PIM.