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During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1 , Notch2 and Trp53 , which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium. Deep sequencing and lineage tracing analysis of esophageal epithelium of mutagen-treated aging mice leads to a model in which the proliferative advantage of positively selected mutations depends on the competitive fitness of neighboring cells.

We investigate whether quantum theory can be understood as the continuum limit of a mechanical theory, in which there is a huge, but finite, number of classical “worlds,” and quantum effects arise solely from a universal interaction between these worlds, without reference to any wave function. Here, a “world” means an entire universe with well-defined properties, determined by the classical configuration of its particles and fields. In our approach, each world evolves deterministically, probabilities arise due to ignorance as to which world a given observer occupies, and we argue that in the limit of infinitely many worlds the wave function can be recovered (as a secondary object) from the motion of these worlds. We introduce a simple model of such a “many interacting worlds” approach and show that it can reproduce some generic quantum phenomena—such as Ehrenfest’s theorem, wave packet spreading, barrier tunneling, and zero-point energy—as a direct consequence of mutual repulsion between worlds. Finally, we perform numerical simulations using our approach. We demonstrate, first, that it can be used to calculate quantum ground states, and second, that it is capable of reproducing, at least qualitatively, the double-slit interference phenomenon.

Microbial biofilms are composed of a hydrated matrix of biopolymers including polypeptides, polysaccharides and nucleic acids and act as a protective barrier and microenvironment for the inhabiting microbes. While studying marine biofilms, we observed that supernatant produced by a marine isolate of Bacillus licheniformis was capable of dispersing bacterial biofilms. We investigated the source of this activity and identified the active compound as an extracellular DNase (NucB). We have shown that this enzyme rapidly breaks up the biofilms of both Gram-positive and Gram-negative bacteria. We demonstrate that bacteria can use secreted nucleases as an elegant strategy to disperse established biofilms and to prevent de novo formation of biofilms of competitors. DNA therefore plays an important dynamic role as a reversible structural adhesin within the biofilm.

Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours. Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS–TMB-H, dMMR/MSI-H, and MSS–TMB-low (L) tumours, using χ2 or Fisher's exact tests. Antitumour immune response within the tumour environment was predicted by analysing the infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The Kaplan-Meier method and the log-rank test were used to evaluate the impact of gene alterations on the efficacy of immune checkpoint inhibitors in MSS gastrointestinal cancers from the CARIS database, a Memorial Sloan Kettering Cancer Center cohort, and a Peking University Cancer Hospital cohort. MSS–TMB-H was observed in 1600 (3·29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4·67%), and MSS–TMB-L in 44 734 (92·03%). Gene mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT, and RASA1 might impair antitumour immune response despite TMB-H, while mutations in 16 other genes (CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2, and XPO1) were related to TMB-H with enhanced antitumour immune response independent of dMMR/MSI-H, constructing a predictive model (modified TMB [mTMB]) for immune checkpoint inhibitor efficacy. Patients with any mutation in the mTMB gene signature, in comparison with patients with mTMB wildtype tumours, showed a superior survival benefit from immune checkpoint inhibitors in MSS gastrointestinal cancers in the CARIS cohort (n=95, median overall survival 18·77 months [95% CI 17·30–20·23] vs 7·03 months [5·73–8·34]; hazard ratio 0·55 [95% CI 0·31–0·99], p=0·044). In addition, copy number amplification in chromosome 11q13 (eg, CCND1, FGF genes) was more prevalent in MSS–TMB-H tumours than in the dMMR/MSI-H or MSS–TMB-L subgroups. Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs. US National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong Research Project, Ming Hsieh Research Fund, Shanghai Sailing Program, China National Postdoctoral Program for Innovative Talents, China Postdoctoral Science Foundation, National Natural Science Foundation of China.

An uncertainty relation for the Rényi entropies of conjugate quantum observables is used to obtain a strong Heisenberg limit of the form RMSE≥f(α)/(⟨N⟩+12), bounding the root mean square error of any estimate of a random optical phase shift in terms of average photon number, where f(α) is maximised for non-Shannon entropies. Related simple yet strong uncertainty relations linking phase uncertainty to the photon number distribution, such as ΔΦ≥maxnpn, are also obtained. These results are significantly strengthened via upper and lower bounds on the Rényi mutual information of quantum communication channels, related to asymmetry and convolution, and applied to the estimation (with prior information) of unitary shift parameters such as rotation angle and time, and to obtain strong bounds on measures of coherence. Sharper Rényi entropic uncertainty relations are also obtained, including time-energy uncertainty relations for Hamiltonians with discrete spectra. In the latter case almost-periodic Rényi entropies are introduced for nonperiodic systems.

As people age, they accumulate somatic mutations in healthy cells. About 25% of cells in normal, sun-exposed skin harbor cancer driver mutations. What about tissues not exposed to powerful mutagens like ultraviolet light? Martincorena et al. performed targeted gene sequencing of normal esophageal epithelium from nine human donors of varying age (see the Perspective by Chanock). The mutation rate was lower in esophagus than in skin, but there was a strong positive selection of clones carrying mutations in 14 cancer-associated genes. By middle age, more than half of the esophageal epithelium was colonized by mutant clones. Interestingly, mutations in the cancer driver gene NOTCH1 were more common in normal esophageal epithelium than in esophageal cancer. Science , this issue p. 911 ; see also p. 893 Cancer-associated mutations are surprisingly common in normal esophageal epithelium from human donors. The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.

This paper investigates the microscale engineering aspects of n-type doped GaSb to address the challenges associated with achieving high electrical conductivity and precise dopant distribution in this semiconductor material. AC impedance spectroscopy is employed as a reliable technique to characterize the microstructural and electrical properties of GaSb, providing valuable insights into the impact of grain boundaries on overall electrical performance. The uneven distribution of dopants, caused by diffusion, and the incomplete activation of introduced dopants pose significant obstacles in achieving consistent material properties. To overcome these challenges, a careful selection of alloying elements, such as bismuth, is explored to suppress the formation of native acceptor defects and modulate band structures, thereby influencing the doping and compensator formation processes. Additionally, the paper examines the effect of microwave annealing as a potential solution for enhancing dopant activation, minimizing diffusion, and reducing precipitate formation. Microwave annealing shows promise due to its rapid heating and shorter processing times, making it a viable alternative to traditional annealing methods. The study underscores the need for a stable grain boundary passivation strategy to achieve significant improvements in GaSb material performance. Simple grain size reduction strategies alone do not result in better thermoelectric performance, for example, and increasing the grain boundary area per unit volume exacerbates the issue of free carrier compensation. These findings highlight the complexity of achieving optimal doping in GaSb materials and the importance of innovative analytical techniques and controlled doping processes. The comprehensive exploration of n-type doped GaSb presented in this research provides valuable insights for future advancements in the synthesis and optimization of high-conductivity nanostructured n-type GaSb, with potential applications in thermoelectric devices and other electronic systems.

Prognostic tests and treatment approaches for optimized clinical care of prostatic neoplasms are an unmet need. Prostate cancer (PCa) and derived extracellular vesicles (EVs) proteome changes occur during initiation and progression of the disease. PCa tissue proteome has been previously characterized, but screening of tissue samples constitutes an invasive procedure. Consequently, we focused this study on liquid biopsies, such as urine samples. More specifically, urinary small extracellular vesicle and particles proteome profiles of 100 subjects were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC–MS/MS). We identified 171 proteins that were differentially expressed between intraductal prostate cancer/cribriform (IDC/Crib) and non-IDC/non-Crib after correction for multiple testing. However, the strong correlation between IDC/Crib and Gleason Grade complicates the disentanglement of the underlying factors driving this association. Nevertheless, even after accounting for multiple testing and adjusting for ISUP (International Society of Urological Pathology) grading, two proteins continued to exhibit significant differential expression between IDC/Crib and non-IDC/non-Crib. Functional enrichment analysis based on cancer hallmark proteins disclosed a clear pattern of androgen response down-regulation in urinary EVs from IDC/Crib compared to non-IDC/non-Crib. Interestingly, proteome differences between IDC and cribriform were more subtle, suggesting high proteome heterogeneity. Overall, the urinary EV proteome reflected partly the prostate pathology.

To explore associations of recent moderate-to-vigorous aerobic exercise (MVAE) participation and lifetime mild traumatic brain injury (mTBI) history with measures of brain gray matter volumes among military service members and Veterans (SMVs). Participants (n = 1,340; aged 41.3 ± 10.3 years; 13% female) were SMV's who participated in the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium Prospective Longitudinal Study (LIMBIC-CENC PLS). MVAE participation was self-reported via the Behavioral Risk Factor Surveillance System and categorized according to current MVAE recommendations (Inactive, Insufficiently Active, Active, and Highly Active). Lifetime mTBI history was queried via validated structured interview and categorized as 0 mTBI, 1-2 mTBIs, 3 + mTBIs. Structural MRI (T1- and T2-weighted images) were used to measure gray matter volumetrics: ventricle-to-brain ratio (VBR); bilateral volumes of the frontal, parietal, temporal, occipital, cingulate, hippocampus, amygdala, and thalamus regions. Multivariable linear regression models were fit to test associations of MVAE participation, mTBI history, and their interaction on each of the volumetric outcomes while controlling for age, sex, education attainment, and PTSD symptoms. Effects were considered statistically significant if the corresponding unstandardized beta (B) and 95% CI did not include 0. Regarding main effects, participants in the Inactive MVAE group had significantly larger VBR values (worse outcome) than those in the Insufficiently Active group (B[95%CI] = -0.137[-0.260, -0.014]). Interaction effects showed participants with no lifetime mTBIs in the Highly Active group had larger VBR values (worse outcome) when compared to those in the Inactive and Insufficiently Active groups. SMVs with 3 + lifetime mTBIs who were Highly Active also had smaller VBR values (better outcome) when compared to Highly Active SMVs with fewer lifetime mTBIs. There were no other statistically significant differences for MVAE participation, mTBI history, or their interactions. History of one or more lifetime mTBIs was not associated with measures of brain gray matter volumes, suggesting that declines in structural brain health are not expected for the most SMVs with mTBI(s). Although MVAE may benefit brain health, a positive association between self-reported MVAE participation and gray matter volumes was not observed.

Background Tumor genomic profiling (TGP) identifies targets for precision cancer treatments, but also secondary hereditary risks. Oncologists are poorly trained to communicate the results of TGP, especially among patients with lower health literacy, poorer genetics knowledge, and higher mistrust. African American (AA) patients are especially vulnerable to poor understanding due to significant cancer disparities and lower uptake of TGP. The goal of this research is to inform the development of an internet-based brief educational support for oncologists to prepare them to provide better decisional support related to TGP for their AA cancer patients. Methods This mixed-methods study used semi-structured interviews of oncologists to inform development of an online survey with a convenience sample of US-based oncologists ( n  = 50) to assess perceptions of the challenges of TGP and communicating results to AA patients. Results Most interviewed oncologists felt it was important to consider racial/cultural differences when communicating about hereditary risks. Cost, family dynamics, discrimination concerns, and medical mistrust were identified as particularly salient. Survey respondents’ views related to AAs and perceptions of TGP were strongly associated with years since completing training, with recent graduates expressing stronger agreement with statements identifying barriers/disadvantages to TGP for AA patients. Conclusions Oncologists who had more recently completed training expressed more negative perceptions of TGP and more perceived challenges in communicating about TGP with their AA patients. Focused training for oncologists that addresses barriers specific to AAs may be helpful in supporting improved communication about TGP and improved decisional support for AA patients with cancer considering TGP to evaluate their tumors.