Browse Articles

Author Correction: Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension

Linking DNA-packing density distribution and TAD boundary locations

DNA is heterogeneously packaged into chromatin, which is further organized into topologically associating domains (TADs) with sharp boundaries. These boundary locations are critical for genome regulation. Here, we explore how the distribution of DNA-packing density across chromatin affects the TAD boundary locations. We develop a polymer-physics-based model that utilizes DNA accessibility data to parameterize DNA-packing density along chromosomes, treating them as heteropolymers, and simulates the stochastic folding of these heteropolymers within a nucleus to yield a conformation ensemble. Such an ensemble reproduces a subset (over 60%) of TAD boundaries across the human genome, as confirmed by Hi-C data. Additionally, it reproduces the spatial distance matrices of 2-Mb genomic regions provided by FISH experiments. Furthermore, our model suggests that utilizing DNA accessibility data alone as input is sufficient to predict the emergence and disappearance of key TADs during early T cell differentiation. We show that stochastic folding of heteropolymers in a confined space can replicate both the prevalence of chromatin domain structures and the cell-to-cell variation in domain boundary positions observed in single-cell experiments. Furthermore, regions of lower DNA-packing density preferentially form domain boundaries, and this preference drives the emergence of TAD boundaries observed in ensemble-averaged Hi-C maps. The enrichment of TAD boundaries at CTCF binding sites can be attributed to the influence of CTCF binding on local DNA-packing density in our model. Collectively, our findings establish a strong link between TAD boundaries and regions of lower DNA-packing density, providing insights into the mechanisms underlying TAD formation.

Localized modes and acoustic band gaps using different quasi-periodic structures based on closed and open resonators

Protective role of parenthood on age-related brain function in mid- to late-life

The experience of human parenthood is near ubiquitous and can profoundly alter one’s body, mind, and environment. However, we know very little about the long-term neural effects of parenthood for parents themselves, or the implications of pregnancy and caregiving experience on the aging adult brain. Here, we investigate the link between the number of children parented and age on brain function in 19,964 females and 17,607 males from the UK Biobank. In both females and males, parenthood was positively correlated with functional connectivity, such that higher number of children parented was associated with higher connectivity, particularly within the somato/motor network. Critically, the spatial topography of parenthood-linked effects was inversely correlated with the impact of age on functional connectivity across the brain for both females and males, such that the connections that were positively correlated with number of children were negatively correlated with age. This result suggests that a higher number of children is associated with patterns of brain function in the opposite direction to age-related alterations. Overall, these results indicate that the changes accompanying parenthood may confer benefits to brain health across the lifespan, altering aging trajectories, consistent with animal models of parenthood and preliminary findings of “younger-looking” brain structure in human parents. Observing this effect in both females and males implicates the caregiving environment, rather than pregnancy alone, and highlights the importance of future work to disentangle the underlying mechanisms related to the direct impact of caregiving, the indirect impact of the environment, and the result of covarying sociodemographic factors.

Evaluation of ovarian functions in girls treated for hematological malignancy

Van der Waals quantum dots on layered hexagonal boron nitride

Semiconductor quantum dots (QD) promise unique electronic, optical, and chemical properties, which can be exquisitely tuned by controlling the composition, size, and morphology. Semiconductor QDs have been synthesized primarily via two approaches, namely, epitaxial growth and wet-chemical synthesis. However, the properties of epitaxial QDs (eQDs) are susceptible to wetting layer formation and substrate dislocations, while colloidal QDs (cQDs) face fluorescence intermittency issues. Here, we report on the synthesis of a class of QDs that can overcome the fundamental limitations of eQDs and cQDs. By exploiting the sp 2 bonding of layered hexagonal boron nitride (hBN), we show that GaN QDs can be epitaxially grown through a weak van der Waals (vdW) interaction without two-dimensional wetting layer formation. The photoluminescence intensity of GaN van der Waals quantum dots (vQDs) is more than six times stronger than that of conventional GaN eQDs and no optical blinking was observed from vQDs. We show that the interadatom bond strength is about one order of magnitude stronger compared with that between the adatoms and the hBN substrate. This work shows that vQDs have unique properties that are difficult to achieve using existing QDs synthesis methods and thus can potentially enable new classes of high-performance optoelectronic and quantum devices.

Targeted degradation of CDK4/6 by LA-CB1 inhibits EMT and suppresses tumor growth in orthotopic breast cancer

Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) are central regulators of cell cycle progression and frequently dysregulated in cancers, including breast cancer. While selective CDK4/6 inhibitors like Palbociclib, Ribociclib, and Abemaciclib have shown clinical benefit in hormone receptor-positive (HR+) breast cancer, their efficacy is often limited by resistance mechanisms and dose-limiting toxicities. In this study, we developed LA-CB1, a novel Abemaciclib derivative that induces CDK4/6 degradation through the ubiquitin-proteasome pathway, aiming to achieve sustained inhibition of the CDK4/6-Rb axis. LA-CB1 demonstrated potent anti-proliferative effects in various breast cancer cell lines, with notable efficacy in triple-negative breast cancer (TNBC) and HR + breast cancer models. Molecular docking studies confirmed high-affinity binding of LA-CB1 to the ATP-binding pocket of CDK4/6. Mechanistic studies revealed that LA-CB1 induces G0/G1 cell cycle arrest and promotes apoptosis through the degradation of CDK4/6. Importantly, LA-CB1 also suppressed epithelial-mesenchymal transition (EMT), inhibiting key processes such as cell migration, invasion, and angiogenesis, indicating its ability to disrupt multiple hallmarks of cancer. In an orthotopic breast cancer model, LA-CB1 significantly reduced tumor growth in a dose-dependent manner. These results suggest that LA-CB1 represents a promising therapeutic strategy by targeting CDK4/6 for degradation, addressing limitations associated with current CDK4/6 inhibitors, and providing broad anti-tumor activity in aggressive cancer types like TNBC.

Measuring criticism of the police in the local news media using large language models

High-profile incidents of police violence against Black citizens over the past decade have spawned contentious debates in the United States on the role of police. This debate has played out prominently in the news media, leading to a perception that media outlets have become more critical of the police. There is currently, however, little empirical evidence supporting this perceived shift. We construct a large dataset of local news reporting on the police from 2013 to 2023 in 10 politically diverse U.S. cities. Leveraging advanced language models, we measure criticism by analyzing whether reporting supports or is critical of two contentions: 1) that the police protect citizens and 2) that the police are racist. To validate this approach, we collect labels from members of different political parties. We find that contrary to public perceptions, local media criticism of the police has remained relatively stable along these two dimensions over the past decade. While criticism spiked in the aftermath of high-profile police killings, such as George Floyd’s murder, these events did not produce sustained increases in negative police news. In fact, reporting supportive of police effectiveness has increased slightly since Floyd’s death. We find only small differences in coverage trends in more conservative and more liberal cities, undermining the idea that local outlets cater to the politics of their audiences. Last, although Republicans are more likely to view a piece of news as supportive of the police than Democrats, readers across parties see reporting as no more critical than it was a decade ago.

Spatial pattern of groundwater chemistry in a typical piedmont plain of Northern China driven by natural and anthropogenic forces

Innovation in ant larval feeding facilitated queen–worker divergence and social complexity

Building differences between genetically equivalent units is a fundamental challenge for all multicellular organisms and superorganisms. In ants, reproductive or worker fate is typically determined during the larval stage, through feeding regimes managed by adult caretakers. However, the feeding care provided to larvae varies significantly across ants, as does phenotypic divergence between queen and worker castes. Here, we employed comparative phylogenetic methods and causal inference to investigate the relationships between larval feeding care, caste size dimorphism, and social complexity across ant diversity. We digitized the life’s work of George and Jeanette Wheeler, cataloging the larval morphology of over 700 species, and we compiled data on species diets and larval feeding behaviors from the literature and our own observations. We measured queen–worker size dimorphism in 392 species and gathered data for colony size, worker polymorphism, and worker reproduction. Our analyses revealed that ancestral active-feeding larvae evolved passive morphologies when adults began feeding them individually, typically with processed material and often following a shift to nonpredatory diets. Greater queen–worker size dimorphism coevolved with larval passiveness, alongside traits indicative of increased social complexity, including larger colony sizes, worker subcastes, and a reduction in workers’ reproductive potential. Likelihood comparisons of causal phylogenetic models support that extended alloparental care facilitated stronger caste dimorphism, which, in turn and along with increased colony sizes, promoted higher social complexity. Our results suggest that enhanced adult control over larval development enabled greater phenotypic specialization within colonies, with profound implications for social evolution.

A practical approach to derive heterogeneity index using an integrated petrophysical data analysis

pTDP-43 levels correlate with cell type–specific molecular alterations in the prefrontal cortex of <i>C9orf72</i> ALS/FTD patients

Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal progressive functional changes in major cell types found in the prefrontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.

Research on damage characterization of SCC and rock composite specimens based on CPU and GPU heterogeneous code acceleration

The RNA-binding protein RBPMS inhibits smooth muscle cell–driven vascular remodeling in atherosclerosis and vascular injury

Atherosclerosis and vessel wall trauma induce vascular smooth muscle cell (VSMC) phenotypic modulation, leading to plaque cap growth and postintervention restenosis. Our systems biology approach identified RNA binding protein, mRNA processing factor ( RBPMS ) as a conserved, VSMC-specific gene associated with VSMC modulation in atherosclerosis. RBPMS gene expression positively correlates with VSMC contractile markers in human and murine atherosclerotic arteries as well as in two vascular injury models during the postinjury intimal hyperplasia phase. RBPMS promotes contractile VSMC differentiation, reduces plaque cap development in high-fat diet-fed apolipoprotein E-null ( ApoE −/− ) murine atherosclerotic arteries, and inhibits intimal hyperplasia. Mechanistically, the RBPMS protein interacts with the myocardin ( MYOCD ) pre-mRNA and enhances MYOCD_v3 / MYOCD_v1 transcript balance through alternative exon 2a splicing. RBPMS promotes the VSMC contractile phenotype and reduces their fibroproliferative activity in a MYOCD_v3a-dependent manner. RBPMS enhances Myocd_v3 / Myocd_v1 transcript balance in both atherosclerotic and injured vessels. RBPMS may inhibit VSMC-driven plaque cap development and intervention-induced restenosis.

Factors influencing unsafe acts in the automotive industry using grounded theory and fuzzy DEMATEL

A bipartite interaction with the processivity clamp potentiates Pol IV-mediated TLS

Processivity clamps mediate polymerase switching for translesion synthesis (TLS). All three Escherichia coli TLS polymerases interact with the β 2 processivity clamp through a conserved clamp-binding motif (CBM), which is indispensable for TLS. Notably, Pol IV also interacts weakly with the rim of the clamp through non-CBM residues. Ablating this “rim contact” in cells results in selective sensitivity to DNA-damaging agents, raising the question how the rim contact contributes to TLS. Here, we show that the rim contact is critical for TLS past a strong replication block but barely necessary for a weak blocking lesion. Within the in vitro reconstituted E. coli replisome, the rim mutation compromises Pol IV-mediated TLS past 3-deaza-methyl dA, a strong block, whereas barely affecting TLS past N 2 -furfuryl dG, a weak block. Similar observations are also made in E. coli cells bearing a single copy of these lesions in the genome. At lesion-stalled replication forks, single-stranded DNA binding protein locally enriches Pol IV, enabling it to bind the low-affinity rim site. This interaction poises Pol IV to better compete with Pol III, the replicative polymerase, which competitively inhibits Pol IV from interacting with the clamp through its CBM. We propose that this bipartite clamp interaction enables Pol IV to rapidly resolve lesion-stalled replication at a strong block through TLS, which reduces damage-induced mutagenesis.

Prevalence and impact of fertility preservation among young women with breast cancer

Weakening AMOC reduces ocean carbon uptake and increases the social cost of carbon

A weakening of the Atlantic Meridional Overturning Circulation (AMOC) has been found to be globally beneficial by economic assessments. This result emerges because AMOC weakening would cool the Northern Hemisphere, thereby reducing expected climate damages and decreasing estimates of the global social cost of carbon dioxide (SCC). There are, however, many other impacts of AMOC weakening that are not yet taken into account. Here, we add a second impact channel by quantifying the effects of AMOC weakening on ocean carbon uptake, using biogeochemically-only coupled freshwater hosing simulations in the Max Planck Institute Earth System Model. Our simulations reveal an approximately linear relationship between AMOC strength and carbon uptake reductions, constituting a carbon cycle feedback that leads to higher atmospheric CO 2 concentrations and stronger global warming. This AMOC carbon feedback, when incorporated into an integrated climate-economy model, leads to additional economic damages of several trillion US dollars and raises the SCC by about 1%. The SCC increase is similar in magnitude, but of opposite sign, to the SCC effect of Northern Hemisphere cooling. While there are many other potentially relevant economic impact channels, the AMOC carbon feedback alone could thus flip the consequences of AMOC weakening into a net cost to society.

Predictive performance of risk prediction models for lung cancer incidence in Western and Asian countries: a systematic review and meta-analysis

Thiopurine therapy enhances immune checkpoint inhibitor efficacy in low-mutational burden melanoma: A promising anticancer approach

A key limitation of immune checkpoint inhibitors (ICI) therapy is their reduced efficacy toward cancers with a low tumor mutational burden (TMB). Since low-TMB tumors express fewer neoantigens, they are less responsive to ICI therapy like anti-PD-1 and anti-CTLA-4. In preclinical immunocompetent mouse models of low-TMB melanoma, we recently demonstrated that exposure to 6-thioguanine (6TG) significantly improved tumor control by increasing TMB and creating a proinflammatory tumor microenvironment. The combination of 6TG with anti-PD-1 further improved tumor control, although it did not fully inhibit tumor growth. We here investigated additional ICI combinations, assessing anti-CTLA-4 with anti-PD-1 to improve efficacy. ICI eliminated tumors in 6TG-exposed mice when ICI treatment was initiated at tumor volumes of 20 mm 3 , stopped tumor growth at volumes of 120 mm 3 , and had no effect at volumes of 300 mm 3 . Finally, we showed that mice achieving complete tumor regression with 6TG and ICI treatment exhibited lasting immune memory, which effectively suppressed tumor growth at relapse upon re-exposure to tumor cells. These findings may pave the way to effective application of ICI to low-TMB cancers, when initiated at low tumor volume.