Epigenetic regulation of gene expression is studied at three physical scales: micro: DNA sequence-level methylation/demethylation; meso: nucleosome occupancy and remodeling; and macro: chromosomal domain silencing by Polycomb complexes, heterochromatin, and topologically associating domain (TAD) boundaries. The challenge to fully understand epigenetic gene regulation patterns is that these scales are not independent. Their influence overlaps and they share a recurring architectural theme across scales of a targeted molecular pattern followed by cooperative, feedback-driven, spatially bounded spreading. We argue here that disruption of this shared architecture at any one scale is independently sufficient to tip a bistable silencing domain into an oncogenic state. This paper discusses how such a cross-scale architectural rule set has concrete implications (yet underexploited) for computational cancer epigenomics, e.g., functional enrichment analyses generally focus on epigenetic features at one scale as an independent line of evidence, ignoring corroborating signals that could be reinforced by underlying hierarchical levels. This paper outlines options for functional enrichment statistics that combine multiple corroborating molecular features within a scale and corroborating evidence across scales into composite confidence scores calibrated against an empirical null that preserves correlations between assays. We propose benchmarking this approach against conventional single-feature enrichment in matched multi-omic cancer datasets as a direct test of the model.

Circulating tumor cells (CTCs) carry a migration risk, prone to forming metastatic foci and exacerbating the disease. Therefore, it is of great importance to improve the capture efficiency and killing effect of CTCs. First, Ni-doped covalent organic framework (Ni-COF) is used as a precursor for calcination at 900 °C, which reduces Ni2+ to magnetic Ni nanoparticles, and COF evolve into carbon nanospheres exhibiting enzyme activity (Ni-C-900). Then, with the photosensitizer meso-Tetrakis (4-carboxyphenyl) porphyrin (TCPP) as the first ligand and (2,5-dicarboxyphenyl) boronic acid (DCBA) as the second ligand, a metal-organic framework shell is in-situ grown on the surface of Ni-C-900 to obtain Ni-C@MOF. Finally, the aptamers are orderly linked via DCBA ligands to obtain Ni-C@MOF-Apt microspheres. Ni-C@MOF-Apt exhibits excellent targeting towards MCF-7 cancer cells, with a capture efficiency of 82.6% in whole-blood samples (1000 cells per milliliter), and the capture efficiency can still be maintained at 71% within a relatively low cell-concentration range (50 cells per milliliter). In addition, under weakly acidic conditions, Ni-C@MOF-Apt exhibits peroxidase (POD) and oxidase (OXD) activities, which can generate reactive oxygen species (ROS) to eliminate MCF-7 cells in synergy with photodynamic effects. This strategy combines nanozyme activity with photodynamic effects and improves the killing efficacy against MCF-7 cells.

Chirality wildly exists in natural products and pharmaceuticals. The efficient construction of multiple chiral centers in a single catalytic step is challenging due to the issues of both enantioselectivity and diastereoselectivity. Herein, a catalytic protocol for simultaneous generation of multiple chiral centers is developed: a stereodivergent reaction of non-symmetric cyclic anhydrides with 1,1-disubstituted allenes affords the products with either 1,3- or 1,4-two chiral centers, which is governed by the absolute configurations of the chiral centers in the enantiomeric ligands of (R,R)-Ph-BPE or (S,S)-Ph-BPE, respectively; the Cu-catalyzed enantioselective allylative desymmetrization of meso bicyclic anhydrides with 1,1-disubstituted allenes generates chiral γ-keto carboxylic acids bearing three stereocenters. Such a protocol is successfully demonstrated for its application to prepare compounds containing four to five stereocenters. Density functional theory studies reveal that the allylation proceeds through a six-membered transition state, where the ligand-substrate steric interactions govern the observed regio-, enantio-, and diastereoselectivity.

Recognition of amyloid-β (Aβ) by structurally defined inorganic scaffolds offers a route to dissecting how framework geometry and surface chemistry govern peptide-material interactions. We report transferrin (Tf)/KLVFF-PCN-222, a bioinorganic recognition platform built by covalently co-grafting the Aβ-homologous pentapeptide KLVFF and transferrin (Tf) onto the csq-topology porphyrinic zirconium MOF PCN-222 via EDC/NHS chemistry. The one-dimensional hexagonal mesopore channels (∼3.7 nm) and the dense meso-tetrakis (4-carboxyphenyl)porphyrin (TCPP) sites of the csq framework provide geometric access for Aβ1-42 monomer diffusion and an array of peptide-porphyrin recognition contacts. Fluorescence quenching and isothermal titration calorimetry returned an apparent dissociation constant (K d,app) of 33.5 ± 4.2 nM for the Aβ1-42 monomer (apparent fluorescence-mode limit of detection (LOD) = 1.8 nM), and circular dichroism showed that the probe suppressed Aβ β-sheet conversion (14% vs. 41% β-sheet content at 24 h). A panel of structural controls-scrambled FFKLV, the narrow-pore fcu MOF UiO-66-NH2, and the TCPP-based ftw MOF-525-together with a selectivity screen against BSA, IgG, Tau, α-synuclein, and lysozyme (selectivity ratio >12 for Aβ1-42) indicates that KLVFF sequence specificity and csq mesopore geometry act cooperatively to drive recognition. The framework retains an intrinsic NIR photothermal property (photothermal conversion efficiency, η = 47.3 ± 1.8% at 808 nm); the photoacoustic measurement reported here is a probe concentration calibration only, and no Aβ-responsive photoacoustic signal was established. In an hCMEC/D3 in vitro monolayer, the apparent permeability coefficient (P app) reached 1.78 × 10[-5] cm s[-1] with ∼48% of the flux being TfR1-competition-sensitive, and SH-SY5Y viability was partially preserved in a tandem BBB-neuron Transwell model. All validations are in vitro. This work provides a topology-controlled, structure-function proof of concept for csq Zr-TCPP frameworks as bioinorganic platforms for Aβ recognition and conformational modulation.

Chiral self-sorting enables molecular systems to translate stereochemical information from small building blocks into highly organized architectures across length scales, echoing the hierarchical expression of chirality in biological systems. However, predicting whether a system will favor homochiral or heterochiral organization, let alone rationally controlling the sorting outcome, remains challenging. Here we show that the chiral self-sorting of covalent organic pillars (COPs) can be selectively switched through minimal structural variation in the linker units. Two diamine linkers, 2,6-bis(aminomethyl)pyridine and m-xylylenediamine, were used to connect pairs of stereolabile penta-aldehyde tiara[5]arene macrocycles through dynamic covalent [2+5] imine condensation. Despite their close resemblance, these linkers lead to divergent outcomes. Whereas 2,6-bis(aminomethyl)pyridine directs social chiral self-sorting to give a meso COP, m-xylylenediamine promotes narcissistic chiral self-sorting to afford enantiomeric COPs. In both cases, the products form cleanly without detectable stereoisomeric byproducts, and their stereochemical assignments are confirmed by X-ray crystallography. Computational analyses support the view that distinct linker conformational preferences provide a rationale for the divergent sorting pathways. This work establishes COPs as a model platform for understanding chiral self-sorting and provides a conceptual basis for selecting, amplifying, and expressing stereochemical information in complex molecular architectures.

Despite legal provisions allowing for abortion in cases of rape and incest, survivors in West and Central Africa still face many access barriers. Understanding these obstacles is vital for their rights and health. This study looked at barriers to safe and legal abortion services for survivors of sexual violence in five West and Central African countries. We did a comparative case study in Benin, Burkina Faso, Cameroon, Côte d'Ivoire, and Togo. Data collection included documentary analysis, 164 semi-structured interviews with institutional actors, civil society members, community leaders, and sexual violence survivors, along with 14 focus group discussions and a multi-level analytical framework. We applied a four-phase collaborative qualitative thematic analysis. This helped us identify barriers at macro (policy), meso (organisational), and micro (individual) levels. The analysis reveals how interconnected barriers restrict access. At the macro level, obstacles include unclear laws, missing regulations, and bans on abortion-related communication. Meso-level barriers feature inconsistent institutional practices, unprepared health facilities, and poor coordination. Micro-level challenges involve limited awareness of legal rights, widespread social and religious stigma, and informal conscientious objection practices. For survivors seeking to end the pregnancy, these barriers lead to unsafe abortion or forced continuation of pregnancy. Legal provisions alone do not guarantee survivors' access to safe and legal abortion. Coordinated efforts are needed to address legal, institutional, and social obstacles, transforming legal rights into real access and reducing unsafe abortion practices.

d-phenylalanine is an important d-amino acid with a wide range of applications in the pharmaceutical and chemical industries. meso-diaminopimelate dehydrogenase (DAPDH) catalyzes the asymmetric reductive amination of α-keto acids to produce d-amino acids with high optical purity, serving as a key enzymatic module for constructing multi-enzyme cascade systems. However, the strict dependence of wild-type DAPDH on NADPH results in high cofactor costs, limiting its industrial application. To address this issue, this study focused on a previously engineered yet still NADPH-preferring type I DAPDH from Corynebacterium glutamicum (CgDAPDH). Based on structural analysis of the protein, a three-pronged engineering strategy involving steric hindrance reduction, local electrostatic potential modulation, and conformational flexibility enhancement was proposed. Through site-directed and combinatorial mutagenesis of residues at the cofactor-binding pocket entrance (Ser35, Arg36, Arg37) and conserved regions (Ser68, Thr88, Asp120), a mutant S35E/R36E/R37A/S68T/T88A was obtained. This mutant exhibited a catalytic efficiency (kcat/Km) of 274.87 mmol/(L·s) toward NADH, representing a 16.9-fold improvement over the starting enzyme, while achieving comparable catalytic competence with both NADH and NADPH. This mutant was coupled with formate dehydrogenase (FDH) to construct an NADH self-regeneration system for whole-cell catalytic reductive amination using phenylpyruvate as the substrate. After 6 h of reaction, the titer of d -phenylalanine reached 36.22 g/L with a conversion rate of 90.12%. When this system was applied to three-enzyme cascade employing l-phenylalanine as the substrate, the d-phenylalanine titer reached 16.25 g/L, which was comparable to that obtained with a glucose dehydrogenase/NADPH regeneration system (17.21 g/L). This study demonstrates that cofactor engineering can alleviate the NADPH dependence of DAPDH and achieve efficient conversion of phenylpyruvate to d-phenylalanine, thereby providing a new enzymatic module and a technical route for cost-effective biomanufacturing of d-amino acids.

Oxygen tension is a critical physiological parameter in deep tissues; however, high-resolution and non-invasive measurement of oxygenation remains challenging. In this study, we developed a prototype for a lifetime measurement system based on a pulsed carbon nanotube X-ray source to evaluate X-ray-excited luminescence oxygen sensing. The X-ray irradiated a PDMS fiber containing the rapidly responding X-ray scintillator cerium-doped lutetium orthosilicate (LSO) and an oxygen sensing dye, (Pt(II) meso-Tetra(pentafluorophenyl)porphine (PtTFPP)), that is excited by the LSO X-ray luminescence and emits red fluorescence quenched by oxygen. At 0 kPa oxygen tension, the sensor showed a lifetime of approximately 62 μs, while at 21 kPa oxygen, the emission was strongly quenched with an estimated lifetime less than 1.33 μs. Covering the oxygen-sensing fiber with chicken breast tissue slices from 1.4 to 8.3 mm thick had minimal effect on measured luminescence lifetime in deoxygenated conditions (lifetime of 62.0 ± 6.1 μs). Control measurements using gadolinium oxysulfide doped with europium (GOS:Eu) powder also confirmed thickness-independent lifetime behavior. These results demonstrate that X-ray-excited lifetime measurement depends primarily on oxygen concentration and is independent of tissue thickness, supporting the feasibility of deep-tissue oxygen sensing and future time-domain X-ray luminescence computed tomography (XLCT) imaging for three-dimensional oxygenation mapping.