Giant Valley Zeeman Splitting in Vanadium-Doped WSe2 Monolayers.

2D dilute magnetic semiconductors (DMS) based on transition metal dichalcogenides (TMD) offer an innovative pathway for advancing spintronic technologies, including the potential to exploit phenomena such as the valley Zeeman effect. However, the impact of magnetic ordering on the valley degeneracy breaking and on the enhancement of the optical transitions g-factors of these materials remains an open question. Here, a giant effective g-factors ranging between ≈-27 and -69 for the bound exciton at 4 K in vanadium-doped WSe2 monolayers, obtained through magneto-photoluminescence (PL) experiments is reported. This giant g-factor disappears at room temperature, suggesting that this response is associated with a magnetic ordering of the vanadium impurity states at low temperatures. Ab initio calculations for the vanadium-doped WSe2 monolayer confirm the existence of magnetic ordering of the vanadium states, which leads to degeneracy breaking of the valence bands at K and K'. A phenomenological analysis is employed to correlate this splitting with the measured enhanced effective g-factor. The findings shed light on the potential of defect engineering of 2D materials for spintronic applications.

Radiotherapy and theranostics: a Lancet Oncology Commission.

Following on from the 2015 Lancet Oncology Commission on expanding global access to radiotherapy, Radiotherapy and theranostics: a Lancet Oncology Commission was created to assess the access and availability of radiotherapy to date and to address the important issue of access to the promising field of theranostics at a global level. A marked disparity in the availability of radiotherapy machines between high-income countries and low-income and middle-income countries (LMICs) has been identified previously and remains a major problem. The availability of a suitably trained and credentialled workforce has also been highlighted as a major limiting factor to effective implementation of radiotherapy, particularly in LMICs. We investigated initiatives that could mitigate these issues in radiotherapy, such as extended treatment hours, hypofractionation protocols, and new technologies. The broad implementation of hypofractionation techniques compared with conventional radiotherapy in prostate cancer and breast cancer was projected to provide radiotherapy for an additional 2·2 million patients (0·8 million patients with prostate cancer and 1·4 million patients with breast cancer) with existing resources, highlighting the importance of implementing new technologies in LMICs. A global survey undertaken for this Commission revealed that use of radiopharmaceutical therapy-other than 131I-was highly variable in high-income countries and LMICs, with supply chains, workforces, and regulatory issues affecting access and availability. The capacity for radioisotope production was highlighted as a key issue, and training and credentialling of health professionals involved in theranostics is required to ensure equitable access and availability for patient treatment. New initiatives-such as the International Atomic Energy Agency's Rays of Hope programme-and interest by international development banks in investing in radiotherapy should be supported by health-care systems and governments, and extended to accelerate the momentum generated by recognising global disparities in access to radiotherapy. In this Commission, we propose actions and investments that could enhance access to radiotherapy and theranostics worldwide, particularly in LMICs, to realise health and economic benefits and reduce the burden of cancer by accessing these treatments.

The Persistence of Hydrogen Bonds in Pyrimidinones: From Solution to Crystal.

Pyrimidinone scaffolds are present in a wide array of molecules with synthetic and pharmacological utility. The inherent properties of these compounds may be attributed to intermolecular interactions analogous to the interactions that molecules tend to establish with active sites. Pyrimidinones and their fused derivatives have garnered significant interest due to their structural features, which resemble nitrogenous bases, the foundational building blocks of DNA and RNA. Similarly, pyrimidinones are predisposed to forming N-H···O hydrogen bonds akin to nitrogenous bases. Given this context, this study explored the supramolecular features and the predisposition to form hydrogen bonds in a series of 18 substituted 4-(trihalomethyl)-2(1H)-pyrimidinones. The formation of hydrogen bonds was observed in solution via nuclear magnetic resonance (NMR) spectroscopy experiments, and subsequently confirmed in the crystalline solid state. Hence, the 18 compounds were crystallized through crystallization assays by slow solvent evaporation, followed by single-crystal X-ray diffraction (SC-XRD). The supramolecular cluster demarcation was employed to evaluate all intermolecular interactions, and all crystalline structures exhibited robust hydrogen bonds, with an average energy of approximately -21.64 kcal mol-1 (∼19% of the total stabilization energy of the supramolecular clusters), irrespective of the substituents at positions 4, 5, or 6 of the pyrimidinone core. To elucidate the nature of these hydrogen bonds, an analysis based on the quantum theory of atoms in molecules (QTAIM) revealed that the predominant intermolecular interactions are N-H···O (average of -16.55 kcal mol-1) and C-H···O (average of -6.48 kcal mol-1). Through proposing crystallization mechanisms based on molecular stabilization energy data and contact areas between molecules and employing the supramolecular cluster and retrocrystallization concepts, it was determined that altering the halogen (F/Cl) at position 4 of the pyrimidinone nucleus modifies the crystallization mechanism pathway. Notably, the hydrogen bonds present in the initial proposed steps were confirmed by 1H NMR experiments using concentration-dependent techniques.

Synthesis and Antimycobacterial Evaluation of Novel Pyrazole-Isoxazolines and Pyrazole-Isoxazoles.

This study reports the synthesis of a new series of pyrazole-isoxazolines, at very good yields, from the cyclocondensation reaction of pyrazole-enaminones with hydroxylamine hydrochloride. Dehydration of the pyrazole-isoxazolines furnished another new series of the respective pyrazole-isoxazoles, at excellent yields. Both series of the obtained compounds were screened for antimycobacterial activity, and compounds 4f and 5c showed significant inhibition of bacterial growth with a time- and concentration-dependent bactericidal effect. Cytotoxicity tests in VERO cell line did not indicate toxicity of compounds 4f and 5c regarding cellular prediction, NO production or dsDNA release. However, both compounds were associated with an increase in total ROS levels, providing induction of oxidative stress, but without compromising cellular targets. These results highlight compounds 4f and 5c as promising candidates for antimycobacterial treatment with a favorable safety profile.

Novel risk loci for COVID-19 hospitalization among admixed American populations.

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.

Synthesis and application of new selanylfullerene derivatives as photosensitizers for photodynamic therapy.

This study aims to describe the synthesis of a new class of selanylfullerene derivatives in a convergent strategy route, affording the desired products in a few steps and in good yields. C60 compounds were evaluated as photosensitizers to be used in photodynamic therapy (PDT) via the generation of singlet oxygen (1O2), using the chemical trapping method. The photooxidation of the chemical probe1,3-diphenylisobenzofuran (DPBF) sensitized by selanylfullerenes followed a first-order kinetic and the values of singlet oxygen quantum yields (ΦΔ) are appropriate for its use in PDT. The electronic absorption spectra, and the intersystem crossing tax rates for the most prominent synthesized compounds were calculated using the density functional theory and the Marcus electron transfer theory, with the theoretical results confirming the experimental findings.

Solar Light CO2 Photoreduction Enhancement by Mononuclear Rhenium(I) Complexes: Characterization and Mechanistic Insights.

The catalytic efficacy of a novel mononuclear rhenium(I) complex in CO2 reduction is remarkable, with a turnover number (TONCO) of 1517 in 3 h, significantly outperforming previous Re(I) catalysts. This complex, synthesized via a substitution reaction on an aromatic ring to form a bromo-bipyridine derivative, L1 = 2-bromo-6-(1H-pyrazol-1-yl)pyridine, and further reacting with [Re(CO)5Cl], results in the facial-tricarbonyl complex [ReL1(CO)3Cl] (1). The light green solid was obtained with an 80% yield and thoroughly characterized using cyclic voltammetry, nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) spectroscopy, and ultraviolet-visible (UV-vis) spectroscopy. Cyclic voltammetry under CO2 atmosphere revealed three distinct redox processes, suggesting the formation of new electroactive compounds. The studies on photoreduction highlighted the ability of the catalyst to reduce CO2, while NMR, FTIR, and electrospray ionization (ESI) mass spectrometry provided insights into the mechanism, revealing the formation of solvent-coordinated complexes and new species under varying conditions. Additionally, computational studies (DFT) were undertaken to better understand the electronic structure and reactivity patterns of 1, focusing on the role of the ligand, the spectroscopic features, and the redox behavior. This comprehensive approach provides insights into the intricate dynamics of CO2 photoreduction, showcasing the potential of Re(I) complexes in catalysis.

Plastome evolution in Santalales involves relaxed selection prior to loss of ndh genes and major boundary shifts of the inverted repeat.

BACKGROUND AND AIMS: Biological aspects of haustorial parasitism have significant effects on the configuration of the plastid genome. Approximately half the diversity of haustorial parasites belongs to the order Santalales, where a clearer picture of plastome evolution in relation to parasitism is starting to emerge. However, in previous studies of plastome evolution there is still a notable under-representation of members from non-parasitic and deep-branching hemiparasitic lineages, limiting evolutionary inference around the time of transition to a parasitic lifestyle. To expand taxon sampling relevant to this transition we therefore targeted three families of non-parasites (Erythropalaceae, Strombosiaceae, and Coulaceae), two families of root-feeding hemiparasites (Ximeniaceae and Olacaceae), and two families of uncertain parasitic status (Aptandraceae and Octoknemaceae). With data from these lineages we aimed to explore plastome evolution in relation to evolution of parasitism. METHODS: From 29 new samples we sequenced and annotated plastomes and the nuclear ribosomal cistron. We examined phylogenetic patterns, plastome evolution, and patterns of relaxed or intensified selection in plastid genes. Available transcriptome data were analyzed to investigate potential transfer of infA to the nuclear genome. RESULTS: Phylogenetic relationships indicate a single functional loss of all plastid ndh genes (ndhA-K) in a clade formed by confirmed parasites and Aptandraceae, and the loss coincides with major size and boundary shifts of the inverted repeat (IR) region. Depending on an autotrophic or heterotrophic lifestyle in Aptandraceae, plastome changes are either correlated with or predate evolution of parasitism. Phylogenetic patterns also indicate repeated loss of infA from the plastome, and based on presence of transcribed sequences with presequences corresponding to thylakoid luminal transit peptides, we infer that the genes were transferred to the nuclear genome. CONCLUSIONS: Except for the loss of the ndh complex, relatively few genes have been lost from the plastome in deep-branching root parasites in Santalales. Prior to loss of the ndh genes, they show signs of relaxed selection indicative of their dispensability. To firmly establish a potential correlation between ndh gene loss, plastome instability and evolution of parasitism, it is pertinent to refute or confirm a parasitic lifestyle all Santalales clades.

Molecular simulation-based insights into dye pollutant adsorption: A perspective review.

Growing concerns about environmental pollution have highlighted the need for efficient and sustainable methods to remove dye contamination from various ecosystems. In this context, computational methods such as molecular dynamics (MD), Monte Carlo (MC) simulations, quantum mechanics (QM) calculations, and machine learning (ML) methods are powerful tools used to study and predict the adsorption processes of dyes on various adsorbents. These methods provide detailed insights into the molecular interactions and mechanisms involved, which can be crucial for designing efficient adsorption systems. MD simulations, detailing molecular arrangements, predict dyes' adsorption behaviour and interaction energies with adsorbents. They simulate the entire adsorption process, including surface diffusion, solvent layer penetration, and physisorption. QM calculations, especially density functional theory (DFT), determine molecular structures and reactivity descriptors, aiding in understanding adsorption mechanisms. They identify stable adsorption configurations and interactions like hydrogen bonding and electrostatic forces. MC simulations predict equilibrium properties and adsorption energies by sampling molecular configurations. ML methods have proven highly effective in predicting and optimizing dye adsorption processes. These models offer significant advantages over traditional methods, including higher accuracy and the ability to handle complex datasets. These methods optimize adsorption conditions, clarify adsorbent functionalization roles, and predict dye removal efficiency under various conditions. This research explores MD, MC, QM, and ML approaches to connect molecular interactions with macroscopic adsorption phenomena. Probing these techniques provides insights into the dynamics and energetics of dye pollutants on adsorption surfaces. The findings will aid in developing and optimizing new materials for dye removal. This review has significant implications for environmental remediation, offering a comprehensive understanding of adsorption at various scales. Merging microscopic data with macroscopic observations enhances knowledge of dye pollutant adsorption, laying the groundwork for efficient, sustainable removal technologies. Addressing the growing challenges of ecosystem protection, this study contributes to a cleaner, more sustainable future.

Efficacy and Safety of Perfluorohexyloctane in Evaporative Dry Eye Disease Associated With Meibomian Gland Dysfunction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Meibomian gland dysfunction (MGD) is the primary cause of evaporative dry eye disease (DED), which negatively affects the physical and mental quality of life of patients. We performed a meta-analysis of randomized controlled trials (RCTs) comparing perfluorohexyloctane to placebo for MGD in order to identify the best course of treatment for DED in these patients. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline recommendations and prospectively registered the study in PROSPERO (CRD42023442172). The PubMed, Cochrane, and Embase databases were searched for RCTs comparing perfluorohexyloctane to placebo on patients with DED associated with MGD. The statistical analysis was carried out using the "R" software. The mean difference (MD) with 95% CIs was computed using a random-effects model, and p < 0.05 was regarded as statistically significant. The study included 1,814 patients from four RCTs, of whom 972 (53.5%) received perfluorohexyloctane. Patients treated with perfluorohexyloctane had significantly lower total corneal fluorescein staining (tCFS) score (MD -1.09; 95% CI -1.37 to -0.82; p < 0.001; I2 = 0%), eye distress Visual Analogue Scale (VAS) (MD -9.69; 95% CI -12.01 to -7.36; p < 0.01; I2 = 0%), Ocular Surface Disease Index (OSDI) (MD -5.79; 95% CI -8.22 to -3.36 p < 0.01; I2 = 0%), and Eye Burning/Stinging Score (VAS) (MD, -7.16; 95% CI -9.55 to -4.80 p < 0.01; I2 = 0%). The meta-analysis results indicate that perfluorohexyloctane was effective and safe in treating evaporative dry eye, reducing tCFS, eye discomfort, OSDI, and burning sensation, despite the included studies only assessing short-term effects and excluding certain patient groups.

Identification of CDK4/6 Inhibitors as Small Molecule NLRP3 Inflammasome Activators that Facilitate IL-1ß Secretion and T Cell Adjuvanticity.

Several FDA-approved adjuvants signal through the NLRP3 inflammasome and IL-1ß release. Identifying small molecules that induce IL-1ß release could allow targeted delivery and structure-function optimization, thereby improving safety and efficacy of next-generation adjuvants. In this work, we leverage our existing high throughput data set to identify small molecules that induce IL-1ß release. We find that ribociclib induces IL-1ß release when coadministered with a TLR4 agonist in an NLRP3- and caspase-dependent fashion. Ribociclib was formulated with a TLR4 agonist into liposomes, which were used as an adjuvant in an ovalbumin prophylactic vaccine model. The liposomes induced antigen-specific immunity in an IL-1 receptor-dependent fashion. Furthermore, the liposomes were coadministered with a tumor antigen and used in a therapeutic cancer vaccine, where they facilitated rejection of E.G7-OVA tumors. While further chemical optimization of the ribociclib scaffold is needed, this study provides proof-of-concept for its use as an IL-1 producing adjuvant in various immunotherapeutic contexts.

MYBL2 Drives Prostate Cancer Plasticity: Inhibiting Its Transcriptional Target CDK2 for RB1-Deficient Neuroendocrine Prostate Cancer.

Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in patients with prostate cancer. Although underlying molecular causations driving phenotypic plasticity have been identified, therapeutic success is yet to be achieved. To identify putative master regulator transcription factors (MR-TF) driving phenotypic plasticity in prostate cancer, this work utilized a multiomic approach using genetically engineered mouse models of prostate cancer combined with patient data to identify MYB proto-oncogene like 2 (MYBL2) as a significantly enriched transcription factor in prostate cancer exhibiting phenotypic plasticity. Genetic inhibition of Mybl2 using independent murine prostate cancer cell lines representing phenotypic plasticity demonstrated Mybl2 loss significantly decreased in vivo growth as well as cell fitness and repressed gene expression signatures involved in pluripotency and stemness. Because MYBL2 is currently not druggable, a MYBL2 gene signature was employed to identify cyclin-dependent kinase-2 (CDK2) as a potential therapeutic target. CDK2 inhibition phenocopied genetic loss of Mybl2 and significantly decreased in vivo tumor growth associated with enrichment of DNA damage. Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in prostate cancer. Furthermore, high MYBL2 activity identifies prostate cancer that would be responsive to CDK2 inhibition. SIGNIFICANCE: Prostate cancers that escape therapy targeting the androgen receptor signaling pathways via phenotypic plasticity are currently untreatable. Our study identifies MYBL2 as a MR-TF in phenotypic plastic prostate cancer and implicates CDK2 inhibition as a novel therapeutic target for this most lethal subtype of prostate cancer.

Can Gentisic Acid Serve as a High-Performance Antioxidant with Lower Toxicity for a Promising New Topical Application?

Gentisic acid (2,5-dihydroxybenzoic acid) is primarily found naturally in plants and has demonstrated a significant range of biological activities; however, its efficacy and safety as a topical application ingredient are not yet well established. Thus, the compound's potential antioxidant and antimicrobial properties were evaluated for efficacy, while the cytotoxicity was evaluated for safety. The antioxidant activity, measured by the DPPH kinetic method, showed an Efficiency Concentration (EC50) of 0.09 with an antioxidant reducing power (ARP) of 11.1. The minimum inhibitory concentration (MIC) against Staphylococcus aureus was 4.15 mg/mL, Escherichia coli was 4.00 mg/mL, Candida albicans was 3.00 mg/mL, and Cutibacterium acnes was 3.60 mg/mL, and the MIC for C. acnes has remained unpublished until now. The substance showed low cytotoxicity by the neutral red uptake (NRU) methodology against HaCat, HDFa, and HepG2 cells at concentrations of up to 10.0, 7.3, and 4.0 mM, respectively, also representing unpublished data. This evidence demonstrates gentisic acid as a promising active substance for skin topical application in the cosmetic or pharmaceutical industry.

Shifts in the gut microbiota of sea urchin Diadema antillarum associated with the 2022 disease outbreak.

Introduction: In recent decades, Caribbean coral reefs have lost many vital marine species due to diseases. The well-documented mass mortality event of the long-spined black sea urchin Diadema antillarum in the early 1980s stands out among these collapses. This die-off killed over 90% of D. antillarum changing the reefscape from coral to algal-dominated. Nearly 40 years later, D. antillarum populations have yet to recover. In early 2022, a new mortality event of D. antillarum was reported along the Caribbean, including Puerto Rico. Methods: This study identifies the gut microbiota changes associated with the D. antillarum during this mortality event. It contrasts them with the bacterial composition of gut samples from healthy individuals collected in 2019 by using 16S rRNA sequencing analyses. Results: Notably, the die-off group's core microbiome resembled bacteria commonly found in the human skin and gut, suggesting potential anthropogenic contamination and wastewater pollution as contributing factors to the 2022 dysbiosis. The animals collected in 2022, especially those with signs of disease, lacked keystone taxa normally found in Diadema including Photobacterium and Propionigenium. Discussion: The association between human microbes and disease stages in the long-spined urchin D. antillarum, especially in relation to anthropogenic contamination, highlights a complex interplay between environmental stressors and marine health. While these microbes might not be the direct cause of death in this species of sea urchins, their presence and proliferation can indicate underlying issues, such as immune depletion due to pollution, habitat destruction, or climate change, that ultimately compromise the health of these marine organisms.

Causes and investigation of stillbirths in Brazil: A multicentre cross-sectional study in 10 referral maternity hospitals.

OBJECTIVE: Understanding the local characteristics and statistics related to stillbirths may be the first step in a series of strategies associated with a reduction in stillbirth ratio. The aim of this study was to estimate the fetal mortality ratio and evaluate the investigation processes related to the causes of death, comparing the investigation according to the specific cause of death. METHODS: A cross-sectional study was retrospectively conducted in 10 tertiary obstetric care centers. Medical records of women with stillbirth managed between January 1, 2009 and December 31, 2018 were analyzed and classified, according to sociodemographic characteristics, and gestational and childbirth data, culminating in stillbirth. The stillbirth ratio and its causes were presented in proportions for the study period and individually for each health facility. RESULTS: Cases of 3390 stillbirths were analyzed. The stillbirth ratio varied from 10.74/1000 live births (LBs) in 2009 to 9.31/1000 in 2018. "Intrauterine hypoxia and asphyxia" (ICD-10 P20) and "unspecific causes of death" (ICD-10 P95) represented 40.8% of the causes of death. Investigation for TORCHS and diabetes occurred in 90.8% and 61.4% of deaths, respectively. Placental and necroscopic tests were performed in 36.6% of the cases. CONCLUSION: The adoption of a rational and standardized investigation of stillbirth remains an unmet need; the use of additional tests and examinations are lacking, especially when unspecific causes are attributed.

The effect of an 8-week fitness regime on low back pain and core strength in high-risk professionals.

BACKGROUND: Low back pain is prevalent among various populations and greatly impacts their quality of life. Professions that incorporate several working hours combined with heavy labor are the most affected. The aim of this study was to examine the effects of an 8-week core training intervention in emergency personnel. METHODS: Sixteen randomly selected male participants; police officers (N.=8) and firefighters (N.=8) (mean age: 40.75 years; mean height: 177.69 cm; mean body mass: 85.50 kg) performed various testing procedures that assessed core muscle strength and endurance and filled the Oswestry Disability Index Questionnaire regarding the level of low back pain before and after the intervention. The 8-week intervention consisted of two 45-60-minute sessions per week that included ten core-related exercises. RESULTS: Statistical analysis; paired samples t-test and Wilcoxon Signed-Rank Test, demonstrated significant effects in the 30-sec sit-up test, the Double Leg Lowering Test and the isometric abdominal strength measurements; p value level of significance was set at P≤0.05. All participants had minimal lower back disability before and after the intervention. CONCLUSIONS: The results demonstrated that the prescribed regime could improve core strength and endurance in high-risk professionals. The most important finding is that training interventions for emergency personnel are most effective when they incorporate a variety of exercises that target the core musculature in all planes of movement and engage the whole range of motion.

Optimal Brassicaceae family microgreens from a phytochemical and sensory perspective.

Microgreens, also called superfoods, emerge because of their high levels of nutrients, diverse flavour profiles, and sustainable cultivation methods, which make them culinary delights and valuable to a healthy and flavorful diet. The present study investigated Brassicaceae family microgreens, proposing a novel system (quality indices) that allows scoring among them. Fourteen Brassica microgreen species were morphological, phytochemical, and sensorial investigated. The morphological assessment revealed that radish microgreens exhibited the highest leaf area (p < 0.05), while red mizuna demonstrated superior yield. Cauliflower microgreens contained the highest concentrations of ascorbic acid (HPLC-DAD) and total phenolic content (p < 0.05). Phytochemical analysis using HPLC-MS/MS identified over 18 glucosinolates and phenolic compounds. Red mustard and red cabbage showed the highest glucosinolate content (p < 0.05). Watercress exhibited the highest phenolic compound content (p < 0.05), primarily flavonoids, while broccoli and radish contained the highest isothiocyanate levels. Cauliflower microgreens resulted in the most consumer-accepted variety. Appling quality indices scoring system identified radish, cauliflower, and broccoli microgreens as the most promising species. This study underscores the potential of Brassica microgreens as an excellent source of health-promoting phytochemicals with favorable market acceptance, providing valuable insights for both nutritional research and commercial applications.

The Enigma of Transcriptional Activation Domains.

Activation domains (ADs) of eukaryotic gene activators remain enigmatic for decades as short, extremely variable sequences which often are intrinsically disordered in structure and interact with an uncertain number of targets. The general absence of specificity increasingly complicates the utilization of the widely accepted mechanism of AD function by recruitment of coactivators. The long-standing enigma at the heart of molecular biology demands a fundamental rethinking of established concepts. Here, we review the experimental evidence supporting a novel mechanistic model of gene activation, based on ADs functioning via surfactant-like near-stochastic interactions with gene promoter nucleosomes. This new model is consistent with recent information-rich experimental data obtained using high-throughput synthetic biology and bioinformatics analysis methods, including machine learning. We clarify why the conventional biochemical principle of specificity for sequence, structures, and interactions fails to explain activation domain function. This perspective provides connections to the liquid-liquid phase separation model, signifies near-stochastic interactions as fundamental for the biochemical function, and can be generalized to other cellular functions.

Dynamics of Corneal Swelling With Hypoosmolar Riboflavin After Induction During Corneal Collagen Crosslinking in Patients With Progressive Keratoconus.

PURPOSE: To evaluate the rate of corneal swelling induced by hypoosmolar riboflavin in patients with progressive keratoconus (KCN) with corneal thickness <400 µm after the induction phase using riboflavin with 20% dextran during epithelium-off corneal crosslinking (CXL). METHODS: Prospective, nonrandomized, single-center consecutive case series. Preoperative assessments included tomography, specular microscopy, and hysteresis. After epithelial debridement, riboflavin with 20% dextran (Photrexa Viscous; Glaukos, Burlington, MA) was applied at 2-min intervals during a 30-min induction phase. Eyes that dehydrated to a minimum corneal thickness (MCT) of <400 µm after induction (postinduction pachymetry) were recruited. Hypoosmolar riboflavin 0.146% (Photrexa; Glaukos) was used every 10 s to induce stromal swelling, with pachymetry performed every 30 s until the MCT was ≥400 µm (postswelling pachymetry). Corneal swelling rate was compared with variables using regression analysis. RESULTS: In 31 eyes of 31 patients, mean postinduction pachymetry was 338.4 ± 28.7 µm. Hypoosmolar riboflavin induced a postswelling pachymetry of 413.4 ± 15.0 µm over a mean of 5.2 ± 3.2 min, and the average stromal swelling rate was 10.3 ± 8.7 µm/30 s. All eyes reached a postswelling pachymetry MCT ≥400 µm and no cases were aborted. Eyes with highly severe KCN (Kmax >70 and Belin/Ambrosio enhanced ectasia display final D score >17) experienced quicker swelling (14.4 ± 12.8 µm/30 s and 14.9 ± 12.4 µm/30 s, respectively; P < 0.05 for both). A thicker postinduction pachymetry was moderately associated with a faster rate of swelling (rs = 0.389; P = 0.030). CONCLUSIONS: Hypoosmolar riboflavin 0.146% can be safely employed in thinner corneas, allowing for swelling to ≥400 µm for epithelium-off CXL. Associations between swelling rate, KCN severity, and postinduction pachymetry were determined, allowing for a more accurate prediction of procedure time during CXL.