Combination of dual JAK/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer.

BACKGROUND: Treatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models. METHODS: The cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized. RESULTS: The combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib. CONCLUSIONS: The combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted.

Longitudinal gut microbial signals are associated with weight loss: insights from a digital therapeutics program.

Introduction: The gut microbiome's influence on weight management has gained significant interest for its potential to support better obesity therapeutics. Patient stratification leading to personalized nutritional intervention has shown benefits over one-size-fit-all diets. However, the efficacy and impact on the gut's microbiome of personalizing weight loss diets based on individual factors remains under-investigated. Methods: This study assessed the impact of Digbi Health's personalized dietary and lifestyle program on weight loss and the gut microbiome end-points in 103 individuals. Participants' weight loss patterns and gut microbiome profiles were analyzed from baseline to follow-up samples. Results: Specific microbial genera, functional pathways, and communities associated with BMI changes and the program's effectiveness were identified. 80% of participants achieved weight loss. Analysis of the gut microbiome identified genera and functional pathways associated with a reduction in BMI, including Akkermansia, Christensenella, Oscillospiraceae, Alistipes, and Sutterella, short-chain fatty acid production, and degradation of simple sugars like arabinose, sucrose, and melibiose. Network analysis identified a microbiome community associated with BMI, which includes multiple taxa known for associations with BMI and obesity. Discussion: The personalized dietary and lifestyle program positively impacted the gut microbiome and demonstrated significant associations between gut microbial changes and weight loss. These findings support the use of the gut microbiome as an endpoint in weight loss interventions, highlighting potential microbiome biomarkers for further research.

Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway.

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar "Western" diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.

The Neuroimmune Axis and Its Therapeutic Potential for Primary Liver Cancer.

The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays a key role in primary liver diseases. Until recently, however, the impact of nerves on cancer development, progression, and metastasis has been unappreciated. This review highlights recent advances in understanding neuroanatomical networks within solid organs and their mechanistic influence on organ function, specifically in the liver and liver cancer. We discuss the interaction between the autonomic nervous system, including sympathetic and parasympathetic nerves, and the liver. We also examine how sympathetic innervation affects metabolic functions and diseases like nonalcoholic fatty liver disease (NAFLD). We also delve into the neurobiology of the liver, the interplay between cancer and nerves, and the neural regulation of the immune response. We emphasize the influence of the neuroimmune axis in cancer progression and the potential of targeted interventions like neurolysis to improve cancer treatment outcomes, especially for hepatocellular carcinoma (HCC).

The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.

The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.

Modulating the effective ionic radii of trivalent dopants in ceria using a combination of dopants to improve catalytic efficiency for the oxygen evolution reaction.

Aliovalent doping in ceria and defect engineering are important aspects in tuning the properties of ceria for advanced technological applications, especially in the emerging field of electrocatalytic water-splitting for harvesting renewable energy. However, the ambiguity regarding the choice of dopants/co-dopants and ways to deal with the size difference between dopants and lattice hosts remains a long-standing problem. In this study, ceria was aliovalently codoped with Sc3+ and La3+ while keeping the total concentration of dopants constant; the ionic radius of the former is smaller and that of the latter is larger than Ce4+. Variations in the relative amounts of these dopants helped to modulate the effective ionic radii and match that of the host. A systematic study on the role of these aliovalent dopants in defect evolution in ceria and in modulating the Ce3+ fraction using powder XRD, Rietveld refinement, positron annihilation lifetime spectroscopy, X-ray photoelectron spectroscopy, Eu3+ photoluminescence, and Raman spectroscopy is presented here. The evolved defects and their dependence on subtle factors other than charge compensation are further correlated with their electrocatalytic activity towards oxygen evolution reaction (OER) in alkaline medium. The catalyst with an optimum defect density, maximum Ce3+ fraction at the surface and the least effective ionic radius difference between the dopants and the host demonstrated the best performance towards the OER. This study demonstrates how effective ionic radius modulation in defect-engineered ceria through a judicious choice of codopants can enhance the catalytic property of ceria and provides immensely helpful information for designing ceria-based heterogeneous catalysts with desired functionalities.

Electrocatalytic OER behavior of the Bi-Fe-O system: an understanding from the perspective of the presence of oxygen vacancies.

This study aims to understand and correlate the role of the nature and relative concentration of oxygen vacancies with the trend observed in the OER with the Bi-Fe-O system. To understand this, we first investigated the system of oxides using X-ray photoelectron spectroscopy (XPS) and electron paramagnetic resonance (EPR), which revealed the presence of oxygen vacancies in the system. Density functional theory (DFT) was employed to investigate the relative concentration of these vacancies by calculating their formation energies. Positron annihilation lifetime spectroscopy (PALS) was carried out to understand the nature of these oxygen vacancies. We observed that the presence of a higher concentration of monovacancies created due to the absence of oxygen from the structure of Bi2Fe4O9 was mainly responsible for the high performance of the oxide towards the OER compared to that of the other oxides viz-BiFeO3 and Bi25FeO40 of the Bi-Fe-O system.

Antibacterial and cytotoxicity studies of pyrrolo-based organic scaffolds and their binding interaction with bovine serum albumin.

Two pyrrolo-based compounds, 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (L1) and 1H-pyrrolo[3,2-c]pyridine-4-carboxylic acid (L2), were employed for the detection of bovine serum albumin (BSA) by UV-Vis and fluorescence spectroscopic methods in phosphate buffer solution (pH = 7). In the presence of L1 and L2, the fluorescence emission of BSA at 340 nm was quenched and concomitantly a red-shifted emission band appeared at 420 nm (L1)/450 nm (L2). The fluorescence spectral changes indicate the protein-ligand complex formation between BSA and L1/L2. An isothermal titration calorimetry (ITC) experiment was conducted to determine the binding ability between BSA and L1/L2. The binding constants are found to be 4.45 ± 0.22 × 104 M-1 for L1 and 2.29 ± 0.11 × 104 M-1 for L2, respectively. The thermodynamic parameters were calculated from ITC measurements (i.e. ∆rH = -40 ± 2 kcal/mol, ∆rG = -4.57 ± 0.22 kcal/mol and -T∆rS = 35.4 ± 1.77 kcal/mol), which indicated that the protein-ligand complex formation between L1/L2 with BSA is mainly due to the electrostatic interactions. The protein-ligand interactions were studied by performing molecular docking. Further, the antibacterial assay of L1 and L2 was conducted against gram-positive and gram-negative bacterial strains in an effort to address the difficulties caused by the co-occurrence of antimicrobial and multidrug-resistant bacteria. E. coli and S. aureus were significantly inhibited by L1 and L2. The L1 exhibits 13, 12 and 15 mm, whereas L2 exhibits a 2, 3 and 5 mm zone of inhibition against S. aureus, S. pyogenes and E. coli, respectively. In silico molecular docking of L1 and L2 was performed with bacterial DNA gyrase to establish the intermolecular interactions. Finally, the in vitro cytotoxicity activities of the ligands L1 and L2 have been carried out using drosophila.

Emerging Trends in Nanotechnology for Endometriosis: Diagnosis to Therapy.

Endometriosis, an incurable gynecological disease that causes abnormal growth of uterine-like tissue outside the uterine cavity, leads to pelvic pain and infertility in millions of individuals. Endometriosis can be treated with medicine and surgery, but recurrence and comorbidities impair quality of life. In recent years, nanoparticle (NP)-based therapy has drawn global attention, notably in medicine. Studies have shown that NPs could revolutionize conventional therapeutics and imaging. Researchers aim to enhance the prognosis of endometriosis patients with less invasive and more effective NP-based treatments. This study evaluates this potential paradigm shift in endometriosis management, exploring NP-based systems for improved treatments and diagnostics. Insights into nanotechnology applications, including gene therapy, photothermal therapy, immunotherapy, and magnetic hyperthermia, offering a theoretical reference for the clinical use of nanotechnology in endometriosis treatment, are discussed in this review.

Redox modulator iron complexes trigger intrinsic apoptosis pathway in cancer cells.

The emergence of multidrug resistance in cancer cells necessitates the development of new therapeutic modalities. One way cancer cells orchestrate energy metabolism and redox homeostasis is through overloaded iron pools directed by iron regulatory proteins, including transferrin. Here, we demonstrate that targeting redox homeostasis using nitrogen-based heterocyclic iron chelators and their iron complexes efficiently prevents the proliferation of liver cancer cells (EC50: 340 nM for IITK4003) and liver cancer 3D spheroids. These iron complexes generate highly reactive Fe(IV)=O species and accumulate lipid peroxides to promote oxidative stress in cells that impair mitochondrial function. Subsequent leakage of mitochondrial cytochrome c activates the caspase cascade to trigger the intrinsic apoptosis pathway in cancer cells. This strategy could be applied to leverage the inherent iron overload in cancer cells to selectively promote intrinsic cellular apoptosis for the development of unique iron-complex-based anticancer therapeutics.

Comparison of Three Methods of Umbilical Cord Management in Late Preterm and Term Newborns on Hemoglobin and Ferritin Levels at Six Weeks of Age: A Randomized Controlled Trial.

BACKGROUND: Umbilical cord milking (UCM) and delayed cord clamping (DCC) are strategies that improve the hemodynamic condition of the newborn and also increase the storage of iron. This study aimed to compare the effects of DCC with or without milking in late preterm and term neonates at different time intervals after birth (60, 120, and 180 seconds) on hematological and hemodynamic parameters in neonates at six weeks of age. MATERIALS AND METHODS: In this double-arm, parallel-group, triple-blind, and active-controlled trial, all 150 eligible neonates were randomized with allocation concealment into three groups: Group A (DCC with UCM at 60 seconds), Group B (DCC with UCM at 120 seconds), and Group C (only DCC for 180 seconds). Hemodynamic parameters were recorded and compared during the first 48 hours, and hematological parameters were compared at six weeks of age. RESULTS: At six weeks, a significant difference in hemoglobin levels was noted between Groups A, B, and C (p<0.001). The difference in serum ferritin values at six weeks was also statistically significant in comparisons across all three groups (p=0.003). Regarding secondary outcomes examined, hemodynamic parameters and the incidence of neonatal hyperbilirubinemia were found to be comparable at 48 hours after birth. CONCLUSION: DCC followed by UCM at 120 seconds and DCC till 180 seconds proves superior to DCC with UCM at 60 seconds in preserving elevated hemoglobin levels and iron stores in neonates at six weeks of age. DCC for 180 seconds yielded comparable results, followed by UCM at 120 seconds. All three methods are considered safe and effective without compromising the neonate's hemodynamics.

UCP1-dependent brown adipose activation accelerates cardiac metabolic remodeling and reduces initial hypertrophic and fibrotic responses to pathological stress.

Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of ß-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-ß1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.

Role of plant neurotransmitters in salt stress: A critical review.

Neurotransmitters are naturally found in many plants, but the molecular processes that govern their actions still need to be better understood. Acetylcholine, γ-Aminobutyric acid, histamine, melatonin, serotonin, and glutamate are the most common neurotransmitters in animals, and they all play a part in the development and information processing. It is worth noting that all these chemicals have been found in plants. Although much emphasis has been placed on understanding how neurotransmitters regulate mood and behaviour in humans, little is known about how they regulate plant growth and development. In this article, the information was reviewed and updated considering current thinking on neurotransmitter signaling in plants' metabolism, growth, development, salt tolerance, and the associated avenues for underlying research. The goal of this study is to advance neurotransmitter signaling research in plant biology, especially in the area of salt stress physiology.

Design, Synthesis, DFT, docking Studies, and antimicrobial evaluation of novel benzimidazole containing sulphonamide derivatives.

In silico approaches have been employed to design a new series of benzimidazole-containing sulphonamide derivatives and qualified compounds have been synthesized to analyze their potential as antimicrobial agents. Antibacterial screening of all synthesized compounds was done using the broth microdilution method against several human pathogenic bacteria, viz. Gram-positive bacteria [B. cerus (NCIN-2156), B. subtilis (ATCC-6051), S. aureus (NCIM-2079)] and Gram-negative bacteria [P. aeruginosa (NCIM-2036), E. coli (NCIM-2065), and a drug-resistant strain of E. coli (U-621)], and the compounds presented admirable MIC values, ranging between 100-1.56 µg/mL. The combinatorial analysis showed the magnificent inhibitory efficiency of the tested compounds, acquired equipotent to ten-fold more potency compared to original MIC values. An immense synergistic effect was exhibited by the compounds during combination studies with reference drugs chloramphenicol and sulfamethoxazole was presented as fractional inhibitory concentration (∑FIC). Enzyme inhibition studies of all synthesized compounds were done by using peptidyl transferase and dihydropteroate synthase enzymes isolated from E. coli and S. aureus and each of the compound presented the admirable IC50 values, where the lead compound 3 bound to peptidyl transferase (of S. aureus with IC50 363.51 ± 2.54 µM and E. coli IC50 1.04 ± 0.08 µM) & dihydropteroate synthase (of S. aureus IC50 3.51 ± 0.82 µM and E. coli IC50 2.77 ± 0.65 µM), might account for the antimicrobial effect, exhibited excellent inhibition potential. Antifungal screening was also performed employing food poisoning methods against several pathogenic fungal species, viz A. flavus, F. oxysporum, A. niger, and A. brassicae. The obtained result indicated that few compounds can prove to be a potent drug regimen against dreaded MDR strains of microbes. Structural activity relationship (SAR) analysis and docking studies reveal that the presence of electron-withdrawing, polar, and more lipophilic substituents positively favor the antibacterial activity, whereas, electron-withdrawing, more polar, and hydrophilic substituents favor the antifungal activities. A robust coherence has been found in in-silico and in-vitro biological screening results of the compounds.

Progenitors of distinct lineages shape the diversity of mature type 2 conventional dendritic cells.

Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8+ and CD4+ T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300ciCre-hCD2R26tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c-traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3CreR26tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c-traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses.

Tiny Tummies, Big Challenges: A Case Series of Neonatal Gastric Perforations.

The main aim of this article is to highlight the clinical features indicating gastric perforation in neonates so that prompt surgery can provide a good outcome for an otherwise fatal condition. Data was collected retrospectively from all neonates who presented to our tertiary care institute with subsequent diagnosis of gastric perforation from January 2020 to December 2023 (three years). Simple statistical analysis involving sums, means, averages, and percentages was used. Five neonates were operated over a period of three years with a diagnosis of gastric perforation. Two of them were spontaneous. Of the remaining three, each one was associated with malrotation, prematurity, and COVID-19. All five cases could be diagnosed with the finding of free gas in the peritoneum on the abdominal radiograph. Overall mortality was 60% (three of five neonates). Neonatal gastric perforation typically occurs in the first week of life, specifically within the second to seventh day. Symptom onset is usually sudden, with abdominal distension as the first sign, with acidic contents causing severe peritonitis and rapid progression to sepsis and shock. Early diagnosis with subsequent timely resuscitation and surgical repair is crucial to good outcomes. Massive pneumoperitoneum on abdominal radiographs with typical signs in a neonate should raise suspicion of gastric perforation, especially in the first week of life.

Remediation of pharmacophoric laboratory waste by using biodegradable carbon nanoparticles of bacterial biofilm origin.

Research laboratories generate a broad range of hazardous pharmacophoric chemical contaminants, from drugs to dyes used during various experimental procedures. In the recent past, biological methods have demonstrated great potential in the remediation of such contaminants. However, the presence of pharmacophoric chemicals containing antibiotics, xenobiotics, and heavy metals suppresses the growth and survivability of used microbial agents, thus decreasing the overall efficiency of biological remediation processes. Bacterial biofilm is a natural arrangement to counter some of these inhibitions but its use in a systemic manner, portable devices, and pollutant remediation plants post serious challenges. This could be countered by synthesizing a biodegradable carbon nanoparticle from bacterial biofilm. In this study, extracellular polymeric substance-based carbon nanoparticles (Bio-EPS-CNPs) were synthesized from bacterial biofilm derived from Bacillus subtilis NCIB 3610, as a model bacterial system. The produced Bio-EPS-CNPs were investigated for physiochemical properties by dynamic light scattering, optical, Fourier-transformed infrared, and Raman spectroscopy techniques, whereas X-ray diffraction study, scanning electron microscopy, and transmission electron microscopy were used to investigate structural and morphological features. The Bio-EPS-CNPs exhibited negative surface charge with spherical morphology having a uniform size of sub-100 nm. The maximum remediation of some laboratory-produced pharmacophoric chemicals was achieved through a five-round scavenging process and confirmed by UV/Vis spectroscopic analysis with respect to the used pharmacophore. This bioinspired remediation of used pharmacophoric chemicals was achieved through the mechanism of surface adsorption via hydrogen bonding and electrostatic interactions, as revealed by different characterizations. Further experiments were performed to investigate the effects of pH, temperature, stirring, and the protocol of scavenging to establish Bio-EPS-CNP as a possible alternative to be used in research laboratories for efficient removal of pharmacophoric chemicals by incorporating it in a portable, filter-based device.

BRD2 promotes antibody class switch recombination by facilitating DNA repair in collaboration with NIPBL.

Efficient repair of DNA double-strand breaks in the Ig heavy chain gene locus is crucial for B-cell antibody class switch recombination (CSR). The regulatory dynamics of the repair pathway direct CSR preferentially through nonhomologous end joining (NHEJ) over alternative end joining (AEJ). Here, we demonstrate that the histone acetyl reader BRD2 suppresses AEJ and aberrant recombination as well as random genomic sequence capture at the CSR junctions. BRD2 deficiency impairs switch (S) region synapse, optimal DNA damage response (DDR), and increases DNA break end resection. Unlike BRD4, a similar bromodomain protein involved in NHEJ and CSR, BRD2 loss does not elevate RPA phosphorylation and R-loop formation in the S region. As BRD2 stabilizes the cohesion loader protein NIPBL in the S regions, the loss of BRD2 or NIPBL shows comparable deregulation of S-S synapsis, DDR, and DNA repair pathway choice during CSR. This finding extends beyond CSR, as NIPBL and BRD4 have been linked to Cornelia de Lange syndrome, a developmental disorder exhibiting defective NHEJ and Ig isotype switching. The interplay between these proteins sheds light on the intricate mechanisms governing DNA repair and immune system functionality.

In situ carbonization metamorphoses porous silica particles into biodegradable therapeutic carriers of lesser consequence on TGF-ß1 mediated fibrosis.

Extensive modifications have been made to the synthesis protocol for porous silica particles to improve the shape, size and yield percentage, but problems associated with improvement in biodegradability and decrease in chances to induce side effects still remain a concern. To circumvent these limitations, a facile modification strategy has been employed through in situ carbonization of porous silica particles. Herein, carbon particles were integrated within porous silica core-shell particles (Si-P-CNPs) during the synthesis process and found to preserve the ordered structural morphology. Curcumin was used as a model drug for loading in prepared Si-P-CNPs whereas lung cancer cells were used as a model system to study the in vitro fate. These Si-P-CNPs showed improved drug loading, drug effectivity, biodegradability and avoidance of interaction with transforming growth factor ß1 (TGF-ß1) indicating the possibility of reducing the chances of lung fibrosis and thereby enhancing the safety profile over conventional porous silica particles.