Molecular dynamics (MD) study to predict performances of a novel hexanitrohexaazaisowurtzitane/1,4-dinitroimidazole (CL-20/1,4-DNI) energetic cocrystal under different temperatures.

CONTEXT: To estimate the influence of temperature on properties of 2,4,6,8,10,12-hexanitro- 2,4,6,8,10,12-hexaazaisowurtzitane/1,4-dinitroimidazole (CL-20/1,4-DNI) cocrystal explosive, the supercell crystal of CL-20/1,4-DNI cocrystal model was established. The mechanical properties, sensitivity, and stability of cocrystal model under different temperatures (T = 225 K, 250 K, 275 K, 300 K, 325 K, 350 K) were predicted. Results show that mechanical parameters, including bulk modulus, tensile modulus and shear modulus are the lowest when temperature is 300 K, while Cauchy pressure is the highest, indicating that CL-20/1,4-DNI cocrystal model has better mechanical properties at 300 K. Cohesive energy density (CED) and its components energies decrease monotonically with the increase of temperature, illustrating that the CL-20 and 1,4-DNI molecules are activated and the safety of cocrystal explosive is worsened with the increase of temperature. Cocrystal model has relatively higher binding energy when the temperature is 300 K, implying that the CL-20/1,4-DNI cocrystal explosive is more stable under this condition. METHODS: The CL-20/1,4-DNI cocrystal model was optimized and the properties were predicted through molecular dynamics (MD) method. The MD simulation was performed with COMPASS force field and the ensemble was set as NPT, external pressure was set as 0.0001 GPa.

Computational method on highly efficient D-π-A-π-D-based different molecular acceptors for organic solar cells applications and non-linear optical behaviour.

Eight molecular structures (BT-A1 to BT-A8) with high-performance non-fullerene acceptor (NFA) were selected for organic solar cells (OSCs) and non-linear optical (NLO) applications. Their electronic, photovoltaic (PV) and optoelectronic properties were tuned by adding powerful electron-withdrawing groups to the acceptor (A) of the D-π-A-π-D structure. Using time-dependent density functional theory (TD-DFT) techniques, based on the laws of quantum chemical calculations, the absorption spectra, stability of the highest and lowest-energy molecular orbitals (HOMO/LUMOs), electron density, intramolecular charge transfer (ICT), transition density matrix (TDM), were examined. The binding energy (Eb) and density of states (DOS) were probed to realize the optoelectronic analysis of the structures BT-A1 to BT-A8. Noncovalent interactions (NCIs) based on a reduced density gradient (RDG) were used to describe the nature and strength of D-A interactions in the molecules BT-A1 to BT-A8. The new refined molecules BT-A1 to BT-A8 exhibited strong absorbance bands between 408-721 nm and high electron transfer contribution (ETC) ranges between 87-96 %, along with the smallest excitation energies (Ex) between 1.71-3.55 eV in the solvent dichloromethane. Dipolar moment strengths ranging from 0.38 to 4.72 Debye in both the excited and ground states have determined with good solubility properties of BT-A1 to BT-A8 in polar solvent. Highly effective charge mobilities and prevention of charge recombination have been demonstrated by the electron (0.18-0.41 eV) and hole RE values (0.13-0.89 eV) for the new compounds. Power conversion efficiencies (PCE) of BT-A1 to BT-A8 were nearly the same because of better outcomes compared to the molecules in the BT. Compared to poly[4.8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b: 4,5-b']dithiophene-2,6- diyl-alt-(4-2-ethylhexyl)-3-fluorothieno[3,4-b]thiophene-)-2-carboxylate-2-6-diyl)] (PTB7-Th), the open circuit voltages (Voc) of compounds BT-A1 to BT-A8 were ranged from 1.52 to 2.13 eV. The polarizability (α) and hyperpolarizability (ß) of the molecules BT-A1 to BT-A8 were used to determine the non-linear optical (NLO) properties. The results showed that BT-A2, BT-A6 and BT-A7 have good NLO activity. This computational analysis demonstrates the superiority of the molecules with NFA. Hence the compounds are advised for the use in production of high-performance OSCs and NLO activity.

Treatment of anastomotic stricture after rectal cancer operation by magnetic compression technique: A case report.

BACKGROUND: The treatment of postoperative anastomotic stenosis (AS) after resection of colorectal cancer is challenging. Endoscopic balloon dilation is used to treat stenosis in such cases, but some patients do not show improvement even after multiple balloon dilations. Magnetic compression technique (MCT) has been used for gastrointestinal anastomosis, but its use for the treatment of postoperative AS after colorectal cancer surgery has rarely been reported. CASE SUMMARY: We report a 72-year-old man who underwent radical resection of colorectal cancer and ileostomy one year ago. An ileostomy closure was prepared six months ago, but colonoscopy revealed a narrowing of the rectal anastomosis. Endoscopic balloon dilation was performed three times, but colonoscopy showed no significant improvement in stenosis. The AS was successfully treated using MCT. CONCLUSION: MCT is a minimally invasive method that can be used for the treatment of postoperative AS after colorectal cancer surgery.

Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

SMYD2-Methylated PPARγ Facilitates Hypoxia-Induced Pulmonary Hypertension by Activating Mitophagy.

BACKGROUND: Hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) and consequent pulmonary vascular remodeling are the crucial pathological features of pulmonary hypertension (PH). Protein methylation has been shown to be critically involved in PASMC proliferation and PH, but the underlying mechanism remains largely unknown. METHODS: PH animal models were generated by treating mice/rats with chronic hypoxia for 4 weeks. SMYD2-vTg mice (vascular smooth muscle cell-specific suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 (deformed epidural auto-regulatory factor-1) domain-containing protein 2 transgenic) or wild-type rats and mice treated with LLY-507 (3-cyano-5-{2-[4-[2-(3-methylindol-1-yl)ethyl]piperazin-1-yl]-phenyl}-N-[(3-pyrrolidin-1-yl)propyl]benzamide) were used to investigate the function of SMYD2 (suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 domain-containing protein 2) on PH development in vivo. Primary cultured rat PASMCs with SMYD2 knockdown or overexpression were used to explore the effects of SMYD2 on proliferation and to decipher the underlying mechanism. RESULTS: We demonstrated that the expression of the lysine methyltransferase SMYD2 was upregulated in the smooth muscle cells of pulmonary arteries from patients with PH and hypoxia-exposed rats/mice and in the cytoplasm of hypoxia-induced rat PASMCs. More importantly, targeted inhibition of SMYD2 by LLY-507 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in both male and female rats in vivo and reduced rat PASMC hyperproliferation in vitro. In contrast, SMYD2-vTg mice exhibited more severe PH phenotypes and related pathological changes than nontransgenic mice after 4 weeks of chronic hypoxia treatment. Furthermore, SMYD2 overexpression promoted, while SMYD2 knockdown suppressed, the proliferation of rat PASMCs by affecting the cell cycle checkpoint between S and G2 phases. Mechanistically, we revealed that SMYD2 directly interacted with and monomethylated PPARγ (peroxisome proliferator-activated receptor gamma) to inhibit the nuclear translocation and transcriptional activity of PPARγ, which further promoted mitophagy to facilitate PASMC proliferation and PH development. Furthermore, rosiglitazone, a PPARγ agonist, largely abolished the detrimental effects of SMYD2 overexpression on PASMC proliferation and PH. CONCLUSIONS: Our results demonstrated that SMYD2 monomethylates nonhistone PPARγ and inhibits its nuclear translocation and activation to accelerate PASMC proliferation and PH by triggering mitophagy, indicating that targeting SMYD2 or activating PPARγ are potential strategies for the prevention of PH.

[Treatment of open fracture bone defect of distal femur with antibiotic cement column and bone graft].

OBJECTIVE: To investigate the efficacy of antibiotic cement column combined with iliac bone graft in the treatment of open fracture with bone defect of distal femur. METHODS: From October 2014 to March 2021, 16 patients of open fracture bone defect of distal femur were treated with antibiotic bone cement column and iliac bone graft, including 12 males and 4 females. The age ranged from 28 to 68 years old. There were 11 cases of traffic accident injury, 5 cases of falling injury, 3 cases as Gustilo type Ⅰ, 5 cases as type Ⅱ and 8 cases as type ⅢA. AO classification was used:9 cases of C2 type and 7 cases of C3 type. The time from injury to final bone grafting ranged from 4 to 119 days. The length of bone defect ranged from 2 to10 cm. Fractures healing time, complications and knee function Merchan score were recorded. RESULTS: All the 16 patients were followed up from 9 to 29 months. The incisions of 16 patients healed in one stage without postoperative infection, plate fracture, limb shortening and valgus and varus deformity. The healing time randed from 4 to 10 months . Knee joint function according to the Merchant scoring standard, showed that 8 cases were excellent, 4 cases were good, 3 cases were fair, and 1 case was poor. CONCLUSION: The use of antibiotic bone cement column combined with iliac bone graft in the treatment of open and complex bone defects of distal femur is an effective surgical method to prevent infection, assist fracture reduction, increase fixation strength and significantly reduce the amount of bone grafting.

Synthesis of sinomenine derivatives with potential anti-leukemia activity.

In recent years, with sinomenine hydrochloride as the main ingredient, Qingfengteng had been formulated as various dosage forms for clinical treatment. Subsequent findings confirmed a variety of biological roles for sinomenine. Here, 15 H2S-donating sinomenine derivatives were synthesized. Target hybrids a11 displayed substantial cytotoxic effects on cancer cell lines, particularly against K562 cells, with an IC50 value of 1.36 µM. In-depth studies demonstrated that a11 arrested cell cycle at G1 phase, induced apoptosis via both morphological changes in nucleus and membrane potential collapse in mitochondria. These results indicated a11 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

Comparison of Locking Plate Alone and Locking Plate Combined with 3D Printed Polymethylmethacrylate Augmentation in Treating Proximal Humerus Fractures in the Elderly.

BACKGROUND: Locking plates are widely used in open reduction internal fixation (ORIF) for proximal humeral fracture (PHF). However, the optimal surgical treatment of unstable, displaced PHF in elderly patients remains controversial. This study aimed to compare the radiological and clinical outcomes of surgical treatment of PHF in the elderly with locking plate (LP) alone and locking plate combined with 3D printed polymethylmethacrylate (PMMA) prosthesis augmentation (LP-PA). METHODS: From May 2015 to April 2021, a total of 97 patients aged ≥ 60 years with acute unstable PHF who underwent osteosynthesis with either LP (46 patients) or LP-PA (51 patients) were retrospectively analyzed. For the LP-PA group, a customized proximal humeral prosthesis made of PMMA cement was intra-operatively fabricated by a three-dimensional (3D) printed prototype mold for the humeral medial support. Radiological outcomes were analyzed by measuring the value of neck-shaft angle (NSA) and humeral head height (HHH). The clinical outcomes were evaluated using Constant-Murley Score (CMS), Disabilities of the Arm Shoulder and Hand (DASH) score, American Shoulder and Elbow Surgeons (ASES) score, and the shoulder range of motion (ROM). Pain was measured using a visual analogue scale (VAS). RESULTS: At the one-year follow-up, all fractures healed radiologically and clinically. The mean changes of NSA and HHH over the follow-up period were markedly smaller in the LP-PA group (3.8 ± 0.9° and 1.7 ± 0.3 mm) than those in the LP group (9.7 ± 2.1° and 3.2 ± 0.6 mm, both P < 0.0001). The LP-PA group also presented lower DASH score (17.1 ± 3.6), higher ASES score (89.5 ± 11.2) and better ROM in forward elevation (142 ± 26°) and external rotation (59 ± 11°) compared to the LP group (28.9 ± 4.8 for DASH score, P < 0.0001; 82.3 ± 9.0 for ASES score, P < 0.001; 129 ± 21° for forward elevation, P = 0.008; and 52 ± 9° for external rotation, P = 0.001). There was no significant difference in overall complication rate between the two groups, although the complication rate of screw perforation was higher in the LP-PA group (P = 0.172). CONCLUSIONS: For PHF in elderly patients, the combination of LP fixation and PMMA prosthesis augmentation effectively improved humeral head support and reduction maintenance, providing satisfactory outcomes both radiologically and clinically. This technique also reduced the incidence of screw perforation associated with plate fixation alone, making it a reasonable option to ensure satisfactory clinical outcomes.

[Effects of Exogenous Zinc on Growth and Root Architecture Classification of Maize Seedlings Under Cadmium Stress].

To explore the effects of different concentrations of zinc （Zn） on the growth and root architecture classification of maize seedlings under cadmium （Cd） stress， a hydroponic experiment was conducted to study the effects of different concentrations of Zn （0， 10， 25， 50， 100， 200， and 400 µmol·L-1） on the growth， root architecture and classification characteristics， Cd content， root Cd uptake capacity， and photosynthetic system of maize seedlings under Cd stress （50 µmol·L-1） by using Zhengdan 958 as the experimental material. Principal component analysis and the membership function method were used for comprehensive evaluation. The results showed that the 50 µmol·L-1 Cd stress had a significant toxic effect on maize seedlings， which significantly reduced chlorophyll content and photosynthetic parameters. The main root length， plant height， biomass， root forks， and root tips， including the root length and root surface area of the grade Ⅰ-Ⅲ diameter range and the root volume of the grade Ⅰ-Ⅱ diameter range， decreased significantly， which hindered the normal growth and development of maize seedlings. Compared with that under no Zn application， 100 µmol·L-1 and 200 µmol·L-1 Zn application reduced the uptake of Cd by maize seedlings， significantly reduced the Cd content in shoots and roots and the Cd uptake efficiency. The toxic effect on maize seedlings was alleviated， and the fresh weight， dry weight， tolerance index， and root forks of shoots and roots were significantly increased. The photosynthesis of maize seedlings was significantly enhanced， and the photosynthetic rate and the total chlorophyll content was significantly increased. The RL， SA， and RV in the Ⅰ-Ⅱ diameter range reached the maximum at 100 µmol·L-1 Zn， and the RL， SA， and RV in the Ⅲ diameter range reached the maximum at 200 µmol·L-1 Zn， which were significantly higher than those without Zn treatment. The comprehensive evaluation of the growth tolerance of maize seedlings showed that 100 µmol·L-1 and 200 µmol·L-1 Zn had better effects on alleviating Cd toxicity. Comprehensive analysis showed that the application of appropriate concentration of Zn could reduce the Cd content in maize seedlings， the Cd uptake capacity， and Cd uptake efficiency of roots； increase the biomass accumulation of maize seedlings； reduce the effect of Cd toxicity on root architecture； reduce the effect on the light and system； and improve the tolerance of maize seedlings to Cd.

Theoretical investigation on regulating photophysical properties and proton transfer behavior by electronegativity for near-infrared emitting styryl dyes.

Our main focus is to explore the atomic electronegativity-dependent photoinduced behavior of styryl derivatives (HBO, HBS, and HBSe). The results of structural parameter calculation by the DFT method show that the intramolecular hydrogen bonds of normal and tautomer form are strengthened and weakened, respectively, in an excited state (S1), which is conducive to the excited intramolecular proton transfer (ESIPT) process. The enhancement of excited hydrogen bond is beneficial to the ESIPT process from the aspects of infrared vibration frequency (IR), Mulliken's charge analysis, and density gradient reduction (RDG). Additionally, by determining the bond energy with the band critical point (BCP) parameter, we found that the lower the electronegativity of the atom, the larger the hydrogen bond strength at the excited state and the more likely ESIPT reaction occurs. Meanwhile, the intramolecular H-bonds O-H…N in HBO, HBS, and HBSe are enhanced with the weakened electron-withdrawing capacity of the atom (from O to S and Se). Subsequently, frontier molecular orbital (FMOs) and charge density difference (CDD) analyses essentially revealed that electron redistribution induces the ESIPT process. Low atomic electronegativity exhibits the high chemical activity of the excited state. Furthermore, to demonstrate the electronegativity-dependent ESIPT behavior of the system, we built potential energy curves (PECs) and located the transition states (TS) of proton transfer processes.

Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

The transcriptional cofactor Tle3 reciprocally controls effector and central memory CD8+ T cell fates.

Antigen-experienced CD8+ T cells form effector and central memory T cells (TEM and TCM cells, respectively); however, the mechanism(s) controlling their lineage plasticity remains incompletely understood. Here we show that the transcription cofactor Tle3 critically regulates TEM and TCM cell fates and lineage stability through dynamic redistribution in antigen-responding CD8+ T cell genome. Genetic ablation of Tle3 promoted CD8+ TCM cell formation at the expense of CD8+ TEM cells. Lineage tracing showed that Tle3-deficient CD8+ TEM cells underwent accelerated conversion into CD8+ TCM cells while retaining robust recall capacity. Tle3 acted as a coactivator for Tbet to increase chromatin opening at CD8+ TEM cell-characteristic sites and to activate CD8+ TEM cell signature gene transcription, while engaging Runx3 and Tcf1 to limit CD8+ TCM cell-characteristic molecular features. Thus, Tle3 integrated functions of multiple transcription factors to guard lineage fidelity of CD8+ TEM cells, and manipulation of Tle3 activity could favor CD8+ TCM cell production.

Comparison of Second-Generation Cryoballoon Ablation and Quantitative Radiofrequency Ablation Guided by Ablation Index for Atrial Fibrillation.

We compared the efficacy and complication rates of quantitative radiofrequency ablation guided by ablation index (RFCA-AI) with those of second-generation cryoballoon ablation (CBA-2). Consecutive patients (n = 230) with symptomatic atrial fibrillation (AF) undergoing a first ablation CBA-2 (92 patients) or RFCA-AI (138 patients) procedure were enrolled in this study. The late recurrence rate in the CBA-2 group was higher than that in the RFCA-AI group (P = .012). Subgroup analysis showed the same result in patients with paroxysmal AF (PAF) (P = .039), but no difference was found in patients with persistent AF (P = .21). The average operation duration in the CBA-2 group (85 [75-99.5] minutes) was shorter than that in the RFCA-AI group (100 [84.5-120] minutes) (P < .0001), but the average exposure time (17.36(13.87-22.49) vs 5.49(4.00-8.24) minutes) in the CBA-2 group and X-ray dose (223.25(149.15-336.95) vs 109.15(80.75-168.7) mGym) were significantly longer than those in RFCA-AI group (P < .0001). Multivariate logistic regression analysis showed that left atrial diameter (LAD), early recurrence, and methods of ablation (cryoballoon ablation) were independent risk factors for late recurrence after AF ablation. Early recurrence of AF and LAD were independent risk factors for predicting late recurrence after AF ablation.

Tissue-infiltrating alloreactive T cells require Id3 to deflect PD-1-mediated immune suppression during GVHD.

ABSTRACT: Persisting alloreactive donor T cells in target tissues are a determinant of graft-versus-host disease (GVHD), but the transcriptional regulators that control the persistence and function of tissue-infiltrating T cells remain elusive. We demonstrate here that Id3, a DNA-binding inhibitor, is critical for sustaining T-cell responses in GVHD target tissues in mice, including the liver and intestine. Id3 loss results in aberrantly expressed PD-1 in polyfunctional T helper 1 (Th1) cells, decreased tissue-infiltrating PD-1+ polyfunctional Th1 cell numbers, impaired maintenance of liver TCF-1+ progenitor-like T cells, and inhibition of GVHD. PD-1 blockade restores the capacity of Id3-ablated donor T cells to mediate GVHD. Single-cell RNA-sequencing analysis revealed that Id3 loss leads to significantly decreased CD28- and PI3K/AKT-signaling activity in tissue-infiltrating polyfunctional Th1 cells, an indicator of active PD-1/PD-L1 effects. Id3 is also required for protecting CD8+ T cells from the PD-1 pathway-mediated suppression during GVHD. Genome-wide RNA-sequencing analysis reveals that Id3 represses transcription factors (e.g., Nfatc2, Fos, Jun, Ets1, and Prdm1) that are critical for PD-1 transcription, exuberant effector differentiation, and interferon responses and dysfunction of activated T cells. Id3 achieves these effects by restraining the chromatin accessibility for these transcription factors. Id3 ablation in donor T cells preserved their graft vs tumor effects in mice undergoing allogeneic hematopoietic stem cell transplantation. Furthermore, CRISPR/Cas9 knockout of ID3 in human CD19-directed chimeric antigen receptor T cells retained their antitumor activity in NOD/SCID/IL2Rg-/- mice early after administration. These findings identify that ID3 is an important target to reduce GVHD, and the gene-editing program of ID3 may have broad implications in T-cell-based immunotherapy.

Regulated cell death in myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion (I/R) injury most commonly occurs in coronary artery disease when prompt reperfusion is used to salvage the ischemic myocardium. Cardiomyocyte death is a significant component of myocardial I/R injury and its mechanism was previously thought to be limited to apoptosis and necrosis. With the discovery of novel types of cell death, ferroptosis, necroptosis, and pyroptosis have been shown to be involved in myocardial I/R. These new forms of regulated cell death cause cardiomyocyte loss and exacerbate I/R injury by affecting reactive oxygen species (ROS) generation, calcium stress, and inflammatory cascades, subsequently mediating adverse remodeling, cardiac dysfunction, and heart failure. Herein, we review the roles of ferroptosis, necroptosis, and pyroptosis in myocardial I/R and discuss their contribution to pathology.

Antigen exposure reshapes chromatin architecture in central memory CD8+ T cells and imprints enhanced recall capacity.

CD62L+ central memory CD8+ T (TCM) cells provide enhanced protection than naive cells; however, the underlying mechanism, especially the contribution of higher-order genomic organization, remains unclear. Systematic Hi-C analyses reveal that antigen-experienced CD8+ T cells undergo extensive rewiring of chromatin interactions (ChrInt), with TCM cells harboring specific interaction hubs compared with naive CD8+ T cells, as observed at cytotoxic effector genes such as Ifng and Tbx21. TCM cells also acquire de novo CTCF (CCCTC-binding factor) binding sites, which are not only strongly associated with TCM-specific hubs but also linked to increased activities of local gene promoters and enhancers. Specific ablation of CTCF in TCM cells impairs rapid induction of genes in cytotoxic program, energy supplies, transcription, and translation by recall stimulation. Therefore, acquisition of CTCF binding and ChrInt hubs by TCM cells serves as a chromatin architectural basis for their transcriptomic dynamics in primary response and for imprinting the code of "recall readiness" against secondary challenge.

The functions of SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) in biological process and disease.

Histone methyltransferase SETDB1 (SET domain bifurcated histone lysine methyltransferase 1, also known as ESET or KMT1E) is known to be involved in the deposition of the di- and tri-methyl marks on H3K9 (H3K9me2 and H3K9me3), which are associated with transcription repression. SETDB1 exerts an essential role in the silencing of endogenous retroviruses (ERVs) in embryonic stem cells (mESCs) by tri-methylating H3K9 (H3K9me3) and interacting with DNA methyltransferases (DNMTs). Additionally, SETDB1 is engaged in regulating multiple biological processes and diseases, such as ageing, tumors, and inflammatory bowel disease (IBD), by methylating both histones and non-histone proteins. In this review, we provide an overview of the complex biology of SETDB1, review the upstream regulatory mechanisms of SETDB1 and its partners, discuss the functions and molecular mechanisms of SETDB1 in cell fate determination and stem cell, as well as in tumors and other diseases. Finally, we discuss the current challenges and prospects of targeting SETDB1 for the treatment of different diseases, and we also suggest some future research directions in the field of SETDB1 research.

Theoretical design and evaluation of efficient small donor molecules for organic solar cells.

CONTEXT: The development of high-efficiency photovoltaic devices is the need of time with increasing demand for energy. Herein, we designed seven small molecule donors (SMDs) with A-π-D-π-A backbones containing various acceptor groups for high-efficiency organic solar cells (OSCs). Molecular engineering was performed by substituting the acceptor group in the synthesized compound (BPR) with another highly efficient acceptor group to improve the photoelectric performance of the molecule. METHOD: The photovoltaic, optoelectronic, and photophysical properties of the proposed compounds (BP1-BP7) were investigated in comparison to BPR using DFT and TD-DFT at MPW1PW91/6-311G(d,p) level of theory. All molecules we designed have red-shifted absorption spectra. The modification of the acceptor fragment of the BPR resulted in a reduced HOMO-LUMO energy gap; thus, the designed compounds (BP1-BP7) had improved optoelectronic responses as compared with the BPR molecule. Various key factors that are crucial for efficient SMDs such as exciton binding energy, frontier molecular orbitals (FMOs), absorption maximum (λmax), open circuit voltage (VOC), dipole moment (µ), excitation charge mobilities, and the transition density matrix of (BPR, BP1-BP7) have also been studied. Low reorganizational energy (holes and electrons) values provide high charge mobility, and all the designed compounds are efficient in this regard. Here, BP6 exhibits low excitation energy (1.66 eV), highest open circuit voltage (2.00 V), normalized VOC (77.23), and fill factor (0.931). Consequently, the superiority of the designed molecules advises experimenters to envision future developments in extremely effective OSC devices.

TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma.

Intraepithelial lymphocytes (IELs), including αß and γδ T cells (T-IELs), constantly survey and play a critical role in maintaining the gastrointestinal epithelium. We show that cytotoxic molecules important for defense against cancer were highly expressed by T-IELs in the small intestine. In contrast, abundance of colonic T-IELs was dependent on the microbiome and displayed higher expression of TCF-1/TCF7 and a reduced effector and cytotoxic profile, including low expression of granzymes. Targeted deletion of TCF-1 in γδ T-IELs induced a distinct effector profile and reduced colon tumor formation in mice. In addition, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers (CRCs) compared with normal healthy colon, which strongly correlated with an enhanced γδ T-IEL effector phenotype and improved patient survival. Our work identifies TCF-1 as a colon-specific T-IEL transcriptional regulator that could inform new immunotherapy strategies to treat CRC.