Exploring the efficacy of (R)-PFI-2 hydrochloride in mitigating noise-induced hearing loss by targeting NLRP3 inflammasome and NF-κB pathway to reduce inner ear inflammation.

Noise-induced hearing loss (NIHL) is primarily driven by inflammatory processes within the cochlea, where noise exposure triggers the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, leading to an inflammatory cascade. The interaction between increased NLRP3 expression and NF-κB activity can further amplify cochlear inflammation. Our findings reveal that (R)-PFI-2 hydrochloride, a selective inhibitor of the SETD7 enzyme, effectively inhibits the activation of the cochlear NF-κB pathway, suppresses the release of pro-inflammatory factors, and prevents inflammasome assembly.

A Phase 1 randomized trial of homologous and heterologous filovirus vaccines with a late booster dose.

Filoviruses, including Ebola, Marburg, Sudan, and Taï Forest viruses, are zoonotic pathogens that can cause severe viral hemorrhagic fever and death. Developing vaccines that provide durable, broad immunity against multiple filoviruses is a high global health priority. In this Phase 1 trial, we enrolled 60 healthy U.

Mineralized Nanofiber Substrates Enabling High-Performance Dually Charged Nanofiltration Membranes with Enhanced Permeability.

Nanofiltration membranes (NFMs) with superior permeability and high rejection of both divalent anions and cations are highly desirable to meet the increasing separation demands of complex systems. Herein, we propose a three-in-one strategy to develop a state-of-the-art dually charged thin-film composite (TFC) nanofiltration membrane consisting of a positively charged electrospun nanofiber substrate (NFS) with surface mineralization and a negatively charged polyamide (PA) selective layer prepared by interfacial polymerization (IP). The highly hydrophilic mineralized nanofiber substrate not only effectively reduces the thickness of the PA selective layer but also crumples its structures by the abundant zirconia nanoparticles on the substrate surface, resulting in excellent water flux (15.

Structural insights into the recognition of purine-pyrimidine dinucleotide repeats by zinc finger protein ZBTB43.

Purine-pyrimidine repeats (PPRs) can form left-handed Z-form DNA and induce DNA double-strand breaks (DSBs), posing a risk for genomic rearrangements and cancer. The zinc finger (ZF) and BTB domain-containing protein 43 (ZBTB43) is a transcription factor containing two Cys2-His2 (C2H2) and one C3H1 zinc fingers and plays a crucial role in maintaining genomic and epigenomic integrity by converting mutagenic Z-form PPRs to the B-form in prospermatogonia. Despite its importance, the molecular mechanism underlying the recognition of PPRs by ZBTB43 remains elusive.

Paralogue-Selective Degradation of the Lysine Acetyltransferase EP300.

The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit nonredundant functions in basal and pathological contexts. Here, we report the development of a bifunctional small molecule, MC-1, capable of selectively degrading EP300 over CREBBP. Using a potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic domain in combination with a VHL ligand, we demonstrate that MC-1 preferentially degrades EP300 in a proteasome-dependent manner.

Improved assessment of radiofrequency electromagnetic field power deposition near orthopaedic device using a bone-inclusive ASTM phantom under 1.5T and 3T MRI.

A bone-inclusive ASTM phantom is proposed to improve the assessment of radiofrequency electromagnetic field (RF-EMF) power deposition near orthopedic device under 1.5 T and 3 T magnetic resonance imaging (MRI).A phantom is created by introducing a cylindrical bone structure inside the American Society for Testing and Materials (ASTM) phantom.

HIV-1 Intasomes Assembled with Excess Integrase C-Terminal Domain Protein Facilitate Structural Studies by Cryo-EM and Reveal the Role of the Integrase C-Terminal Tail in HIV-1 Integration.

Retroviral integration is mediated by intasome nucleoprotein complexes wherein a pair of viral DNA ends are bridged together by a multimer of integrase (IN). Atomic-resolution structures of HIV-1 intasomes provide detailed insights into the mechanism of integration and inhibition by clinical IN inhibitors. However, previously described HIV-1 intasomes are highly heterogeneous and have the tendency to form stacks, which is a limiting factor in determining high-resolution cryo-EM maps.

MEN1 Deficiency-Driven Activation of the β-Catenin-MGMT Axis Promotes Pancreatic Neuroendocrine Tumor Growth and Confers Temozolomide Resistance.

O6-methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the guanine O6 position (O-MG) and repairs DNA damage. High MGMT expression results in poor response to temozolomide (TMZ). However, the biological importance of MGMT and the mechanism underlying its high expression in pancreatic neuroendocrine tumors (PanNETs) remain elusive.

A deep learning-based method for the detection and segmentation of breast masses in ultrasound images.

Automated detection and segmentation of breast masses in ultrasound images are critical for breast cancer diagnosis, but remain challenging due to limited image quality and complex breast tissues. This study aims to develop a deep learning-based method that enables accurate breast mass detection and segmentation in ultrasound images.A novel convolutional neural network-based framework that combines the You Only Look Once (YOLO) v5 network and the Global-Local (GOLO) strategy was developed.

Structural studies of WDR5 in complex with MBD3C WIN motif reveal a unique binding mode.

The nucleosome remodeling and deacetylase (NuRD) complex plays a pivotal role in chromatin regulation and transcriptional repression. In mice, methyl-CpG binding domain 3 isoform C (MBD3C) interacts specifically with the histone H3 binding protein WD repeat-containing protein 5 (WDR5) and forms the WDR5-MBD3C/Norde complex. Despite the functional significance of this interaction on embryonic stem cell gene regulation, the molecular mechanism underlying MBD3C recognition by WDR5 remains elusive.

Paralogue-selective degradation of the lysine acetyltransferase EP300.

The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit non-redundant functions in basal and pathological contexts. Here, we report the development of a bifunctional small molecule, MC-1, capable of selectively degrading EP300 over CREBBP. Using a potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic domain in combination with a VHL ligand, we demonstrate that MC-1 preferentially degrades EP300 in a proteasome-dependent manner.

Comprehensive Analysis of the Immunosuppressive Function of Regulatory T Cells in Human Hepatocellular Carcinoma Tissues.

Background: Immune-based therapies are commonly employed to combat hepatocellular carcinoma (HCC). However, the presence of immune-regulating elements, especially regulatory T cells (Tregs), can dramatically impact the treatment efficacy. A deeper examination of the immune-regulation mechanisms linked to these inhibitory factors and their impact on HCC patient outcomes is warranted.

PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis.

Ferroptosis inhibits tumor progression in pancreatic cancer cells, while PITX2 is known to function as a pro-oncogenic factor in various tumor types, protecting them from ferroptosis and thereby promoting tumor progression. In this study, we sought to investigate the regulatory role of PITX2 in tumor cell ferroptosis within the context of pancreatic cancer. We conducted PITX2 knockdown experiments using lentiviral infection in two pancreatic cancer cell lines, namely PANC-1 and BxPC-3.

High-frequency hearing vulnerability associated with the different supporting potential of Hensen's cells: SMART-Seq2 RNA sequencing.

Hearing loss is the third most prevalent physical condition affecting communication, well-being, and healthcare costs. Sensorineural hearing loss often occurs first in the high-frequency region (basal turn), then towards the low-frequency region (apical turn). However, the mechanism is still unclear.

HIV-1 Integrase Assembles Multiple Species of Stable Synaptic Complex Intasomes That Are Active for Concerted DNA Integration In vitro.

Retroviral DNA integration is mediated by nucleoprotein complexes (intasomes) in which a pair of viral DNA ends are bridged by a multimer of integrase (IN). Most of the high-resolution structures of HIV-1 intasomes are based on an HIV-1 IN with an Sso7d protein domain fused to the N-terminus. Sso7d-IN aggregates much less than wild-type IN and has been critical for structural studies of HIV-1 intasomes.

Analysis of factors influencing pancreatic fistula after minimally invasive pancreaticoduodenectomy and establishment of a new prediction model for clinically relevant pancreatic fistula.

Background: Postoperative pancreatic fistula (POPF) is the most prevalent complications following minimally invasive pancreaticoduodenectomy (MIPD). Only one model related to MIPD exists, and previous POPF scoring prediction methods are based on open pancreaticoduodenectomy patients. Our objectives are to determine the variables that may increase the probability of pancreatic fistula following MIPD and to develop and validate a POPF predictive risk model.

The stromal microenvironment endows pancreatic neuroendocrine tumors with spatially specific invasive and metastatic phenotypes.

Cancer-associated fibroblasts (CAFs) play an important role in a variety of cancers. However, the role of tumor stroma in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is often neglected. Profiling the heterogeneity of CAFs can reveal the causes of malignant phenotypes in NF-PanNETs.

Microbial metabolism of diosgenin by a novel isolated Mycolicibacterium sp. HK-90: A promising biosynthetic platform to produce 19-carbon and 21-carbon steroids.

Green manufacture of steroid precursors from diosgenin by microbial replacing multistep chemical synthesis has been elusive. It is currently limited by the lack of strain and degradation mechanisms. Here, we demonstrated the feasibility of this process using a novel strain Mycolicibacterium sp.

Diesel degradation capability and environmental robustness of strain Pseudomonas aeruginosa WS02.

Petroleum hydrocarbon (PHC) degrading bacteria have been frequently discovered. However, in practical application, a single species of PHC degrading bacterium with weak competitiveness may face environmental pressure and competitive exclusion due to the interspecific competition between petroleum-degrading bacteria as well as indigenous microbiota in soil, leading to a reduced efficacy or even malfunction. In this study, the diesel degradation ability and environmental robustness of an endophytic strain Pseudomonas aeruginosa WS02, were investigated.

SARS-CoV-2 Antibody Profiles in Maternal Serum and Breast Milk Following mRNA COVID-19 Vaccination: A Longitudinal Prospective Observational Cohort Study.

COVID-19 vaccination during pregnancy protects infants against symptomatic COVID-19. Vaccination of lactating mothers may offer additional protection, but our understanding of immune responses in breast milk is limited. We, therefore, performed a single-center prospective cohort study of lactating mothers who received a COVID-19 mRNA primary vaccine series to evaluate the durability, breadth, and neutralizing capacity of the antibody responses in breast milk.

Effect of Laparoscopic and Open Pancreaticoduodenectomy for Pancreatic or Periampullary Tumors: Three-year Follow-up of a Randomized Clinical Trial.

Objective: This study aimed to estimate whether the potential short-term advantages of laparoscopic pancreaticoduodenectomy (LPD) could allow patients to recover in a more timely manner and achieve better long-term survival than with open pancreaticoduodenectomy (OPD) in patients with pancreatic or periampullary tumors.

Background: LPD has been demonstrated to be feasible and may have several potential advantages over OPD in terms of shorter hospital stay and accelerated recovery than OPD.

Methods: This noninferiority, open-label, randomized clinical trial was conducted in 14 centers in China.

A Hybrid Model with New Word Weighting for Fast Filtering Spam Short Texts.

Short message services (SMS), microblogging tools, instant message apps, and commercial websites produce numerous short text messages every day. These short text messages are usually guaranteed to reach mass audience with low cost. Spammers take advantage of short texts by sending bulk malicious or unwanted messages.