[Correction of the pathogenic mutation in the deafness gene via prime editor and adenine base editor ].

To investigate the feasibility of prime editor (PE) and adenine base editor (ABE) for correction the pathogenic variant of the human deafness gene c.1229C>T. From March 2023 to April 2024, prime editing guide RNA (pegRNA) expression vectors as well as single guide RNA (sgRNA) were designed and constructed for the c.

Intercellular mRNA transfer alters the human pluripotent stem cell state.

Intercellular transmission of messenger RNA (mRNA) is being explored in mammalian species using immortal cell lines. Here, we uncover an intercellular mRNA transfer phenomenon that allows for the adaptation and reprogramming of human primed pluripotent stem cells (hPSCs). This process is induced by the direct cell contact-mediated coculture with mouse embryonic stem cells under the condition impermissible for primed hPSC culture.

Examining the integration of refugees into the national health system in Uganda: an analysis using the policy triangle framework.

Background: Uganda has been confronted with a sustained influx of refugees for decades. This prompted the government to explore opportunities to integrate refugees into local service structures including its national health system. This paper chronicles the history of policies and strategies that have influenced the integration of refugees into the national health system in Uganda and investigates factors that impacted policy evolution and progression.

Pembrolizumab and chemotherapy in high-risk, early-stage, ER/HER2 breast cancer: a randomized phase 3 trial.

Addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab improved outcomes in patients with high-risk, early-stage, triple-negative breast cancer. However, whether the addition of neoadjuvant pembrolizumab to chemotherapy would improve outcomes in high-risk, early-stage, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER/HER2) breast cancer remains unclear. We conducted a double-blind, placebo-controlled phase 3 study (KEYNOTE-756) in which patients with previously untreated ER/HER2 grade 3 high-risk invasive breast cancer (T1c-2 (≥2 cm), cN1-2 or T3-4, cN0-2) were randomly assigned (1:1) to neoadjuvant pembrolizumab 200 mg or placebo Q3W given with paclitaxel QW for 12 weeks, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide Q2W or Q3W.

β-Aminobutyric acid activates SA-signalling systemic acquired resistance in peach fruit by suppressing the circadian clock associated protein1.

Circadian clock regulates plant development and physiology by anticipating daily environmental changes. Here we studied the core clock protein involved in β-aminobutyric acid (BABA)-inducible SAR resistance to Rhizopus stolonifer in peach fruit. BABA elicitation barely primed the accumulation of jasmonate or ethylene, whose regulation was associated with morning-loop gene expression.

Transient chemical-mediated epigenetic modulation confers unrestricted lineage potential on human primed pluripotent stem cells.

Human primed pluripotent stem cells are capable of generating all the embryonic lineages. However, their extraembryonic trophectoderm potentials are limited. It remains unclear how to expand their developmental potential to trophectoderm lineages.

A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer.

Fewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI). Identifying and expanding this patient population remains a pressing clinical need. Here, we report that an interferon-high immunophenotype locally enriched in cytotoxic lymphocytes and antigen-presenting macrophages is required for response.

Validation of an acute kidney injury prediction model as a clinical decision support system.

Background: Acute kidney injury (AKI) is a critical clinical condition that requires immediate intervention. We developed an artificial intelligence (AI) model called PRIME Solution to predict AKI and evaluated its ability to enhance clinicians' predictions.

Methods: The PRIME Solution was developed using convolutional neural networks with residual blocks on 183,221 inpatient admissions from a tertiary hospital (2013-2017) and externally validated with 4,501 admissions at another tertiary hospital (2020-2021).

Genetically Reprogrammed Exosomes for Immunotherapy of Acute Myeloid Leukemia.

Current treatments for acute myeloid leukemia (AML) remain challenging, characterized by poor clinical outcomes. Exosomes, cell-derived membranous vesicles, has been emerging as a new modality of therapy. Here we designed and generated genetically reprogrammed exosomes with surface displayed antibodies and immunoregulatory proteins, namely programmed immune-engaging exosomes (PRIME Exos).

Blood Culture Use in Medical and Surgical Intensive Care Units and Wards.

Importance: Blood culture (BC) use benchmarks in US hospitals have not been defined.

Objective: To characterize BC use in adult intensive care units (ICUs) and wards in US hospitals.

Design, Setting, And Participants: A retrospective cross-sectional study of BC use in adult medical ICUs, medical-surgical ICUs, medical wards, and medical-surgical wards from acute care hospitals from the 4 US geographic regions was conducted.

Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.

Members of the KMT2C/D-KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation.

Recessive but damaging alleles of muscle-specific ribosomal protein gene drive neonatal dilated cardiomyopathy.

The heart employs a specialized ribosome in its muscle cells to translate genetic information into proteins, a fundamental adaptation with an elusive physiological role. Its significance is underscored by the discovery of neonatal patients suffering from often fatal heart failure caused by rare compound heterozygous variants in RPL3L, a muscle-specific ribosomal protein that replaces the ubiquitous RPL3 in cardiac ribosomes. -linked heart failure represents the only known human disease arising from mutations in tissue-specific ribosomes, yet the underlying pathogenetic mechanisms remain poorly understood despite an increasing number of reported cases.

The GAA repeat expansion is a major cause of ataxia in the Cypriot population.

Dominantly inherited intronic GAA repeat expansions in the fibroblast growth factor 14 gene have recently been shown to cause spinocerebellar ataxia 27B. Currently, the pathogenic threshold of (GAA) repeat units is considered highly penetrant, while (GAA) is likely pathogenic with reduced penetrance. This study investigated the frequency of the GAA repeat expansion and the phenotypic profile in a Cypriot cohort with unresolved late-onset cerebellar ataxia.

Asian Thoracic Oncology Research Group expert consensus statement on the peri-operative management of non-small cell lung cancer.

The peri-operative management of non-small cell lung cancer (NSCLC) in earlier stage disease has seen significant advances in recent years with the incorporation of immune checkpoint inhibitors and targeted therapy. However, many unanswered questions and challenges remain, including the application of clinical trial data to routine clinical practice. Recognising the unique demographic profile of Asian patients with NSCLC and heterogeneous healthcare systems, the Asian Thoracic Oncology Research Group (ATORG) convened a consensus meeting in Singapore on 26 April 2024 to discuss relevant issues spanning diagnostic testing to post-neoadjuvant treatment considerations and future directions.

Baseline predictors of cross-sectional and longitudinal performance on the symbol digit modalities test in individuals with multiple sclerosis.

Background: Cognitive impairment occurs frequently in persons with multiple sclerosis (PwMS) at some point in the course of the disease. However, not all PwMS develop cognitive difficulties suggesting a role for important moderating factors. We examined baseline predictors of cross-sectional and longitudinal change in cognitive performance in PwMS.

Developmental & Comparative Immunology Lipoxin B and lipocalin play a crucial role in insect immune-priming induced by a gut microbial commensal.

Host cabbage possesses an endophyte, Bacillus subtilis, which induced immune-priming of the diamondback moth, Plutella xylostella. In contrast, larvae raised under axenic conditions lost the chance to feed the bacteria and were highly susceptible to various pathogens. Addition of B.

DNTT-mediated DNA Damage Response Drives Inotuzumab Ozogamicin Resistance in B-cell Acute Lymphoblastic Leukemia.

Inotuzumab Ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide inter-patient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered the loss of DNTT as a primary driver of InO resistance.

Incipient and subclinical tuberculosis: a narrative review.

Mycobacterium tuberculosis has been known to infect humans for eons. It is an airborne infectious disease transmitted through droplet nuclei of 1 to 5 µm in diameter. Historically, tuberculosis (TB) was considered a distinct condition characterized by TB infection and active TB disease.

The Role of Atrial Fibrillation and Oral Anticoagulation Status in Health-Related Quality of Life 12 Months After Ischemic Stroke or TIA.

Aims: Atrial fibrillation (AF) accounts for about 20% of all ischemic strokes worldwide. It is known that AF impairs health-related quality of life (HRQOL) in the general population, but data on HRQOL in stroke patients with newly diagnosed AF are sparse.

Methods: Post hoc analysis of the prospective, investigator-initiated, multicenter MonDAFIS study (NCT02204267) to analyze whether AF-related oral anticoagulation (OAC), and/or AF-symptom severity are associated with HRQOL after ischemic stroke or transient ischemic attack (TIA).

Helminth infection induces innate immune priming in plasmacytoid dendritic cells.

Heligmosomoides polygyrus co-infection is reported to have protective antiviral effects against pulmonary viral infections. To investigate a potential underlying mechanism, we infected C57BL/6 mice with H. polygyrus larvae for two weeks.

Direct oral anticoagulants or warfarin in patients with left ventricular thrombus after ST-elevation myocardial infarction: a pilot trial and a prespecified meta-analysis of randomised trials.

Background: The role of direct oral anticoagulants (DOACs) in the treatment of left ventricular thrombus (LVT) after ST-elevation myocardial infarction (STEMI) remains uncertain.

Aims: We aimed to compare the effect of rivaroxaban versus warfarin in patients with STEMI complicated by LVT.

Methods: Adult patients with STEMI and two-dimensional transthoracic echocardiography showing LVT were assigned to rivaroxaban (15 mg once daily) or warfarin (international normalised ratio goal of 2.

Importance of Lactobacilli for Human Health.

As an extraordinarily diverse group of bacteria, lactobacilli are now classified into several genera, many of which still include "Lactobacillus" in their names. Despite their names, this group of lactic acid bacteria comprises microorganisms that are crucial for human health, especially during the early development of the human microbiota and immune system. The interactions between lactobacilli and components of the mucosal immunity lead to its shaping and development, which is possibly considered a prime mover in the advancement of the human immune system.