Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint.

Errors during cell division lead to aneuploidy, which is associated with genomic instability and cell transformation. In response to aneuploidy, cells activate the tumour suppressor p53 to elicit a surveillance mechanism that halts proliferation and promotes senescence. The molecular sensors that trigger this checkpoint are unclear.

High-efficiency base editing in the retina in primates and human tissues.

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.

A hybrid machine learning approach for the personalized prognostication of aggressive skin cancers.

Accurate prognostication guides optimal clinical management in skin cancer. Merkel cell carcinoma (MCC) is the most aggressive form of skin cancer that often presents in advanced stages and is associated with poor survival rates. There are no personalized prognostic tools in use in MCC.

Satellite DNA shapes dictate pericentromere packaging in female meiosis.

The abundance and sequence of satellite DNA at and around centromeres is evolving rapidly despite the highly conserved and essential process through which the centromere directs chromosome inheritance. The impact of such rapid evolution is unclear. Here we find that sequence-dependent DNA shape dictates packaging of pericentromeric satellites in female meiosis through a conserved DNA-shape-recognizing chromatin architectural protein, high mobility group AT-hook 1 (HMGA1).

Small variant benchmark from a complete assembly of X and Y chromosomes.

The sex chromosomes contain complex, important genes impacting medical phenotypes, but differ from the autosomes in their ploidy and large repetitive regions. To enable technology developers along with research and clinical laboratories to evaluate variant detection on male sex chromosomes X and Y, we create a small variant benchmark set with 111,725 variants for the Genome in a Bottle HG002 reference material. We develop an active evaluation approach to demonstrate the benchmark set reliably identifies errors in challenging genomic regions and across short and long read callsets.

Diet-wide analyses for risk of colorectal cancer: prospective study of 12,251 incident cases among 542,778 women in the UK.

Uncertainty remains regarding the role of diet in colorectal cancer development. We examined associations of 97 dietary factors with colorectal cancer risk in 542,778 Million Women Study participants (12,251 incident cases over 16.6 years), and conducted a targeted genetic analysis in the ColoRectal Transdisciplinary Study, Colon Cancer Family Registry, and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO).

Does semaglutide reduce alcohol intake in Danish patients with alcohol use disorder and comorbid obesity? Trial protocol of a randomised, double-blinded, placebo-controlled clinical trial (the SEMALCO trial).

Introduction: Alcohol use disorder (AUD) is a massive burden for the individual, relatives and society. Despite this, the treatment gap is wide compared with other mental health disorders. Treatment options are sparse, with only three Food and Drug Administration (FDA)-approved pharmacotherapies.

Updated Appropriate Use Criteria for Amyloid and Tau PET: A Report from the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging Workgroup.

The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered.

Chromosome-level echidna genome illuminates evolution of multiple sex chromosome system in monotremes.

Background: A thorough analysis of genome evolution is fundamental for biodiversity understanding. The iconic monotremes (platypus and echidna) feature extraordinary biology. However, they also exhibit rearrangements in several chromosomes, especially in the sex chromosome chain.

A comparative study of Merkel cell carcinoma and melanoma incidence and survival in the United States, 2000-2021.

Merkel cell carcinoma (MCC) and melanoma are important contributors to skin cancer mortality in the United States. We evaluated their epidemiology using US cancer registry data. During 2000-2021, 19,444 MCCs and 646,619 melanomas of the skin were diagnosed.

The Metabolic Treatabolome and Inborn Errors of Metabolism Knowledgebase therapy tool: Do not miss the opportunity to treat!

Inborn errors of metabolism (IEMs) are rare genetic conditions with significant morbidity and mortality. Technological advances have increased therapeutic options, making it challenging to remain up to date. A centralized therapy knowledgebase is needed for early diagnosis and targeted treatment.

Rigidity in Parkinson's Disease: The Objective Effect of Levodopa.

Background: Quantitative evidence of levodopa-induced beneficial effects on parkinsonian rigidity in Parkinson's disease (PD) is lacking. Recent research has demonstrated the velocity-dependent nature of objective rigidity in PD and revealed its neural underpinning.

Objective: The present study aimed to examine the effect of levodopa on objective rigidity in PD.

CD28 shapes T cell receptor signaling by regulating Lck dynamics and ZAP70 activation.

Introduction: T cell activation requires T cell receptor (TCR) engagement by its specific ligand. This interaction initiates a series of proximal events including tyrosine phosphorylation of the CD3 and TCRζ chains, recruitment, and activation of the protein tyrosine kinases Lck and ZAP70, followed by recruitment of adapter and signaling proteins. CD28 co-stimulation is also required to generate a functional immune response.

Assessing Artificial Intelligence (AI) Implementation for Assisting Gene Linking (at the National Library of Medicine).

Objectives: The National Library of Medicine (NLM) currently indexes close to a million articles each year pertaining to more than 5300 medicine and life sciences journals. Of these, a significant number of articles contain critical information about the structure, genetics, and function of genes and proteins in normal and disease states. These articles are identified by the NLM curators, and a manual link is created between these articles and the corresponding gene records at the NCBI Gene database.

Unraveling melorheostosis: insights into clinical features, diagnosis, and treatment.

Melorheostosis is a rare bone disease characterized by abundant bone formation with a characteristic radiographic appearance that resembles "dripping candle wax." Recent data have shown that the majority of cases are due to somatic activating mutations in bone. Melorheostosis has several clinical and radiographic presentations, which are now known to be caused by different somatic mutations such as , , , and .

Updated appropriate use criteria for amyloid and tau PET: A report from the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging Workgroup.

Introduction: The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET.

Methods: The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered.

Metabolic stimulation improves bioenergetics and haematologic indices of circulating erythrocytes from sickle cell mice.

Circulating mature red blood cells (RBCs) from patients and mice with sickle cell disease (SCD) abnormally retain mitochondria, a factor shown to contribute to the disease's pathobiology. To further understand the functional implications of RBC mitochondria retention in SCD, we used mitochondria inhibitors and metabolites/substrates from the tricarboxylic acid cycle, oxidative phosphorylation and glycolysis pathways (ADP, glutamate, malate, pyruvate, succinate or all metabolites combined) and examined RBC bioenergetics, reactive oxygen species (ROS) levels, calcium flux and hydration. In RBCs from sickle mice, mitochondria inhibition reduced ATP levels by 30%-60%, whereas control RBCs were unaffected.

Effects of early, late and self-selected time-restricted eating on visceral adipose tissue and cardiometabolic health in participants with overweight or obesity: a randomized controlled trial.

The optimal eating window for time-restricted eating (TRE) remains unclear, particularly its impact on visceral adipose tissue (VAT), which is associated with cardiometabolic morbidity and mortality. We investigated the effects of three TRE schedules (8 h windows in the early day, late day and participant-chosen times) combined with usual care (UC, based on education about the Mediterranean diet) versus UC alone over 12 weeks in adults with overweight or obesity. The primary outcome was VAT changes measured by magnetic resonance imaging.

Enhanced D614G and Omicron Variants Antibody Persistence in Infants at 2 Months of Age Following Maternal mRNA Booster Vaccination During Pregnancy or Postpartum.

Background: Following maternal COVID-19 vaccination, the persistence of antibodies in sera and breast milk for mothers and infants is not well characterized. We sought to describe the persistence of antibodies through 2 months after delivery in maternal and infant serum and breast milk following maternal COVID-19 mRNA vaccination and to examine differences by receipt of booster dose during pregnancy or postpartum.

Methods: This is a prospective cohort study with enrollment from July 2021 to January 2022 at 9 US academic sites.

Potentiating CD20 monoclonal antibody therapy by targeting complement C3 fragment covalently deposited on lymphoma cells.

Monoclonal antibodies (mAbs) improve survival of patients with mature B-cell malignancies. Fcγ-receptor dependent effector mechanisms kill tumor cells but can promote antigen loss through trogocytosis, contributing to treatment failures. Cell-bound mAbs trigger the complement cascade to deposit C3 activation fragments and lyse cells.

PDE11A is a phenotype modulator of Primary Bilateral Macronodular Adrenal Hyperplasia: results of a 334 patients' series.

Purpose: Primary bilateral macronodular adrenal hyperplasia (PBMAH), the most common cause of Cushing's syndrome due to bilateral nodules, is a heterogeneous disease at the clinical, hormonal and morphological levels. ARMC5 inactivating pathogenic variants are causative of PBMAH and rare variants of PDE11A have been associated with PBMAH.

Methods: Leukocyte DNA of 354 PBMAH index cases was sequenced for ARMC5 and PDE11A genes by Next generation sequencing (NGS).

Disruption of seasonal influenza circulation and evolution during the 2009 H1N1 and COVID-19 pandemics in Southeastern Asia.

East, South, and Southeast Asia (together referred to as Southeastern Asia hereafter) have been recognized as critical areas fuelling the global circulation of seasonal influenza. However, the seasonal influenza migration network within Southeastern Asia remains unclear, including how pandemic-related disruptions altered this network. We leveraged genetic, epidemiological, and airline travel data between 2007-2023 to characterise the dispersal patterns of influenza A/H3N2 and B/Victoria viruses both out of and within Southeastern Asia, including during perturbations by the 2009 A/H1N1 and COVID-19 pandemics.

Prenatal cfDNA Sequencing and Incidental Detection of Maternal Cancer.

Background: Cell-free DNA (cfDNA) sequence analysis to screen for fetal aneuploidy can incidentally detect maternal cancer. Additional data are needed to identify DNA-sequencing patterns and other biomarkers that can identify pregnant persons who are most likely to have cancer and to determine the best approach for follow-up.

Methods: In this ongoing study we performed cancer screening in pregnant or postpartum persons who did not perceive signs or symptoms of cancer but received unusual clinical cfDNA-sequencing results or results that were nonreportable (i.

Mitochondrial YME1L1 governs unoccupied protein translocase channels.

Mitochondrial protein import through the outer and inner membranes is key to mitochondrial biogenesis. Recent studies have explored how cells respond when import is impaired by a variety of different insults. Here, we developed a mammalian import blocking system using dihydrofolate reductase fused to the N terminus of the inner membrane protein MIC60.

Activity of the mammalian DNA transposon piggyBat from Myotis lucifugus is restricted by its own transposon ends.

Members of the piggyBac superfamily of DNA transposons are widely distributed in host genomes ranging from insects to mammals. The human genome has retained five piggyBac-derived genes as domesticated elements although they are no longer mobile. Here, we have investigated the transposition properties of piggyBat from Myotis lucifugus, the only known active mammalian DNA transposon, and show that its low activity in human cells is due to subterminal inhibitory DNA sequences.