Cripto-1 acts as a molecular bridge linking nodal to ALK4 via distinct structural domains.

The TGF-β family ligand Nodal is an essential regulator of embryonic development, orchestrating key processes such as germ layer specification and body axis formation through activation of SMAD2/3-mediated signaling. Significantly, this activation requires the co-receptor Cripto-1. However, despite their essential roles in embryogenesis, the molecular mechanism through which Cripto-1 enables Nodal to activate the SMAD2/3 pathway has remained elusive.

Engineering of CRISPR-Cas PAM recognition using deep learning of vast evolutionary data.

CRISPR-Cas enzymes must recognize a protospacer-adjacent motif (PAM) to edit a genomic site, significantly limiting the range of targetable sequences in a genome. Machine learning-based protein engineering provides a powerful solution to efficiently generate Cas protein variants tailored to recognize specific PAMs. Here, we present Protein2PAM, an evolution-informed deep learning model trained on a dataset of over 45,000 CRISPR-Cas PAMs.

New Directions for Ophthalmic OCT - Handhelds, Surgery, and Robotics.

The introduction of optical coherence tomography (OCT) in the 1990s revolutionized diagnostic ophthalmic imaging. Initially, OCT's role was primarily in the adult ambulatory ophthalmic clinics. Subsequent advances in handheld form factors, integration into surgical microscopes, and robotic assistance have expanded OCT's utility and impact outside of its initial environment in the adult outpatient ophthalmic clinic.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in .

Recently, a novel African ancestry specific Parkinson's disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (). This variant (rs3115534-G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups, but is almost absent in European and Asian ancestry populations.

Wood-Inhabiting Nematode, sp. n. (Nematoda: Aphelenchoididae) from David Elm, with Molecular Phylogeny of the Genus Based on Partial Mitochondrial Genomes.

A new nematode species, sp. n. is described in the bark beetle-elm tree association ( and var.

Toward expert-level medical question answering with large language models.

Large language models (LLMs) have shown promise in medical question answering, with Med-PaLM being the first to exceed a 'passing' score in United States Medical Licensing Examination style questions. However, challenges remain in long-form medical question answering and handling real-world workflows. Here, we present Med-PaLM 2, which bridges these gaps with a combination of base LLM improvements, medical domain fine-tuning and new strategies for improving reasoning and grounding through ensemble refinement and chain of retrieval.

Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders.

The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels.

DNA targeting by compact Cas9d and its resurrected ancestor.

Type II CRISPR endonucleases are widely used programmable genome editing tools. Recently, CRISPR-Cas systems with highly compact nucleases have been discovered, including Cas9d (a type II-D nuclease). Here, we report the cryo-EM structures of a Cas9d nuclease (747 amino acids in length) in multiple functional states, revealing a stepwise process of DNA targeting involving a conformational switch in a REC2 domain insertion.

A Global Collaborative Comparison of SARS-CoV-2 Antigenicity Across 15 Laboratories.

Setting up a global SARS-CoV-2 surveillance system requires an understanding of how virus isolation and propagation practices, use of animal or human sera, and different neutralisation assay platforms influence assessment of SARS-CoV-2 antigenicity. In this study, with the contribution of 15 independent laboratories across all WHO regions, we carried out a controlled analysis of neutralisation assay platforms using the first WHO International Standard for antibodies to SARS-CoV-2 variants of concern (source: NIBSC). Live virus isolates (source: WHO BioHub or individual labs) or spike plasmids (individual labs) for pseudovirus production were used to perform neutralisation assays using the same serum panels.

Immunogenic Cell Death Traits Emitted from Chronic Lymphocytic Leukemia Cells Following Treatment with a Novel Anti-Cancer Agent, SpiD3.

Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies.

European Hedgehogs as Hosts of Chaphamaparvovirus, Italy.

In 2022, a novel parvovirus was identified from an outbreak of fatal enteritis in weaned European hedgehogs () at a wildlife rescue center in Southern Italy. During sequence analysis, the strain was found to be closely related (90.4% nucleotide identity) to a chaphamaparvovirus (ChPV) discovered in Amur hedgehogs () during a large metaviromic investigation in game animals in China.

Long-read sequencing of hundreds of diverse brains provides insight into the impact of structural variation on gene expression and DNA methylation.

Structural variants (SVs) drive gene expression in the human brain and are causative of many neurological conditions. However, most existing genetic studies have been based on short-read sequencing methods, which capture fewer than half of the SVs present in any one individual. Long-read sequencing (LRS) enhances our ability to detect disease-associated and functionally relevant structural variants (SVs); however, its application in large-scale genomic studies has been limited by challenges in sample preparation and high costs.

Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

Amivantamab Plus Lazertinib in Patients With EGFR-mutant Non-small Cell Lung Cancer (NSCLC) After Progression on Osimertinib and Platinum-based Chemotherapy: Results From CHRYSALIS-2 Cohort A.

Introduction: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with disease progression on/after osimertinib and platinum-based chemotherapy are limited.

Methods: CHRYSALIS-2 Cohort A evaluated amivantamab+lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on/after osimertinib and platinum-based chemotherapy. Primary endpoint was investigator-assessed objective response rate (ORR).

Nanostructured Hydrogels of Carboxylated Cellulose Nanocrystals Crosslinked by Calcium Ions.

Bio-based eco-friendly cellulose nanocrystals (CNCs) gain an increasing interest for diverse applications. We report the results of an investigation of hydrogels spontaneously formed by the self-assembly of carboxylated CNCs in the presence of CaCl using several complementary techniques: rheometry, isothermal titration calorimetry, FTIR-spectroscopy, cryo-electron microscopy, cryo-electron tomography, and polarized optical microscopy. Increasing CaCl concentration was shown to induce a strong increase in the storage modulus of CNC hydrogels accompanied by the growth of CNC aggregates included in the network.

No Difference in Outcomes After Remplissage or Open Bankart Repair Plus Inferior Capsular Shift in Collision and Contact Athletes With Subcritical Glenoid Bone Loss ≤10% and Off-Track Hill-Sachs Lesion.

Purpose: To compare functional outcomes, recurrence rate, range of motion (ROM), and return to sport between arthroscopic Bankart repair with remplissage (BR) and open Bankart repair with inferior capsular shift (OBICS) in contact and collision athletes with recurrent anterior shoulder instability.

Methods: A prospective comparative cohort study of 90 patients separated into 2 study groups (OBICS and BR) of 45 collision and contact athletes each was conducted. All athletes had subcritical glenoid bone loss ≤10% and off-track Hill-Sach lesions.

Predicting the replicability of social and behavioural science claims in COVID-19 preprints.

Replications are important for assessing the reliability of published findings. However, they are costly, and it is infeasible to replicate everything. Accurate, fast, lower-cost alternatives such as eliciting predictions could accelerate assessment for rapid policy implementation in a crisis and help guide a more efficient allocation of scarce replication resources.

Thermoresponsive gel embedding extracellular vesicles from adipose stromal cells improves the healing of colonic anastomoses following irradiation in rats.

Anastomotic leak occurrence is a severe complication after colorectal surgery. Considering the difficulty of treating these leaks and their impact on patient care, there is a strong need for an efficient prevention strategy. We evaluated a combination of extracellular vesicles (EVs) from rat adipose-derived stromal cells with a thermoresponsive gel, Pluronic® F127 (PF-127) to prevent anastomotic leaks.

Novel Mutation Lys30Glu in the Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy via Impairment of Structural and Functional Properties of Cardiac Tropomyosin.

Pediatric dilated cardiomyopathy (DCM) is a rare heart muscle disorder leading to the enlargement of all chambers and systolic dysfunction. We identified a novel de novo variant, c.88A>G (p.

Cardiac Myosin Inhibitors for Obstructive Hypertrophic Cardiomyopathy: A Meta-analysis of Randomized Placebo-Controlled Trials.

Background: Cardiac myosin inhibitors (CMI) have emerged as the first disease-specific, noninvasive therapy with promising results in patients with hypertrophic cardiomyopathy. However, its role in obstructive hypertrophic cardiomyopathy (oHCM) remains uncertain, especially in secondary endpoints of randomized controlled trials (RCTs).

Methods: We systematically searched PubMed, Embase, Web of Science, and Clinicaltrials.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1.

Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations.

Evaluating the Cumulative Benefit of Inspiratory CT, Expiratory CT, and Clinical Data for COPD Diagnosis and Staging through Deep Learning.

Purpose To measure the benefit of single-phase CT, inspiratory-expiratory CT, and clinical data for convolutional neural network (CNN)-based chronic obstructive pulmonary disease (COPD) staging. Materials and Methods This retrospective study included inspiratory and expiratory lung CT images and spirometry measurements acquired between November 2007 and April 2011 from 8893 participants (mean age, 59.6 years ± 9.

Deep Learning-Based Body Composition Analysis for Cancer Patients Using Computed Tomographic Imaging.

Malnutrition is a commonly observed side effect in cancer patients, with a 30-85% worldwide prevalence in this population. Existing malnutrition screening tools miss ~ 20% of at-risk patients at initial screening and do not capture the abnormal body composition phenotype. Meanwhile, the gold-standard clinical criteria to diagnose malnutrition use changes in body composition as key parameters, particularly body fat and skeletal muscle mass loss.