An integrative TAD catalog in lymphoblastoid cell lines discloses the functional impact of deletions and insertions in human genomes.

The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as compartments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes from outside regulatory elements' aberrant regulation.

Programmable Multiplexed Nucleic Acid Detection by Harnessing Specificity Defect of CRISPR-Cas12a.

CRISPR-Cas12a works like a sophisticated algorithm in nucleic acid detection, yet its challenge lies in sometimes failing to distinguish targets with mismatches due to its specificity limitations. Here, the mismatch profiles, including the quantity, location, and type of mismatches in the CRISPR-Cas12a reaction, are investigated and its various tolerances to mismatches are discovered. By harnessing the specificity defect of the CRISPR-Cas12a enzyme, a dual-mode detection strategy is designed, which includes approximate matching and precise querying of target sequences and develop a programmable multiplexed nucleic acid assay.

Nanoliposome functionalized colloidal GelMA inks for 3D printing of scaffolds with multiscale porosity.

Bioprinting has enabled the creation of intricate scaffolds that replicate the physical, chemical, and structural characteristics of natural tissues. Recently, hydrogels have been used to fabricate such scaffolds for several biomedical applications and tissue engineering. However, the small pore size of conventional hydrogels impedes cellular migration into and remodeling of scaffolds, diminishing their regenerative potential.

A robotic arm with open-source reconstructive workflow for bioprinting of patient-specific scaffolds.

bioprinting, fabricating tissue-engineered implants directly in a patient, was recently developed to overcome the logistical and clinical limitations of traditional bioprinting. printing reduces the time to treatment, allows for real-time reconstructive adjustments, minimizes transportation challenges, improves adhesion to remnant tissue and ensuing tissue integration, and utilizes the body as a bioreactor. Unfortunately, most printers are frame-based systems with limited working areas that are incompatible with the human body and lack portability.

The differential orbitofrontal activity and connectivity between atypical and typical major depressive disorder.

Objective: Atypical major depressive disorder (MDD) is a distinct subtype of MDD, characterized by increased appetite and/or weight gain, excessive sleep, leaden paralysis, and interpersonal rejection sensitivity. Delineating different neural circuits associated with atypical and typical MDD would better inform clinical personalized interventions.

Methods: Using resting-state fMRI, we investigated the voxel-level regional homogeneity (ReHo) and functional connectivity (FC) in 55 patients with atypical MDD, 51 patients with typical MDD, and 49 healthy controls (HCs).

Metabolic Chaos in Kidney Disease: Unraveling Energy Dysregulation.

Background: Acute kidney injury (AKI) and chronic kidney disease (CKD) share a fundamental disruption: metabolic dysfunction.

Methods: A literature review was performed to determine the metabolic changes that occur in AKI and CKD as well as potential therapeutic targets related to these changes.

Results: In AKI, increased energy demand in proximal tubular epithelial cells drives a shift from fatty acid oxidation (FAO) to glycolysis.

Interpreting CRISPR-Cas12a enzyme kinetics through free energy change of nucleic acids.

While CRISPR has revolutionized biotechnology, predicting CRISPR-Cas nuclease activity remains a challenge. Herein, through the trans-cleavage feature of CRISPR-Cas12a, we investigate the correlation between CRISPR enzyme kinetics and the free energy change of crRNA and DNA targets from their initial thermodynamic states to a presumed transition state before hybridization. By subjecting computationally designed CRISPR RNAs (crRNAs), we unravel a linear correlation between the trans-cleavage kinetics of Cas12a and the energy barrier for crRNA spacer and single-stranded DNA target unwinding.

Innovative spiral nerve conduits: Addressing nutrient transport and cellular activity for critical-sized nerve defects.

Large-gap nerve defects require nerve guide conduits (NGCs) for complete regeneration and muscle innervation. Many NGCs have been developed using various scaffold designs and tissue engineering strategies to promote axon regeneration. Still, most are tubular with inadequate pore sizes and lack surface cues for nutrient transport, cell attachment, and tissue infiltration.

CalDAG-GEFI acts as a guanine nucleotide exchange factor for LRRK2 to regulate LRRK2 function and neurodegeneration.

Mutations in are the most common genetic cause of Parkinson's disease (PD). LRRK2 protein contains two enzymatic domains: a GTPase (Roc-COR) and a kinase domain. Disease-causing mutations are found in both domains.

Genes Regulate Purkinje Cell Diversity in Cerebellar Development and Evolution.

Mammalian cerebellar development is thought to be influenced by distinct Purkinje cell (PC) subtypes. However, the degree of PC heterogeneity and the molecular drivers of this diversity have remained unclear, hindering efforts to manipulate PC diversification and assess its role in cerebellar development. Here, we demonstrate the critical role of genes in cerebellar development by regulating PC diversification.

Appointment non-attendance is associated with disease modifying therapy persistence the following year.

Background: It is recommended that healthcare providers and persons with multiple sclerosis (MS) have discussions prior to discontinuing a disease modifying therapy (DMT). However, if these appointments missed, either as a no show (NS) or short-notice cancellation (SNC), these discussions do not take place and may result in premature discontinuation. This study aimed to explore whether appointment non-attendance was predictive of DMT persistence the following year.

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer's disease.

Background: The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer's disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits.

Novel Immunotherapeutics for the Treatment of Non-Small Cell Lung Cancer (NSCLC) Resistant to PD-1/PD-L1 Inhibitors.

Immunotherapy with PD-1/PD-L1 inhibitors is the standard method of care for the treatment of newly diagnosed advanced or metastatic NSCLC, with or without chemotherapy. Many tumors, however, develop resistance to these immunotherapy agents. There is a need to develop more effective therapies for patients with metastatic NSCLC in the second-line setting and beyond.

Clinical Utility of a Digital Dermoscopy Image-Based Artificial Intelligence Device in the Diagnosis and Management of Skin Cancer by Dermatologists.

Background: Patients with skin lesions suspicious for skin cancer or atypical melanocytic nevi of uncertain malignant potential often present to dermatologists, who may have variable dermoscopy triage clinical experience.

Objective: To evaluate the clinical utility of a digital dermoscopy image-based artificial intelligence algorithm (DDI-AI device) on the diagnosis and management of skin cancers by dermatologists.

Methods: Thirty-six United States board-certified dermatologists evaluated 50 clinical images and 50 digital dermoscopy images of the same skin lesions (25 malignant and 25 benign), first without and then with knowledge of the DDI-AI device output.

mosGraphGen: a novel tool to generate multi-omics signaling graphs to facilitate integrative and interpretable graph AI model development.

Motivation: Multi-omics data, i.e. genomics, epigenomics, transcriptomics, proteomics, characterize cellular complex signaling systems from multi-level and multi-view and provide a holistic view of complex cellular signaling pathways.

Classifying the molecular functions of transcription factors beyond activation and repression.

Notch signaling is a highly conserved pathway activated by dynamic cellular interactions that initiates a molecular cascade that ultimately drives changes in gene expression. The Notch transcriptional complex (NTC) regulates genes that influence development and homeostasis. In this issue of , Rogers and colleagues (doi:10.

The Drosophila RNA binding protein Hrp48 binds a specific RNA sequence of the msl-2 mRNA 3' UTR to regulate translation.

Repression of msl-2 mRNA translation is essential for viability of Drosophila melanogaster females to prevent hypertranscription of both X chromosomes. This translational control event is coordinated by the female-specific protein Sex-lethal (Sxl) which recruits the RNA binding proteins Unr and Hrp48 to the 3' untranslated region (UTR) of the msl-2 transcript and represses translation initiation. The mechanism exerted by Hrp48 during translation repression and its interaction with msl-2 are not well understood.

Diagnosis and management of metabolic dysfunction- associated steatotic liver disease in South Asians- A clinical review.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed as nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of obesity and metabolic syndrome. It is mainly caused by insulin resistance. With the increased risk of visceral obesity in South Asians, the prevalence of MASLD is on the rise.

Neural net analysis of NMR spectra from strongly-coupled spin systems.

Extracting parameters such as chemical shifts and coupling constants from proton NMR spectra is often a first step in using spectra for compound identification and structure determination. This can become challenging when scalar couplings between protons are comparable in size to chemical shift differences (strongly coupled), as is often the case with low-field (bench top) spectrometers. Here we explore the potential utility of AI methods, in particular neural networks, for extracting parameters from low-field spectra.

Limited Short-Term Evolution of SARS-CoV-2 RNA-Dependent RNA Polymerase under Remdesivir Exposure in Upper Respiratory Compartments.

Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood.

Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, in which they provided specimens from four respiratory compartments. Near full-length genome SARS-CoV-2 sequences were obtained from viral RNA, standard lineage and variant assignments were performed, and viral mutations in the RNA-dependent RNA polymerase (RdRp) region-the RDV target gene-were detected and compared between participants with and without RDV, across the four compartments, within participants across visits, and versus a larger sequence dataset.

Payment and billing strategies to support methadone take-home medication: Perspectives of financial leaders of opioid treatment program organizations in New York State.

Introduction: Recent federal regulatory changes governing the delivery of methadone treatment for opioid use disorder at Opioid Treatment Programs (OTPs) support continued practice changes towards greater and flexible methadone take-home medication. Existing payment models for OTPs were closely tied with onsite medication administration and thus misaligned with the need to conduct more and flexible take-homes. This study aims to understand OTP organizations' experience with the newly created OTP bundled payment model in New York State as an alternative to the pre-existing per-service payment model during 2020-2023 to inform financing strategies to support and sustain practice changes.