A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.

An abnormal expansion of a GGGGCC (GC) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the GC repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits.

Aurora B inhibition induces hyper-polyploidy and loss of long-term proliferative potential in RB and p53 defective cells.

Polyploidy is a common outcome of chemotherapies, but there is conflicting evidence as to whether polyploidy is an adverse, benign or even favourable outcome. We show Aurora B kinase inhibitors efficiently promote polyploidy in many cell types, resulting in the cell cycle exit in RB and p53 functional cells, but hyper-polyploidy in cells with loss of RB and p53 function. These hyper-polyploid cells (>8n DNA content) are viable but have lost long-term proliferative potential in vitro and fail to form tumours in vivo.

Machine learning assisted plasmonic metascreen for enhanced broadband absorption in ultra-thin silicon films.

We propose and demonstrate a data-driven plasmonic metascreen that efficiently absorbs incident light over a wide spectral range in an ultra-thin silicon film. By embedding a double-nanoring silver array within a 20 nm ultrathin amorphous silicon (a-Si) layer, we achieve a significant enhancement of light absorption. This enhancement arises from the interaction between the resonant cavity modes and localized plasmonic modes, requiring precise tuning of plasmon resonances to match the absorption region of the silicon active layer.

YAP-driven malignant reprogramming of oral epithelial stem cells at single cell resolution.

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution.

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).

CCR5-ligand decorated rilpivirine lipid-based nanoparticles for sustained antiretroviral responses.

Antiretroviral therapy (ART) improves the quality of life for those living with the human immunodeficiency virus type one (HIV-1). However, poor compliance reduces ART effectiveness and leads to immune compromise, viral mutations, and disease co-morbidities. Here we develop a drug formulation in which a lipid-based nanoparticle (LBNP) carrying rilpivirine (RPV) is decorated with the C-C chemokine receptor type 5 (CCR5) targeting peptide.

Enhancing genomic-based forward prediction accuracy in wheat by integrating UAV-derived hyperspectral and environmental data with machine learning under heat-stressed environments.

Integrating genomic, hyperspectral imaging (HSI), and environmental data enhances wheat yield predictions, with HSI providing detailed spectral insights for predicting complex grain yield (GY) traits. Incorporating HSI data with single nucleotide polymorphic markers (SNPs) resulted in a substantial improvement in predictive ability compared to the conventional genomic prediction models. Over the course of several years, the prediction ability varied due to diverse weather conditions.

Qualitative assessment of primary care providers' attitudes toward genetic services and genetics education.

As the role of primary care providers (PCPs) in genetic medicine increases, there is a need for training related to the integration of genetics into primary care. However, little is known about PCPs' attitudes towards and perceived needs for such training. We conducted semi-structured interviews with nine PCPs to capture information about their perceptions of their role in genetics and their continuing medical educational needs related to genetics in primary care, and we conducted thematic analysis.

Investigation of the Thermal Stability and Hydrolytic Degradation Kinetics of Poly(Lactide-co-Glycolide) Melts.

Poly(lactide-co-glycolide) (PLGA) is widely used in a variety of long-acting injectables. However, its biodegradable nature creates potential chemical stability challenges during melt extrusion, where PLGA is exposed to elevated temperature (100-140 °C) for several minutes. This study evaluated the thermal stability of three PLGA grades (Resomer® 502, 502H, and 505) with varying molecular weights and chain-ends using a differential scanning calorimeter and twin-screw extruder.

PET Imaging of Sphingosine-1-Phosphate Receptor 1 with [F]TZ4877 in Nonhuman Primates.

Purpose: The sphingosine-1-phosphate receptor-1 (S1PR) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR radiotracer, [F]TZ4877, in nonhuman primates.

Impact of declared wildfire disasters on survival of lung cancer patients undergoing radiation.

Purpose: Oncological treatments, such as radiotherapy, which requires consistent electricity, the presence of specialized clinical teams, and daily patient access to treatment facilities, are frequently disrupted by extreme weather events, posing several health hazards to patients. This study explores the association between declared wildfire disasters during radiotherapy and overall survival among patients with non-small cell lung cancer (NSCLC).

Methods: The study population consisted of 202,935 adults with inoperable Stage III NSCLC, who initiated radiotherapy from 2004 through 2019.

Eligibility for and reach of the National Breast and Cervical Cancer Early Detection Program, 2018-2021.

Purpose: The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides access to timely breast and cervical cancer screening and diagnostic services to women who have low incomes and are uninsured or underinsured. Documenting the number of women eligible and the proportion of eligible women who receive NBCCEDP-funded services is important for identifying opportunities to increase screening and diagnostic services among those who would not otherwise have access.

Methods: Using the Census Bureau's Small Area Health Insurance Estimates data, we estimated the number of women who met the NBCCEDP eligibility criteria based on age, income, and insurance status.

Pilot Testing Digital Stories to Influence College Men's Intentions to Vaccinate Against HPV.

College men are among those least likely to be vaccinated against the human papillomavirus (HPV). Viewing digital stories from other college men who were vaccinated against HPV as young adults may help influence them to seek the vaccine. Guided by the Theory of Planned Behavior, this research reports on the creation and pilot testing of digital stories to increase college men's intentions to vaccinate against HPV.

Comparing Patient-Specific Variations in Intra-Cochlear Neural Health Estimated Using Psychophysical Thresholds and Panoramic Electrically Evoked Compound Action Potentials (PECAPs).

Purpose: Variations in neural survival along the cochlear implant electrode array leads to off-place listening, resulting in poorer speech understanding outcomes for recipients. Therefore, it is important to develop and compare clinically viable tests to identify these patient-specific intra-cochlear neural differences.

Methods: Nineteen experienced cochlear implant recipients (9 males and 10 females) were recruited for this study.

Blood neurofilament light chain and S100B as biomarkers of neurological involvement and functional prognosis in COVID-19: a multicenter study.

Background And Aim: COVID-19 is associated with neurological complications, termed neuro-COVID, affecting patient outcomes. We aimed to evaluate the association between serum neurofilament light chain (NfL) and S100B biomarkers with the presence of neurological manifestations and functional prognosis in COVID-19 patients.

Methods: A multicenter prospective cohort study was conducted in three hospitals in the Emilia-Romagna region, Italy, from March 2020 to April 2022.

The Association of HIV Criminalization Law and Disparities in Transplant Education among People with HIV.

While people with HIV (PWH) experience high rates of end-stage kidney disease (ESKD), they were historically denied kidney transplantation and prohibited from organ donation, both elements of treating ESKD. It remains unknown to what extent such HIV criminalization laws correlate with the provision of transplantation education to PWH. We conducted this study to elucidate the relationship between these structural-level policies and individual-level outcomes.

Long-Acting Injectable Prep for People Who Inject Drugs at a Syringe Services Program: A Qualitative Acceptability and Feasibility Study.

Although people who inject drugs (PWID) are at high risk of acquiring HIV, knowledge and uptake of pre-exposure prophylaxis (PrEP) for HIV prevention among this population remain low due to numerous psychosocial and structural barriers. Multiple implementation strategies have been proposed to address this gap, notably providing long-acting injectable (LAI) formulations of PrEP and offering PrEP at syringe services programs (SSPs). This qualitative study explores the acceptability and feasibility of offering LAI-PrEP for PWID at risk for HIV at Florida's first legal SSP.

The Impacts of Substance Use and Depression on HIV Pre-Exposure Prophylaxis Use and Adherence Among Sexual and Gender Minority Adolescents and Young Adults in the Keeping it LITE Cohort.

Substance use and depression are prevalent in sexual and gender minorities (SGM), but evidence about their impacts on HIV pre-exposure prophylaxis (PrEP) use is mixed. We assessed these impacts in a US-based cohort of 3,330 young SGM who tested negative for HIV and completed baseline and semiannual assessments on substance use (cocaine, methamphetamine, or heroin), depression, and PrEP use and adherence. We estimated prevalence differences (PDs) to compare baseline and 12-month PrEP use and adherence between participants with and without substance use and depression, separately and jointly.

Addressing Factors that Impact Sexual Well-Being and Intimacy in IBD Patients.

Purpose Of Review: This review details the pathophysiologic mechanisms from medical, surgical to psychosocial factors that illustrate how and why sexual health and intimacy are impacted in IBD.

Recent Findings: Recent clinical surveys of practicing gastroenterologists document that clinicians should routinely address sexual health when addressing patient reported outcomes but very few actually make direct inquiry or suggest management into this important aspect of human life. Example 'patter' are suggested to clinicians to demonstrate how to introduce the subject of sexual intimacy and well-being and engender patient trust on this sensitive topic.

Angelica gigas Nakai (Korean Dang-gui) Root Alcoholic Extracts in Health Promotion and Disease Therapy - active Phytochemicals and In Vivo Molecular Targets.

Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extracts have been marketed as dietary supplements in the United States for memory health and pain management. We have recently reviewed the pharmacokinetics (PK) and first-pass hepatic metabolism of ingested AGN supplements in humans for the signature pyranocoumarins decursin (D, C 1x), decursinol angelate (DA, C ~ 10x) and their common botanical precursor and hepatic metabolite decursinol (DOH, C ~ 1000x).

Quantitative Structural and Compositional Elucidation of Real-World Pharmaceutical Tablet Using Large Field-of-View, Correlative Microscopy-Tomography Techniques and AI-Enabled Image Analysis.

Purpose: The purpose of this study is to present a correlative microscopy-tomography approach in conjunction with machine learning-based image segmentation techniques, with the goal of enabling quantitative structural and compositional elucidation of real-world pharmaceutical tablets.

Methods: Specifically, the approach involves three sequential steps: 1) user-oriented tablet constituent identification and characterization using correlative mosaic field-of-view SEM and energy dispersive X-ray spectroscopy techniques, 2) phase contrast synchrotron X-ray micro-computed tomography (SyncCT) characterization of a large, representative volume of the tablet, and 3) constituent segmentation and quantification of the imaging data through user-guided, iterative supervised machine learning and deep learning.

Results: This approach was implemented on a real-world tablet containing 15% API and multiple common excipients.

Targeting protein synthesis pathways in MYC-amplified medulloblastoma.

MYC is one of the most deregulated oncogenic transcription factors in human cancers. MYC amplification/or overexpression is most common in Group 3 medulloblastoma and is positively associated with poor prognosis. MYC is known to regulate the transcription of major components of protein synthesis (translation) machinery, leading to promoted rates of protein synthesis and tumorigenesis.