Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Sequence diversity of apidaecin-like peptides arresting the terminating ribosome.

The Proline-rich Antimicrobial Peptide (PrAMP) apidaecin (Api) inhibits translation by binding in the ribosomal nascent peptide exit tunnel, trapping release factors RF1 or RF2, and arresting ribosomes at stop codons. To explore the extent of sequence variations of the native 18-amino acid Api that allows it to preserve its activity, we screened a library of synthetic mutant Api genes expressed in bacterial cells, resulting in nearly 350000 peptide variants with multiple substitutions. By applying orthogonal negative and positive selection strategies, we identified a number of multi-substituted Api variants capable of arresting ribosomes at stop codons. Our findings underscore the critical contribution of specific amino acid residues of the peptide for its on-target function while significantly expanding the variety of PrAMPs acting on the terminating ribosome. Additionally, some of the tested synthesized multi-substituted Api variants exhibit improved antibacterial activity compared to that of the wild type PrAMP and may constitute the starting point to develop clinically useful antimicrobials.

Involvement of Sclera in Lattice Retinal Degeneration: An Optical Coherence Tomography Study.

The aim of the study was to evaluate the local status of the sclera in lattice retinal degeneration. Patients with lattice degeneration, snail-track degeneration, or horseshoe retinal breaks were included. One lesion of a single eye in each patient was captured with cross-sectional optical coherence tomography (OCT) along and across the greatest lesion dimension. The maximum height of scleral indentation was measured and compared between different lesion types and between lattice lesions with and without retinal breakage or local detachment. The correlation between the maximum height of the scleral indentation of lattice lesions and the age of the patients was calculated. Seventy-five eyes of 75 patients (44.4 ± 14.7 years; 35 males and 30 females) were included. OCT showed variable local scleral indentation in 52 out of 55 (94.5%) lattice lesions, in five out of nine (55.5%) snail-tack lesions, and in three out of eleven (27.3%) horseshoe breaks. The maximum scleral indentation within lattice lesions, snail-tack lesions, and horseshoe breaks was 227.2 ± 111.3, 22.0 ± 49.2, and 88.5 ± 48.4 µm, respectively (p < 0.001 for snail-tack lesions and horseshoe breaks compared to lattice lesions). Lattice lesions with retinal breaks and/or local retinal detachment had statistically significantly lower scleral indentation than those without (p = 0.01). The height of the scleral indentation of lattice lesions was positively correlated with patient age (r = 0.51, p = 0.03). In conclusion, scleral indentation is one of the hallmarks of lattice retinal degeneration and may be associated with a reduced risk of rhegmatogenous retinal detachment.

The Impact of Metabolic Health and Obesity on Liver Transplant Candidates and Recipients.

Poor metabolic health and obesity have significant impacts on the outcomes of patients suffering from chronic liver disease, particularly those with metabolic dysfunction-associated steatotic liver disease. Patients with such comorbidities who require liver transplant evaluation for advancing liver disease or liver failure require special consideration due to increased risk of cardiovascular disease, renal dysfunction, sarcopenic obesity, and cancer. Those who have had a history of prior bariatric surgery pose specific anatomical constraints and may also be at increased risk of alcohol use disorder. Pre-operative risk assessment as well as strict control of metabolic risk factors are essential to reduce intra-operative and post-liver transplant complications. As immunosuppressive therapy exacerbates metabolic dysfunction and risk for cancer, post-liver transplant care must focus on balancing the need to prevent rejection and the impact of progressive metabolic dysfunction in this unique, but growing, patient population.

Comparative connectomics of the descending and ascending neurons of the Drosophila nervous system: stereotypy and sexual dimorphism.

In most complex nervous systems there is a clear anatomical separation between the nerve cord, which contains most of the final motor outputs necessary for behaviour, and the brain. In insects, the neck connective is both a physical and information bottleneck connecting the brain and the ventral nerve cord (VNC, spinal cord analogue) and comprises diverse populations of descending (DN), ascending (AN) and sensory ascending neurons, which are crucial for sensorimotor signalling and control. Integrating three separate EM datasets, we now provide a complete connectomic description of the ascending and descending neurons of the female nervous system of Drosophila and compare them with neurons of the male nerve cord. Proofread neuronal reconstructions have been matched across hemispheres, datasets and sexes. Crucially, we have also matched 51% of DN cell types to light level data defining specific driver lines as well as classifying all ascending populations. We use these results to reveal the general architecture, tracts, neuropil innervation and connectivity of neck connective neurons. We observe connected chains of descending and ascending neurons spanning the neck, which may subserve motor sequences. We provide a complete description of sexually dimorphic DN and AN populations, with detailed analysis of circuits implicated in sex-related behaviours, including female ovipositor extrusion (DNp13), male courtship (DNa12/aSP22) and song production (AN hemilineage 08B). Our work represents the first EM-level circuit analyses spanning the entire central nervous system of an adult animal.

Recent selection and introgression facilitated high-altitude adaptation in cattle.

During the past 3000 years, cattle on the Qinghai-Xizang Plateau have developed adaptive phenotypes under the selective pressure of hypoxia, ultraviolet (UV) radiation, and extreme cold. The genetic mechanism underlying this rapid adaptation is not yet well understood. Here, we present whole-genome resequencing data for 258 cattle from 32 cattle breeds/populations, including 89 Tibetan cattle representing eight populations distributed at altitudes ranging from 3400 m to 4300 m. Our genomic analysis revealed that Tibetan cattle exhibited a continuous phylogeographic cline from the East Asian taurine to the South Asian indicine ancestries. We found that recently selected genes in Tibetan cattle were related to body size (HMGA2 and NCAPG) and energy expenditure (DUOXA2). We identified signals of sympatric introgression from yak into Tibetan cattle at different altitudes, covering 0.64%-3.26% of their genomes, which included introgressed genes responsible for hypoxia response (EGLN1), cold adaptation (LRP11), DNA damage repair (LATS1), and UV radiation resistance (GNPAT). We observed that introgressed yak alleles were associated with noncoding variants, including those in present EGLN1. In Tibetan cattle, three yak introgressed SNPs in the EGLN1 promoter region reduced the expression of EGLN1, suggesting that these genomic variants enhance hypoxia tolerance. Taken together, our results indicated complex adaptation processes in Tibetan cattle, where recently selected genes and introgressed yak alleles jointly facilitated rapid adaptation to high-altitude environments.

The Nephroprotective Effect of Nitric Oxide during Extracorporeal Circulation: An Experimental Study.

This study aims to determine the effectiveness of administering 80 ppm nitric oxide in reducing kidney injury, mitochondrial dysfunction and regulated cell death in kidneys during experimental perfusion. Twenty-four sheep were randomized into four groups: two groups received 80 ppm NO conditioning with 90 min of cardiopulmonary bypass (CPB + NO) or 90 min of CPB and hypothermic circulatory arrest (CPB + CA + NO), while two groups received sham protocols (CPB and CPB + CA). Kidney injury was assessed using laboratory (neutrophil gelatinase-associated lipocalin, an acute kidney injury biomarker) and morphological methods (morphometric histological changes in kidney biopsy specimens). A kidney biopsy was performed 60 min after weaning from mechanical perfusion. NO did not increase the concentrations of inhaled NO2 and methemoglobin significantly. The NO-conditioning groups showed less severe kidney injury and mitochondrial dysfunction, with statistical significance in the CPB + NO group and reduced tumor necrosis factor-α expression as a trigger of apoptosis and necroptosis in renal tissue in the CPB + CA + NO group compared to the CPB + CA group. The severity of mitochondrial dysfunction in renal tissue was insignificantly lower in the NO-conditioning groups. We conclude that NO administration is safe and effective at reducing kidney injury, mitochondrial dysfunction and regulated cell death in kidneys during experimental CPB.

Unusual causes of gastrointestinal bleeding in the intensive care unit through the radiology lens.

The great majority of patients admitted to the intensive care unit (ICU) for critical gastrointestinal bleeding (GIB) will have a predictable etiology. Once the site is localized to the upper versus the lower gastrointestinal tract, the number of typically encountered etiological possibilities is quite limited. On rare occasions, the cause of GIB requiring ICU care is not one of the standard considerations, potentially leading to diagnostic and therapeutic delays. Within a short time period, three patients were admitted to our institution's medical ICU each with a different unexpected cause of GIB. All three cases generated a variety of instructive images, which are used in the present series to illustrate these conditions and the role of radiology in their evaluation and management.

"Mail-slot" technique for minimally-invasive placement of subdural grid electrodes: a single-institution experience.

BACKGROUND: In the management of multi-drug-resistant focal epilepsies, intracranial electrode implantation is employed for precise localization of the ictal onset zone. In select patients, subdural grid electrode implantation is utilized. Subdural grid placement traditionally requires large craniotomies to visualize the cortex prior to mapping. However, smaller craniotomies may enable shorter operations and reduced risks. We aimed to compare surgical outcomes between patients undergoing traditional large craniotomies with those undergoing tailored 'mini' craniotomies (the "Mail-Slot" technique) for subdural grid placement. METHODS: This retrospective cohort study included 23 patients who underwent subdural electrode implantation for epilepsy monitoring between 2014 and 2020. Patients were categorized into mini craniotomies (N=9) and traditional large craniotomies (N=14) groups. Demographics, operative details, and outcomes were reviewed. Craniotomy size and number of electrodes were determined via post-hoc radiographs. RESULTS: Of the 23 patients studied, the mini group had smaller craniotomy sizes (mean=22.71 cm2 vs. 65.17 cm2, p<0.001) and higher electrode-to-size ratios (mean=4.25 vs. 1.71, p<0.0001). The mini group had slightly fewer total electrodes (mean=88.67 vs. 107.43, p=0.047). No significant differences were found in operative duration, blood loss, invasive EEG duration, complications, or Engel scores between the groups. One patient per group required further invasive epilepsy monitoring for localization; all patients underwent therapeutic surgery. CONCLUSION: Our findings suggest that mini craniotomies for subdural grid placement in epilepsy monitoring offer significant advantages, including smaller craniotomy sizes and shorter operation durations, without compromising safety or efficacy. These results support the trend towards minimally invasive, patient-tailored surgical approaches in epilepsy treatment.

Generalized genetic liability to substance use disorders.

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.

Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels.

Structural biology is solving an ever-increasing number of snapshots of ion channel conformational ensembles. Deciphering ion channel mechanisms, however, requires understanding the ensemble dynamics beyond the static structures. Here, we present a molecular modeling-based approach characterizing the ion channel structural intermediates, or their "dynamic molecular portraits", by assessing water and ion conductivity along with the detailed evaluation of pore hydrophobicity and residue packing. We illustrate the power of this approach by analyzing structures of few vanilloid-subfamily transient receptor potential (TRPV) channels. Based on the pore architecture, there are three major states that are common for TRPVs, which we call α-closed, π-closed, and π-open. We show that the pore hydrophobicity and residue packing for the open state is most favorable for the pore conductance. On the contrary, the α-closed state is the most hydrophobic and always non-conducting. Our approach can also be used for structural and functional classification of ion channels.

Development of 225Ac-doped biocompatible nanoparticles for targeted alpha therapy.

Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes. Encapsulating α-emitting radionuclides within nanoparticles can help overcome many of these challenges. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are a biodegradable and biocompatible delivery platform that has been used for drug delivery. In this study, PLGA nanoparticles are utilized for encapsulation and retention of actinium-225 ([225Ac]Ac3+). Encapsulation of [225Ac]Ac3+ within PLGA nanoparticles (Zave = 155.3 nm) was achieved by adapting a double-emulsion solvent evaporation method. The encapsulation efficiency was affected by both the solvent conditions and the chelation of [225Ac]Ac3+. Chelation of [225Ac]Ac3+ to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([225Ac]AcBLPhen) significantly decreased its release (< 2%) and that of its decay daughters (< 50%) from PLGA nanoparticles. PLGA nanoparticles encapsulating [225Ac]AcBLPhen significantly increased the delivery of [225Ac]Ac3+ to murine (E0771) and human (MCF-7 and MDA-MB-231) breast cancer cells with a concomitant increase in cell death over free [225Ac]Ac3+ in solution. These results demonstrate that PLGA nanoparticles have potential as radionuclide delivery platforms for TAT to advance precision radiotherapy for cancer. In addition, this technology offers an alternative use for ligands with poor aqueous solubility, low stability, or low affinity, allowing them to be repurposed for TAT by encapsulation within PLGA nanoparticles.

The Association Between Medicaid Expansion and Disparities in Vestibular Schwannoma Incidence.

OBJECTIVES: The effect of Medicaid expansion as a part of the Affordable Care Act on vestibular schwannoma (VS) incidence overall and in marginalized populations has not yet been elucidated. The goal of this study was to determine if Medicaid expansion was associated with increases in VS incidence overall, as well as in patients of non-white race or in counties of low socioeconomic status (SES). METHODS: We performed a difference-in-difference (DiD) analysis from January 1st 2010-December 31st 2017 utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Our DiD method compared the change in VS rate between counties that did and did not expand Medicaid among patients of white and non-white race, in low and high SES counties, before and after expansion. RESULTS: The study included 17,312 cases across 1020 counties. Medicaid expansion was associated with a 15% increase (incidence rate ratio 95% CI: [11%, 19]) in VS incidence. White populations saw a 10% increase (CI: [1.06, 1.19]), Black populations saw a 20% increase (CI: [1.10, 1.29]), and patients of other races saw a 44% increase in incidence associated with expansion (CI: [1.21, 1.70]). Low SES counties saw an increase in incidence 1.12 times higher than that of high SES counties (CI:[1.04, 1.20]). CONCLUSION: Medicaid expansion was associated with increases in VS incidence across populations. Furthermore, this increase was more evident in disadvantaged populations, such as patients of non-white race and those from low SES counties. These findings emphasize the impact of Medicaid expansion on healthcare utilization for VS diagnosis. LEVEL OF EVIDENCE: Step/Level 3-Retrospective Cohort Study Laryngoscope, 2024.

Trends in surface plasmon resonance biosensing: materials, methods, and machine learning.

Surface plasmon resonance (SPR) proves to be one of the most effective methods of label-free detection and has been integral for the study of biomolecular interactions and the development of biosensors. This trend delves into the latest SPR research and progress built upon the Kretschmann configuration, a pivotal platform, and highlights three key developments that have enhanced the capabilities of the technique. We will first cover a range of explorations of novel plasmonic materials that have shaped SPR performance. Innovative signal transduction and collection, which leverages traditional materials and emerging alternatives, will then be discussed. Finally, the evolving landscape of data analysis, including the integration of machine learning algorithms to navigate complex SPR datasets, will be reviewed. We will also discuss the implementation of these improvements that have enabled new biosensing functions. These advancements not only pave the way for enhanced biosensing in general but also open new avenues for the technique to play a more significant role in research concerning human health.

Reflected acoustic energy from geological layers during seismic reflection surveys.

Acoustic propagation is significantly impacted by seabed characteristics, which play a large role in propagation modeling. Shallow seabed characteristics comprise a notable area of research due to their impacts on bottom loss, but deep seabed characteristics are often ignored. At low frequencies (several hundred Hertz, particularly below 100 Hz) and at ranges less than that corresponding to the seafloor critical angle, these deep layer characteristics have non-negligible effects. Those effects are explored here using a subset of data from a marine seismic reflection survey, MGL2104, in an environment with a nearly constant ∼2.6 km bathymetry. The source is a 5700 in.3 airgun array and reflections are measured by a 1200 channel, ∼15 km streamer, with both arrays at 12 m depth. The results show that in one-third-octave bands below 100 Hz, a significant fraction of the reflected energy (sometimes >50%) at certain ranges in the water column is attributable to sub-seabed layers, and the seafloor reflections only become the dominant source at ranges where the reflection path approaches a critical angle. The analysis also considers the effects of layer depths on reflected energy, demonstrating that increased depth does not necessarily correlate with decreased energy reflected in the water column.

Spectral-fluorescent study of substituted trimethine cyanine dyes in solutions and in complexes with DNA. Effects of aggregation, moderate heating, and decreasing pH.

Trimethine cyanine dyes are widely used as probes for the detection, study and quantification of biomolecules. In particular, cationic trimethine cyanines noncovalently interact with DNA with growing fluorescence. However, their use is often limited by the tendency to self-association - to the formation of aggregates. Disubstituted trimethine cyanines with hydrophobic substituents are especially prone to aggregation. In this work, we studied the interaction of a number of substituted trimethine cyanines with DNA (in aqueous buffer solutions) and showed that their aggregation strongly interfered with their use as fluorescent probes for DNA. To eliminate this drawback, preliminary heating of dye solutions with DNA to 60-70 °C was used, followed by cooling to room temperature. Compared to the experiments without heating, an increase in the dye fluorescence intensity was observed due to the partial thermal decomposition of the aggregates and the interaction of the resulting monomers with DNA. To decompose aggregates, another method was also used - protonation of the dyes with amino substituents in buffer solutions with pH 5.0, which also led to growing the dye fluorescence intensity in the presence of DNA. Complexes of the dyes with DNA were modeled using molecular docking. Effective binding constants of the dyes to DNA and detection limits when using the dyes as probes for DNA (LOD and LOQ) were determined. It is shown that dye 3 with heating in neutral buffer and dye 1 in acidic buffer may be recommended as sensitive probes for DNA. It is concluded that the method of preliminary heating may be applied to dyes prone to aggregation, for improving their properties as biomolecular probes. Another possible means to reduce the interfering effects of dye aggregates is to use easily protonated dyes (with amino substituents) in slightly acidic media.

Inductive detection of temperature-induced magnetization dynamics of molecular spin systems.

The development and technological applications of molecular spin systems require versatile experimental techniques to characterize and control their static and dynamic magnetic properties. In the latter case, bulk spectroscopic and magnetometric techniques, such as AC magnetometry and pulsed electron paramagnetic resonance, are usually employed, showing high sensitivity, wide dynamic range, and flexibility. They are based on creating a nonequilibrium state either by changing the magnetic field or by applying resonant microwave radiation. Another possible source of perturbation is a laser pulse that rapidly heats the sample. This approach has proven to be one of the most useful techniques for studying the kinetics and mechanism of chemical and biochemical reactions. Inspired by these works, we propose an inductive detection of temperature-induced magnetization dynamics as applied to the study of molecular spin systems and describe the general design and construction of a particular induction probehead, taking into account the constraints imposed by the cryostat and electromagnet. To evaluate the performance, several coordination compounds of VO2+, Co2+, and Dy3+ were investigated using low-energy pulses of a terahertz free electron laser of the Novosibirsk free electron laser facility as a heat source. All measured magnetization dynamics were qualitatively or quantitatively described using a proposed basic theoretical model and compared with the data obtained by alternating current magnetometry. Based on the results of the research, the possible scope of applications of inductive detection and its advantages and disadvantages in comparison with standard methods are discussed.

Immunocompetent Intestine-on-Chip Model for Analyzing Gut Mucosal Immune Responses.

An advanced intestine-on-chip model recreating epithelial 3D organotypic villus-like and crypt-like structures has been developed. The immunocompetent model includes Human Umbilical Vein Endothelial Cells (HUVEC), Caco-2 intestinal epithelial cells, tissue-resident macrophages, and dendritic cells, which self-organize within the tissue, mirroring characteristics of the human intestinal mucosa. A unique aspect of this platform is its capacity to integrate circulating human primary immune cells, enhancing physiological relevance. The model is designed to investigate the intestinal immune system's response to bacterial and fungal colonization and infection. Due to its enlarged cavity size, the model offers diverse functional readouts such as permeation assays, cytokine release, and immune cell infiltration, and is compatible with immunofluorescence measurement of 3D structures formed by the epithelial cell layer. It hereby provides comprehensive insights into cell differentiation and function. The intestine-on-chip platform has demonstrated its potential in elucidating complex interactions between surrogates of a living microbiota and human host tissue within a microphysiological perfused biochip platform.

Sweet corn phytoglycogen dendrimers as a lyoprotectant for dry-state protein storage.

Protein biotherapeutics typically require expensive cold-chain storage to maintain their fold and function. Packaging proteins in the dry state via lyophilization can reduce these cold-chain requirements. However, formulating proteins for lyophilization often requires extensive optimization of excipients that both maintain the protein folded state during freezing and drying (i.e., "cryoprotection" and "lyoprotection"), and form a cake to carry the dehydrated protein. Here we show that sweet corn phytoglycogens, which are glucose dendrimers, can act as both a protein lyoprotectant and a cake-forming agent. Phytoglycogen (PG) dendrimers from 16 different maize sources (PG1-16) were extracted via ethanol precipitation. PG size was generally consistent at ~70-100 nm for all variants, whereas the colloidal stability in water, protein contaminant level, and maximum density of cytocompatibility varied for PG1-16. 10 mg/mL PG1, 2, 9, 13, 15, and 16 maintained the activity of various proteins, including green fluorescent protein, lysozyme, ß-galactosidase, and horseradish peroxidase, over a broad range of concentrations, through multiple rounds of lyophilization. PG13 was identified as the lead excipient candidate as it demonstrated narrow dispersity, colloidal stability in phosphate-buffered saline, low protein contaminants, and cytocompatibility up to 10 mg/mL in NIH3T3 cell cultures. All dry protein-PG13 mixtures had a cake-like appearance and all frozen protein-PG13 mixtures had a Tg' of ~ -26°C. The lyoprotection and cake-forming properties of PG13 were density-dependent, requiring a minimum density of 5 mg/mL for maximum activity. Collectively these data establish PG dendrimers as a new class of excipient to formulate proteins in the dry state.

ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma.

Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.