DNA Hierarchical Superstructures from Micellar Units: Stiff Hydrogels and Anisotropic Nanofibers.

Supramolecular materials have been assembled using a wide range of interactions, including the hydrophobic effect, DNA base-pairing, and hydrogen bonding. Specifically, DNA amphiphiles with a hydrophobic building block self-assemble into diverse morphologies depending on the length and composition of both blocks. Herein, we take advantage of the orthogonality of different supramolecular interactions - the hydrophobic effect, Watson-Crick-Franklin base pairing and RNA kissing loops - to create hierarchical self-assemblies with controlled morphologies on both the nanometer and the micrometer scales. Assembly through base-pairing leads to the formation of hybrid, multi-phasic hydrogels with high stiffness and self-healing properties. Assembly via hydrophobic core interactions gives anisotropic, discrete assemblies, where DNA fibers with one sequence are terminated with DNA spheres bearing different sequences. This work opens new avenues for the bottom-up construction of DNA-based materials, with promising applications in drug delivery, tissue engineering, and the creation of complex DNA structures from a minimum array of components.

Tobacco use Prevalence in the Military Health System: A Retrospective Study.

INTRODUCTION: Tobacco use is prevalent and has traditionally been higher in the U.S. Military population than in the civilian population, but studies are limited. The goal of this study was to evaluate tobacco use and tobacco cessation counseling within the US Military health system (MHS). MATERIALS AND METHODS: This was a retrospective study assessing tobacco use and cessation counseling rates within the MHS from July 2016 to March 2022. Data for military tobacco use were obtained from the Defense Health Agency (DHA) Dashboard. US civilian tobacco rates were obtained from the Center for Disease Control and Prevention (CDC). POPULATION: Patients 18+ currently enrolled in direct care in military treatment facilities (MTFs) who had at least one direct primary care or well care gynecology encounter during the measurement years. Current tobacco use is defined as the presence of one coded indicator which included ICD 10CM codes, MEDCIN (a system of standardized medical terminology) Terms, and Vitals. Tobacco use is defined as the use of any form of tobacco (cigarette, cigar, vaping, or smokeless). The prevalence of tobacco use per month was analyzed from July 2016 through March 2022. After searching specifically for procedure codes for tobacco cessation counseling, a month-to- month trend of the rate of tobacco cessation counseling was also established. RESULTS: Data from 1.8 million patients were analyzed. Overall tobacco use within the MHS (including military dependents and retirees) decreased 1.68% (29.94 to 28.26%) from 2016 to 2022. Rates decreased by 3.24% (29.94 to 26.70%) from July 2016 to March 2021 before increasing by 1.56% (26.70 to 28.26%) from March 2021 to March 2022. Tobacco cessation counseling declined by 17.4% (28.4 to 11%) from July 2016 to March 2022. In comparison to the civilian population, tobacco use was 15.0% higher in the MHS. CONCLUSIONS: Tobacco use remains common in the United States but is more prevalent in both active duty military and military retirees than civilians. Tobacco cessation counseling within the MHS steadily declined from 2016 to 2022. While there has been an overall reduction in rates of tobacco use in the military population over the last 5 years there was an increase over the last 2 years. Further research is needed to elucidate tobacco use, the effect of tobacco cessation counseling in the military, and the potential role of tobacco cessation medications in reducing tobacco use within the MHS.

Heat-activated growth of metastable and length-defined DNA fibers expands traditional polymer assembly.

Biopolymers such as nucleic acids and proteins exhibit dynamic backbone folding, wherein site-specific intramolecular interactions determine overall structure. Proteins then hierarchically assemble into supramolecular polymers such as microtubules, that are robust yet dynamic, constantly growing or shortening to adjust to cellular needs. The combination of dynamic, energy-driven folding and growth with structural stiffness and length control is difficult to achieve in synthetic polymer self-assembly. Here we show that highly charged, monodisperse DNA-oligomers assemble via seeded growth into length-controlled supramolecular fibers during heating; when the temperature is lowered, these metastable fibers slowly disassemble. Furthermore, the specific molecular structures of oligomers that promote fiber formation contradict the typical theory of block copolymer self-assembly. Efficient curling and packing of the oligomers - or 'curlamers' - determine morphology, rather than hydrophobic to hydrophilic ratio. Addition of a small molecule stabilises the DNA fibers, enabling temporal control of polymer lifetime and underscoring their potential use in nucleic-acid delivery, stimuli-responsive biomaterials, and soft robotics.

Traumatic Brain Injury and Subsequent Risk of Brain Cancer in US Veterans of the Iraq and Afghanistan Wars.

Importance: While brain cancer is rare, it has a very poor prognosis and few established risk factors. To date, epidemiologic work examining the potential association of traumatic brain injury (TBI) with the subsequent risk of brain cancer is conflicting. Further data may be useful. Objective: To examine whether a history of TBI exposure is associated with the subsequent development of brain cancer. Design, Setting, and Participants: A retrospective cohort study was conducted from October 1, 2004, to September 20, 2019, and data analysis was performed between January 1 and June 26, 2023. The median follow-up for the cohort was 7.2 (IQR, 4.1-10.1) years. Veterans Affairs (VA) and Department of Defense (DoD) administrative data on 1 919 740 veterans from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium were included. Exposure: The main exposure of interest was TBI severity (categorized as mild, moderate or severe [moderate/severe], and penetrating). Main Outcomes and Measures: The outcome of interest was the development of brain cancer based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes in either the DoD/VA medical records or from the National Death Index. Results: After 611 107 exclusions (predominately for no encounter during the study period), a cohort including 1 919 740 veterans was included, most of whom were male (80.25%) and non-Hispanic White (63.11%). Median age at index date was 31 (IQR, 25-42) years. The cohort included 449 880 individuals with TBI (mild, 385 848; moderate/severe, 46 859; and penetrating, 17 173). Brain cancer occurred in 318 individuals without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (≤0.06%). After adjustment, moderate/severe TBI (adjusted hazard ratio [AHR], 1.90; 95% CI, 1.16-3.12) and penetrating TBI (AHR, 3.33; 95% CI, 1.71-6.49), but not mild TBI (AHR, 1.14; 95% CI, 0.88-1.47), were associated with the subsequent development of brain cancer. Conclusions and Relevance: In this cohort study of veterans of the Iraq and Afghanistan wars, moderate/severe TBI and penetrating TBI, but not mild TBI, were associated with the subsequent development of brain cancer.

A Case Series of Ocular Syphilis Cases at Military Treatment Facility From 2020 to 2021.

Syphilis is a sexually transmitted infection, caused by the spirochete Treponema pallidum, that can lead to multi-organ involvement. In 2020, over 138,000 cases were reported in the United States equating to a case report of 40.8 per 100,000 people. Ocular syphilis is a rare manifestation and is defined as the clinical presentation of ocular disease in a person with laboratory-confirmed syphilis infection of any stage, with estimated incidence of 0.6-2% of all cases. Syphilis is known as "The Great Imitator," and can present as nearly any form of ocular disease, though the most common manifestations are posterior uveitis and panuveitis. The highly variable clinical presentation of ocular syphilis often leads to delayed diagnosis allowing the potential for poor, often preventable outcomes. This highlights the need for providers to have a high level of clinical suspicion and awareness of ocular manifestations of syphilis, especially in high risk populations. We present a case series of five patients diagnosed with ocular syphilis at a military treatment facility. Each patient had different presenting symptoms as well as different ocular manifestations.

Association of Traumatic Brain Injury and Glioblastoma Multiforme: A Case Series.

Glioblastoma multiforme (GBM) is an aggressive variant of central nervous system gliomas that carries a dismal prognosis. Although GBM is the most frequently occurring and malignant type of glioma accounting for more than 60% of all brain tumors in adults, its overall incidence is rare, occurring at a rate of 3.21 per 100,000 persons. Little is known about the etiology of GBM, but one proposed theory is that GBM pathogenesis may be linked to a chronic inflammatory course initiated by traumatic injury to the brain. Limited case reports have suggested an association between GBMs and traumatic brain injury (TBI), but larger case-control and epidemiologic studies have been inconclusive. We present three service members (two active duty and one retired) who developed GBM near the original site of prior head trauma. Each service member's military occupation was in the special operations community and shared a common theme of TBI following head trauma/injury. The current research on the association between TBI and GBM is limited and conflicting, predominantly due to the low incidence of the disease in the general population. Evidence has indicated that TBI should be considered a chronic disease with long-term health impacts, including long-term disability, dementia, epilepsy, mental health conditions, and cardiovascular diseases. With the addition of our patients, as well as a recently published study proposing a molecular association between trauma and GBM, further research is needed to better understand the potential relationship.

Supramolecular Nucleic Acid-Based Organosilica Nanoparticles Responsive to Physical and Biological Inputs.

Organosilica nanoparticles that contain responsive organic building blocks as constitutive components of the silica network offer promising opportunities for the development of innovative drug formulations, biomolecule delivery, and diagnostic tools. However, the synthetic challenges required to introduce dynamic and multifunctional building blocks have hindered the realization of biomimicking nanoparticles. In this study, capitalizing on our previous research on responsive nucleic acid-based organosilica nanoparticles, we combine the supramolecular programmability of nucleic acid (NA) interactions with sol-gel chemistry. This approach allows us to create dynamic supramolecular bridging units of nucleic acids in a silica-based scaffold. Two peptide nucleic acid-based monoalkoxysilane derivatives, which self-assemble into a supramolecular bis-alkoxysilane through direct base pairing, were chosen as the noncovalent units inserted into the silica network. In addition, a bridging functional NA aptamer leads to the specific recognition of ATP molecules. In a one-step bottom-up approach, the resulting supramolecular building blocks can be used to prepare responsive organosilica nanoparticles. The supramolecular Watson-Crick-Franklin interactions of the organosilica nanoparticles result in a programmable response to external physical (i.e., temperature) and biological (i.e., DNA and ATP) inputs and thus pave the way for the rational design of multifunctional silica materials with application from drug delivery to theranostics.

Responsive Nucleic Acid-Based Organosilica Nanoparticles.

The development of smart nanoparticles (NPs) that encode responsive features in the structural framework promises to extend the applications of NP-based drugs, vaccines, and diagnostic tools. New nanocarriers would ideally consist of a minimal number of biocompatible components and exhibit multiresponsive behavior to specific biomolecules, but progress is limited by the difficulty of synthesizing suitable building blocks. Through a nature-inspired approach that combines the programmability of nucleic acid interactions and sol-gel chemistry, we report the incorporation of synthetic nucleic acids and analogs, as constitutive components, into organosilica NPs. We prepared different nanomaterials containing single-stranded nucleic acids that are covalently embedded in the silica network. Through the incorporation of functional nucleic acids into the organosilica framework, the particles respond to various biological, physical, and chemical inputs, resulting in detectable physicochemical changes. The one-step bottom-up approach used to prepare organosilica NPs provides multifunctional systems that combine the tunability of oligonucleotides with the stiffness, low cost, and biocompatibility of silica for different applications ranging from drug delivery to sensing.

Paradoxical Increase of Permeability and Lipophilicity with the Increasing Topological Polar Surface Area within a Series of PRMT5 Inhibitors.

An imidazolone → triazolone replacement addressed the limited passive permeability of a series of protein arginine methyl transferase 5 (PRMT5) inhibitors. This increase in passive permeability was unexpected given the increase in the hydrogen bond acceptor (HBA) count and topological polar surface area (TPSA), two descriptors that are typically inversely correlated with permeability. Quantum mechanics (QM) calculations revealed that this unusual effect was due to an electronically driven disconnect between TPSA and 3D-PSA, which manifests in a reduction in overall HBA strength as indicated by the HBA moment descriptor from COSMO-RS (conductor-like screening model for real solvation). HBA moment was subsequently deployed as a design parameter leading to the discovery of inhibitors with not only improved passive permeability but also reduced P-glycoprotein (P-gp) transport. Our case study suggests that hidden polarity as quantified by TPSA-3DPSA can be rationally designed through QM calculations.

DNA Sequence and Length Dictate the Assembly of Nucleic Acid Block Copolymers.

The self-assembly of block copolymers is often rationalized by structure and microphase separation; pathways that diverge from this parameter space may provide new mechanisms of polymer assembly. Here, we show that the sequence and length of single-stranded DNA directly influence the self-assembly of sequence-defined DNA block copolymers. While increasing the length of DNA led to predictable changes in self-assembly, changing only the sequence of DNA produced three distinct structures: spherical micelles (spherical nucleic acids, SNAs) from flexible poly(thymine) DNA, fibers from semirigid mixed-sequence DNA, and networked superstructures from rigid poly(adenine) DNA. The secondary structure of poly(adenine) DNA strands drives a temperature-dependent polymerization and assembly mechanism: copolymers stored in an SNA reservoir form fibers after thermal activation, which then aggregate upon cooling to form interwoven networks. DNA is often used as a programming code that aids in nanostructure addressability and function. Here, we show that the inherent physical and chemical properties of single-stranded DNA sequences also make them an ideal material to direct self-assembled morphologies and select for new methods of supramolecular polymerization.

A dissipative pathway for the structural evolution of DNA fibres.

Biochemical networks interconnect, grow and evolve to express new properties as different chemical pathways are selected during a continuous cycle of energy consumption and transformation. In contrast, synthetic systems that push away from equilibrium usually return to the same self-assembled state, often generating waste that limits system recyclability and prevents the formation of adaptable networks. Here we show that annealing by slow proton dissipation selects for otherwise inaccessible morphologies of fibres built from DNA and cyanuric acid. Using single-molecule fluorescence microscopy, we observe that proton dissipation influences the growth mechanism of supramolecular polymerization, healing gaps within fibres and converting highly branched, interwoven networks into nanocable superstructures. Just as the growth kinetics of natural fibres determine their structural attributes to modulate function, our system of photoacid-enabled depolymerization and repolymerization selects for healed materials to yield organized, robust fibres. Our method provides a chemical route for error-checking, distinct from thermal annealing, that improves the morphologies and properties of supramolecular materials using out-of-equilibrium systems.

Diagnostic Imaging: Appropriate and Safe Use.

The use of diagnostic radiography has doubled in the past two decades. Image Gently (children) and Image Wisely (adults) are multidisciplinary initiatives that seek to reduce radiation exposure by eliminating unnecessary procedures and offering best practices. Patients with an estimated glomerular filtration rate less than 30 mL per minute per 1.73 m2 may have increased risk of nephropathy when exposed to iodinated contrast media and increased risk of nephrogenic systemic fibrosis when exposed to gadolinium-based contrast agents. American College of Radiology Appropriateness Criteria can help guide specific diagnostic imaging choices. Noncontrast head computed tomography is the first-line modality when a stroke is suspected. Magnetic resonance imaging stroke protocols and computed tomography perfusion scans can augment evaluation and potentially expand pharmacologic and endovascular therapy timeframes. Imaging should be avoided in patients with uncomplicated headache syndromes unless the history or physical examination reveals red flag features. Cardiac computed tomography angiography, stress echocardiography, and myocardial perfusion scintigraphy (nuclear stress test) are appropriate for patients with chest pain and low to intermediate cardiovascular risk and have comparable sensitivity and specificity. Computed tomography pulmonary angiography is the preferred test for high-risk patients or those with a positive d-dimer test result, and ventilation-perfusion scintigraphy is reserved for patients with an estimated glomerular filtration rate less than 30 mL per minute per 1.73 m2 or a known contrast allergy. Computed tomography with intravenous contrast is preferred for evaluating adults with suspected appendicitis; however, ultrasonography should precede computed tomography in children, and definitive treatment should be initiated if positive. Ultrasonography is the first-line modality for assessing right upper quadrant pain suggestive of biliary disease. Mass size and patient age dictate surveillance recommendations for adnexal masses. Imaging should not be performed for acute (less than six weeks) low back pain unless red flag features are found on patient history. Ultrasonography should be used for the evaluation of suspicious thyroid nodules identified incidentally on computed tomography.

What imaging can disclose about suspected stroke and its Tx.

Selecting useful modalities is key in early and later management of an acute ischemic event. This review-augmented by an at-a-glance table-can inform your care.

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

Sequence-Defined DNA Amphiphiles for Drug Delivery: Synthesis and Self-Assembly.

DNA nanotechnology has been used to create DNA containing nanostructures with well-defined sizes and shapes-properties highly applicable to drug delivery. By appending sequence-defined hydrophobic segments to DNA, DNA amphiphiles are created whose structures and modes of self-assembly mimic specialized biomacromolecules such as proteins. Automated, solid-phase DNA synthesis is a scalable and robust technique that has been optimized for several decades to make DNA oligomers. Using the same method and with minimal additional cost, DNA amphiphiles are synthesized with total control of monomer sequence. A variety of synthetic monomers may be appended to DNA depending on the application, but of particular interest is a linear twelve-carbon alkyl chain (C12). This chapter describes the synthesis, purification, and characterization of a DNA amphiphile consisting of twelve C12 units covalently attached to a 19mer DNA sequence (C1212-DNA19). These DNA amphiphiles self-assemble into spherical nanoparticles with potential applications for nucleic acid delivery. Methods common to chemistry and molecular biology are employed, including high-performance liquid chromatography and gel electrophoresis, as well as the more specialized imaging technique of atomic force microscopy.