Replication stress as a driver of cellular senescence and aging.

Replication stress refers to slowing or stalling of replication fork progression during DNA synthesis that disrupts faithful copying of the genome. While long considered a nexus for DNA damage, the role of replication stress in aging is under-appreciated. The consequential role of replication stress in promotion of organismal aging phenotypes is evidenced by an extensive list of hereditary accelerated aging disorders marked by molecular defects in factors that promote replication fork progression and operate uniquely in the replication stress response. Additionally, recent studies have revealed cellular pathways and phenotypes elicited by replication stress that align with designated hallmarks of aging. Here we review recent advances demonstrating the role of replication stress as an ultimate driver of cellular senescence and aging. We discuss clinical implications of the intriguing links between cellular senescence and aging including application of senotherapeutic approaches in the context of replication stress.

Purification and biochemical characterization of the G4 resolvase and DNA helicase FANCJ.

G-quadruplex (G4) DNA or RNA poses a unique nucleic acid structure in genomic transactions. Because of the unique topology presented by G4, cells have exquisite mechanisms and pathways to metabolize G4 that arise in guanine-rich regions of the genome such as telomeres, promoter regions, ribosomal DNA, and other chromosomal elements. G4 resolvases are often represented by a class of molecular motors known as helicases that disrupt the Hoogsteen hydrogen bonds in G4 by harnessing the chemical energy of nucleoside triphosphate hydrolysis. Of special interest to researchers in the field, including us, is the human FANCJ DNA helicase that efficiently resolves G4 DNA structures. Notably, FANCJ mutations are linked to Fanconi Anemia and are prominent in breast and ovarian cancer. Since our discovery that FANCJ efficiently resolves G4 DNA structures 15 years ago, we and other labs have characterized mechanistic aspects of FANCJ-catalyzed G4 resolution and its biological importance in genomic integrity and cellular DNA replication. In addition to its G4 resolvase function, FANCJ is also a classic DNA helicase that acts on conventional duplex DNA structures, which are relevant to the enzyme's role in interstrand cross link repair, double-strand break repair via homologous recombination, and response to replication stress. Here, we describe detailed procedures for the purification of recombinant FANCJ protein and characterization of its G4 resolvase and duplex DNA helicase activity.

Dimerization of a Reactive Azaacene Diradical: Synthesis of a Covalent Azaacene Cage.

Two series of regioisomeric dicyanomethylene substituted dithienodiazatetracenes with formal para- or ortho-quinodimethane subunits were synthesized and characterized. Whereas the para-isomers (p-n, diradical index y0 =0.01) are stable and isolable, the ortho-isomer (y0 =0.98) dimerizes into a covalent azaacene cage. Four elongated σ-CC bonds are formed and the former triisopropylsilyl(TIPS) -ethynylene groups transformed into cumulene units. The azaacene cage dimer (o-1)2 was characterized by X-ray single crystal structure analysis and temperature-dependent infrared (IR), electron paramagnetic resonance (EPR, solid-state), nuclear magnetic resonance (NMR) and ultraviolet-visible (UV/Vis) spectroscopies (solution) indicating reformation of o-1.

The American Board of Clinical Neuropsychology (ABCN) and American Academy of Clinical Neuropsychology (AACN): Recent milestones and future goals 2014-2023.

Objective: The American Board of Clinical Neuropsychology (ABCN) and the American Academy of Clinical Neuropsychology (AACN) have become leading organizations in the credentialing of clinical neuropsychologists and promotion of the field, respectively. This paper updates the literature by summarizing the activities and growth of ABCN and AACN during the period 2014 through 2023. Method: Prior papers have reviewed the history of these organizations up to 2014. In this paper, the authors describe milestones that each organization has reached, provide an update reflecting improved functions and new initiatives, and describe how the organizations have responded to numerous challenges. Conclusions: The past decade has witnessed substantial societal and technological evolution, as well as wrenching events including a global pandemic and public outcry over continued racial injustice. ABCN and AACN have evolved in the face of these changes, positioning each organization well to take on future challenges.

Navigating disability insurance in the American healthcare system for the low-grade glioma patient.

In the United States, diagnosis of grade 3 or 4 glioma qualifies patients for Social Security disability benefits. Low-grade gliomas (LGGs) can be similarly debilitating, with at least 31% of patients presenting with cognitive deficits and 80% with tumor-related epilepsy. A diagnosis of LGG does not in and of itself qualify patients for disability benefits; the burden of proof is substantially higher. We outline the American healthcare system process of medical documentation to support disability benefits, Social Security Disability Insurance (SSDI) and Supplemental Security Income (SSI). We provide a template to assist providers in facilitating the application process for patients with LGG. The provider's role is not to simply "declare" a patient disabled, but to provide comprehensive documentation regarding diagnosis, treatment, disease status, symptoms, and functional status in the medical record. As cognitive symptoms and seizures are 2 key sources of disability in LGG patients, selective referrals to neuropsychology and epileptology may improve patient care and bolster documentation of the patient's symptoms in these domains. Likewise, connecting patients with social workers and disability claims representatives can assist them in navigating the complicated application process. We provide an extensive review for patient eligibility in the United States to receive disability. We map a comprehensive care process that may have relevance to multiple regions outside the United States. Providers are better able to help their patients navigate the disability application process when they understand how to address physical and cognitive changes for thorough care of their patient.

Substrate-Independent Surface Energy Tuning via Siloxane Treatment for Printed Electronics.

Digital printing enables solution processing of functional materials and opens a new route to fabricate low-cost electronic devices. One crucial parameter that affects the wettability of inks for all printing techniques is the surface free energy (SFE) of the substrate. Siloxanes, with their huge variety of side chains and their ability to form self-assembled monolayers, offer exhaustive control of the substrate SFE from hydrophilic to hydrophobic. Thus, siloxane treatment is a suitable approach to adjust the substrate conditions to the desired ink, instead of optimizing the ink to an arbitrary substrate. In this work, the influence of different fluorinated and nonfluorinated siloxanes on the SFE of different substrates, such as polymers, glasses, and metals, are examined. By mixing several siloxanes, we demonstrate the fine tuning of the surface energy. The polar and dispersive components of the SFE are determined by the Owens-Wendt-Rabel-Kaelble (OWRK) method. Furthermore, the impact of the siloxanes and therefore the SFE on the pinning of droplets and wet films are assessed via dynamic contact angle measurements. SFE-optimized substrates enable tailoring the resolution of inkjet printed silver structures. A nanoparticulate silver ink was used for printing single drops, lines, and source-drain electrodes for transistors. These were examined in terms of diameter, edge quality, and functionality. We show that by adjusting the SFE of an arbitrary substrate, the printed resolution is substantially increased by minimizing the printed drop size by up to 70%.

Group A streptococcus (GAS) carbohydrate as an immunogen for protection against GAS infection.

Previous studies have shown that human serum containing anti-group A streptococcus carbohydrate (GAS CHO) antibodies were opsonic for different M protein-carrying serotypes. To investigate the role that anti-GAS CHO antibodies play in passive and active protection, mice were immunized subcutaneously or intranasally with GAS CHO conjugated to tetanus toxoid, and mortality and oral colonization were monitored after challenge with live GAS. Compared with control mice, immunized mice were significantly protected against systemic or nasal challenge with GAS. Furthermore, studies of serum samples and throat cultures from Mexican children revealed an inverse relationship between high serum titers of anti-GAS CHO antibodies and the presence of GAS in the throat. Anti-GAS CHO antibodies were also tested for cross-reactivity with human tissues and cytoskeletal proteins. No cross-reactivity was observed in either assay. The present study demonstrates that GAS CHO is both immunogenic and protective against GAS infections.

Shortening of hippocampal spin-spin relaxation time in probable Alzheimer's disease: a 1H magnetic resonance spectroscopy study.

We quantified the differential effects of the spin-spin relaxation times (T2) of tissue water and cerebral spinal fluid in order to examine hippocampal T2 changes as a non-invasive bio-marker of Alzheimer's disease (AD). We measured T2 in the right hippocampus of ten patients fulfilling the NINCDS-ADRDA criteria for AD and 40 healthy adult volunteers using localized proton magnetic resonance spectroscopy. The T2 values of AD patients (73 +/- 8 ms) were significantly shorter (P < 0.01) than those of healthy age-matched controls (81 +/- 5 ms), and there was a reduction in T2 for healthy older vs. healthy younger adults (87 +/- 5 ms, P < 0.05). The reduced T2 values with aging are consistent with age-related decreases in tissue water content. Our results suggest that there may be a severe reduction in tissue water content in AD.