Transient gas-induced differential refractive index effects in as-drawn hollow core optical fibers.

When a hollow core fiber is drawn, the core and cladding holes within the internal cane geometry are pressurized with an inert gas to enable precise control over the internal microstructure of the fiber and counteract surface tension forces. Primarily by considering the temperature drop as the fiber passes through the furnace and the geometrical transformation of the internal microstructure from preform-to-fiber, we recently established that the gas pressure within the final 'as-drawn' fiber is substantially below atmospheric pressure. We have also established that slight changes in the gas refractive index within the core and surrounding cladding holes induced by changes in gas pressure are sufficient to significantly affect both the modality and loss of the fiber. Here we demonstrate, through both simulations and experimental measurements, that the combination of these effects leads to transient changes in the fiber's attenuation when the fibers are opened to atmosphere post-fabrication. It is important to account for this phenomenon for accurate fiber characterization, particularly when long lengths of fiber are drawn where it could take many weeks for every part of the internal microstructure to reach atmospheric pressure.

ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis.

Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC50. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.

CNVoyant: A Highly Performant and Explainable Multi-Classifier Machine Learning Approach for Determining the Clinical Significance of Copy Number Variants.

The precise classification of copy number variants (CNVs) presents a significant challenge in genomic medicine, primarily due to the complex nature of CNVs and their diverse impact on genetic disorders. This complexity is compounded by the limitations of existing methods in accurately distinguishing between benign, uncertain, and pathogenic CNVs. Addressing this gap, we introduce CNVoyant, a machine learning-based multi-class framework designed to enhance the clinical significance classification of CNVs. Trained on a comprehensive dataset of 52,176 ClinVar entries across pathogenic, uncertain, and benign classifications, CNVoyant incorporates a broad spectrum of genomic features, including genome position, disease-gene annotations, dosage sensitivity, and conservation scores. Models to predict the clinical significance of copy number gains and losses were trained independently. Final models were selected after testing 29 machine learning architectures and 10,000 hyperparameter combinations each for deletions and duplications via 5-fold cross-validation. We validate the performance of the CNVoyant by leveraging a comprehensive set of 21,574 CNVs from the DECIPHER database, a highly regarded resource known for its extensive catalog of chromosomal imbalances linked to clinical outcomes. Compared to alternative approaches, CNVoyant shows marked improvements in precision-recall and ROC AUC metrics for binary pathogenic classifications while going one step further, offering multi-classification of clinical significance and corresponding SHAP explainability plots. This large-scale validation demonstrates CNVoyant's superior accuracy and underscores its potential to aid genomic researchers and clinical geneticists in interpreting the clinical implications of real CNVs.

Effect of Peanut Butter Intake on Sleep Health in Firefighters: A Randomized Controlled Trial.

Sleep is often impaired in firefighters due to the psychologically and physiologically intense nature of their work and working shift schedules. Peanut butter is affordable and a substantial source of monounsaturated fatty acids, which may aid sleep health. Thus, this study sought to determine if a daily serving of peanut butter consumed before bedtime for seven weeks altered sleep quality and quantity among full-time firefighters. Forty firefighters (peanut butter group = 20; control group = 20) participated in this eight-week randomized controlled trial. All participants completed a subjective questionnaire on mood, focus, and alertness twice daily and wore an Actigraph wristwatch to measure sleep variables, including latency, efficiency, time in bed, time asleep, wake after sleep onset, number of awakenings, and time spent awake. After a baseline week, the peanut butter group consumed two tablespoons of peanut butter two hours prior to bedtime for seven weeks. Compared to the control group, the peanut butter group did not demonstrate significant changes (p > 0.05) in sleep measures or subjective feelings of mood, focus, or alertness after consuming peanut butter for seven weeks. Therefore, peanut butter as a source of peanuts did not alter sleep quality or quantity in this group of firefighters.

Systems level analysis of time and stimuli specific signaling through PKA.

It is well known that eukaryotic cells create gradients of cAMP across space and time to regulate the cAMP dependent protein kinase (PKA) and, in turn, growth and metabolism. However, it is unclear how PKA responds to different concentrations of cAMP. Here, to address this question, we examine PKA signaling in Saccharomyces cerevisiae in different conditions, timepoints, and concentrations of the chemical inhibitor 1-NM-PP1, using phosphoproteomics. These experiments show that there are numerous proteins that are only phosphorylated when cAMP and PKA activity are at/near their maximum level, while other proteins are phosphorylated even when cAMP levels and PKA activity are low. The data also show that PKA drives cells into distinct growth states by acting on proteins with different thresholds for phosphorylation in different conditions. Analysis of the sequences surrounding the 118 PKA-dependent phosphosites suggests that the phosphorylation thresholds are set, at least in part, by the affinity of PKA for each site.

Multifunction fluorescence open source in vivo/in vitro imaging system (openIVIS).

The widespread availability and diversity of open-source microcontrollers paired with off-the-shelf electronics and 3D printed technology has led to the creation of a wide range of low-cost scientific instruments, including microscopes, spectrometers, sensors, data loggers, and other tools that can be used for research, education, and experimentation. These devices can be used to explore a wide range of scientific topics, from biology and chemistry to physics and engineering. In this study, we designed and built a multifunction fluorescent open source in vivo/in vitro imaging system (openIVIS) system that integrates a Raspberry Pi with commercial cameras and LEDs with 3D printed structures combined with an acrylic housing. Our openIVIS provides three excitation wavelengths of 460 nm, 520 nm, and 630 nm integrated with Python control software to enable fluorescent measurements across the full visible light spectrum. To demonstrate the potential applications of our system, we tested its performance against a diverse set of experiments including laboratory assays (measuring fluorescent dyes, using optical nanosensors, and DNA gel electrophoresis) to potentially fieldable applications (plant and mineral imaging). We also tested the potential use for a high school biology environment by imaging small animals and tracking their development over the course of ten days. Our system demonstrated its ability to measure a wide dynamic range fluorescent response from millimolar to picomolar concentrations in the same sample while measuring responses across visible wavelengths. These results demonstrate the power and flexibility of open-source hardware and software and how it can be integrated with customizable manufacturing to create low-cost scientific instruments with a wide range of applications. Our study provides a promising model for the development of low-cost instruments that can be used in both research and education.

A Swine Burn Model for Investigating the Healing Process in Multiple Depth Burn Wounds.

Burn wound healing is a complex and long process. Despite extensive experience, plastic surgeons and specialized teams in burn centers still face significant challenges. Among these challenges, the extent of the burned soft tissue can evolve in the early phase, creating a delicate balance between conservative treatments and necrosing tissue removal. Thermal burns are the most common type, and burn depth varies depending on multiple parameters, such as temperature and exposure time. Burn depth also varies in time, and the secondary aggravation of the "shadow zone" remains a poorly understood phenomenon. In response to these challenges, several innovative treatments have been studied, and more are in the early development phase. Nanoparticles in modern wound dressings and artificial skin are examples of these modern therapies still under evaluation. Taken together, both burn diagnosis and burn treatments need substantial advancements, and research teams need a reliable and relevant model to test new tools and therapies. Among animal models, swine are the most relevant because of their strong similarities in skin structure with humans. More specifically, Yucatan minipigs show interesting features such as melanin pigmentation and slow growth, allowing for studying high phototypes and long-term healing. This article aims to describe a reliable and reproducible protocol to study multi-depth burn wounds in Yucatan minipigs, enabling long-term follow-up and providing a relevant model for diagnosis and therapeutic studies.

Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells.

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor-positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib-a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle "paths" that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aß burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aß burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Thoracic and Lumbar Spine Injury: Evidence-Based Diagnosis, Management, and Outcomes.

BACKGROUND: Traumatic thoracolumbar spine injuries are associated with significant morbidity and mortality. Targeted for non-spine specialist trauma surgeons, this systematic scoping review aimed to examine literature for up-to-date evidence on presentation, management, and outcomes of thoracolumbar spine injuries in adult trauma patients. METHODS: This review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. We searched four bibliographic databases: PubMed, EMBASE, Web of Science, and the Cochrane Library. Eligible studies included experimental, observational, and evidence-synthesis articles evaluating patients with thoracic, lumbar, or thoracolumbar spine injury, published in English between January 1, 2010 and January 31, 2021. Studies which focused on animals, cadavers, cohorts with N <30, and pediatric cohorts (age <18 years old), as well as case studies, abstracts, and commentaries were excluded. RESULTS: A total of 2501 studies were screened, of which 326 unique studies were fully text reviewed and twelve aspects of injury management were identified and discussed: injury patterns, determination of injury status and imaging options, considerations in management, and patient quality of life. We found: (1) imaging is a necessary diagnostic tool, (2) no consensus exists for preferred injury characterization scoring systems, (3) operative management should be considered for unstable fractures, decompression, and deformity, and (4) certain patients experience significant burden following injury. DISCUSSION: In this systematic scoping review, we present the most up-to-date information regarding the management of traumatic thoracolumbar spine injuries. This allows non-specialist trauma surgeons to become more familiar with thoracolumbar spine injuries in trauma patients and provides a framework for their management.

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

The Molecular Logic of Gtr1/2 and Pib2 Dependent TORC1 Regulation in Budding Yeast.

The Target of Rapamycin kinase Complex I (TORC1) regulates cell growth and metabolism in eukaryotes. Previous studies have shown that, in Saccharomyces cerevisiae, nitrogen and amino acid signals activate TORC1 via the highly conserved small GTPases, Gtr1/2, and the phosphatidylinositol 3-phosphate binding protein, Pib2. However, it was unclear if/how Gtr1/2 and Pib2 cooperate to control TORC1. Here we report that this dual regulator system pushes TORC1 into three distinct signaling states: (i) a Gtr1/2 on, Pib2 on, rapid growth state in nutrient replete conditions; (ii) a Gtr1/2 off, Pib2 on, adaptive/slow growth state in poor-quality growth medium; and (iii) a Gtr1/2 off, Pib2 off, quiescent state in starvation conditions. We suggest that other signaling pathways work in a similar way, to drive a multi-level response via a single kinase, but the behavior has been overlooked since most studies follow signaling to a single reporter protein.

Homicide in the context of psychosis: analysis of prior service utilisation and age at onset of illness and violence.

BACKGROUND: Public stigma and fear are heightened in cases of extreme violence perpetrated by persons with serious mental illness (SMI). Prevention efforts require understanding of illness patterns and treatment needs prior to these events unfolding. AIMS: To examine mental health service utilisation by persons who committed homicide and entered into forensic care, to investigate the adequacy of mental healthcare preceding these offences. METHOD: Forensic patients across two mental health hospitals in Ontario with an admitting offence of homicide between 2011 and 2021 were identified (n = 112). Sociodemographic, clinical and offence-related variables were coded from the health record and reports prepared for the forensic tribunal. RESULTS: Most patients (75.7%) had mental health contacts preceding the homicide, with 28.4% having a psychiatric in-patient admission in the year prior. For those with service contacts in the year preceding, 50.9% had had only sporadic contact and 70.7% were non-adherent with prescribed medications. Victims were commonly known to the individual (35.7%) and were often family members in care-providing roles (55.4%). Examination of age at onset of illness and offending patterns suggested that most persons admitted to forensic care for homicide act in the context of illness and exhibit a low frequency of pre-homicide offending. CONCLUSIONS: Many individuals admitted to forensic care for homicide have had inadequate mental healthcare leading up to this point. Effective responses to reduce and manage risk should encompass services that proactively address illness-related (e.g. earlier access and better maintenance in care) and criminogenic (e.g. substance use treatment, employment and psychosocial supports) domains.

Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors.

PURPOSE: In estrogen receptor-positive (ER+)/HER2- breast cancer, multiple measures of intratumor heterogeneity are associated with a worse response to endocrine therapy. We sought to develop a novel experimental model to measure heterogeneity in response to tamoxifen treatment in primary breast tumors. EXPERIMENTAL DESIGN: To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live normal breast specimens and human tumors immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. Live primary cell suspensions were treated ex vivo with tamoxifen (10 µmol/L) or control media for 12 hours, and single-cell RNA libraries were generated using the 10X Genomics droplet-based kit. RESULTS: In total, we obtained and processed normal breast tissue from two women undergoing reduction mammoplasty and tumor tissue from 10 women with ER+/HER2- invasive breast carcinoma. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from resistant subpopulations predict poor outcomes in two large cohorts of ER+ breast cancer patients and are enriched in endocrine therapy-resistant tumors. CONCLUSIONS: This novel ex vivo model system now provides the foundation to define responsive and resistant subpopulations within heterogeneous human tumors, which can be used to develop precise single cell-based predictors of response to therapy and to identify genes and pathways driving therapeutic resistance.

A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations.

The SARS-CoV-2 main protease (Mpro) is a major therapeutic target. The Mpro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As Mpro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as an approximation for Mpro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays identified substitutions which conferred strong nirmatrelvir resistance and others that compromised activity. On the other hand, N142A and the P132H mutation, carried by the Omicron variant, caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of Mpro E166R, and Mpro E166N, providing insights into how arginine may drive drug resistance while asparagine leads to reduced activity. The work presented here will help characterize novel resistant variants of Mpro that may arise as Mpro antivirals become more widely used.

Non-cell-autonomous cancer progression from chromosomal instability.

Chromosomal instability (CIN) is a driver of cancer metastasis1-4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing-a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data-we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.

Exposure to Arsenic and Subclinical Cardiovascular Disease in 9- to 11-Year-Old Children, Syracuse, New York.

Importance: Studies in adults have demonstrated associations between arsenic exposure and clinical and subclinical cardiovascular disease (CVD). No studies to date have considered potential associations in children. Objective: To examine the association between total urinary arsenic levels in children and subclinical indicators of CVD. Design, Setting, and Participants: This cross-sectional study considered 245 children, a subset from the Environmental Exposures and Child Health Outcomes (EECHO) cohort. Children from the Syracuse, New York, metropolitan area were recruited from August 1, 2013, until November 30, 2017, with enrollment throughout the year. Statistical analysis was performed from January 1, 2022, to February 28, 2023. Exposures: Total urinary arsenic was measured using inductively coupled plasma mass spectrometry. Creatinine concentration was used to adjust for urinary dilution. In addition, potential exposure routes (eg, diet) were measured. Main Outcomes and Measures: Three indicators of subclinical CVD were assessed: carotid-femoral pulse wave velocity, carotid intima media thickness, and echocardiographic measures of cardiac remodeling. Results: The study sample included 245 children aged 9 to 11 years (mean [SD] age, 10.52 [0.93] years; 133 [54.3%] female). The geometric mean of the creatinine-adjusted total arsenic level in the population was 7.76 µg/g creatinine. After adjustment for covariates, elevated total arsenic levels were associated with significantly greater carotid intima media thickness (ß = 0.21; 95% CI, 0.08-0.33; P = .001). In addition, echocardiography revealed that elevated total arsenic was significantly higher for children with concentric hypertrophy (indicated by greater left ventricular mass and greater relative wall thickness; geometric mean, 16.77 µg/g creatinine; 95% CI, 9.87-28.79 µg/g) relative to the reference group (geometric mean, 7.39 µg/g creatinine; 95% CI, 6.36-8.58 µg/g). With respect to exposure source, significant geographic clustering of total arsenic was found in 1 urban area of Syracuse, New York. Conclusions and Relevance: These findings suggest a significant association between arsenic exposure and subclinical CVD in children. Elevated total arsenic levels were found in an area of Syracuse with known elevations of toxic metals from industrial waste, suggesting historical pollution as a possible source. Given the novelty and potential importance of this association, further research is needed to confirm our findings. Any potential effect of urinary arsenic exposure in childhood on actual clinical CVD outcomes in adulthood remains to be determined.

Tamoxifen Response at Single Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors.

In ER+/HER2- breast cancer, multiple measures of intra-tumor heterogeneity are associated with worse response to endocrine therapy. To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live human tumors and normal breast specimens immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from 3 distinct resistant subpopulations are prognostic in large cohorts of ER+ breast cancer patients and enriched in endocrine therapy resistant tumors. This novel ex vivo model system now provides a foundation to define responsive and resistant sub-populations within heterogeneous tumors, to develop precise single cell-based predictors of response to therapy, and to identify genes and pathways driving resistance to therapy.

DNA damage-induced stalling of transcription drives aging through gene expression imbalance.

Age-related changes in gene expression have long been examined to understand the biology of aging. The hallmarks of aging are biological processes known to be associated with aging, but whether there is a unifying driver of these attributes, is not well understood. With the advent of technology over the last few years, it is quite clear that aging leads to global decline in transcription. In this Perspective, we highlight a new study in Nature Genetics that aimed to determine why global transcription rate reduces with age and how this phenomenon is the driver that interconnects multiple hallmarks of aging. This study recognizes that age-related accumulation of DNA damage, particularly transcription-blocking lesions, stalls RNA polymerase. This phenomenon affects longer genes leading to a gradual loss of transcription and skewing the transcriptome. In order to design a successful aging intervention, future work will be needed to test how some promising therapies in pre-clinical trials target affect transcriptional rate.

Insight into the conserved structural dynamics of the C-terminus of mammal PrPC identifies structural core and possible structural role of pharmacological chaperones.

Misfolding of the prion protein is central to prion disease aetiology. Although understanding the dynamics of the native fold helps to decipher the conformational conversion mechanism, a complete depiction of distal but coupled prion protein sites common across species is lacking. To fill this gap, we used normal mode analysis and network analysis to examine a collection of prion protein structures deposited on the protein data bank. Our study identified a core of conserved residues that sustains the connectivity across the C-terminus of the prion protein. We propose how a well-characterized pharmacological chaperone may stabilize the fold. Also, we provide insight into the effect on the native fold of initial misfolding pathways identified by others using kinetics studies.