More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome.

Aging is a leading risk factor for cancer. While it is proposed that age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. We show that aging and cancer share a common epigenetic replication signature, which we modeled using DNA methylation from extensively passaged immortalized human cells in vitro and tested on clinical tissues. This signature, termed CellDRIFT, increased with age across multiple tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and was transiently reset upon reprogramming. In addition, within-person tissue differences were correlated with predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Our findings suggest that age-related replication may drive epigenetic changes in cells and could push them toward a more tumorigenic state.

Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4.

Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-ß-lactams and 3,3-dichloro-ß-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound 10n (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound 11n (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC50 values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound 10n demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that ß-lactam 10n caused a mitotic catastrophe by targeting tubulin. In addition, compound 10n promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-ß-lactams and the amino acid residues of the colchicine binding active site cavity of ß-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound 10n, could be promising lead compounds for further clinical anti-cancer drug development.

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI).

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

Narrative review of mental illness in cricket with recommendations for mental health support.

INTRODUCTION: Epidemiology reporting within the cricketing medical literature has emerged over the past 2 years, with a focus on physical injuries. Despite mental health in elite sport gaining increasing recognition, few studies have addressed mental health symptoms and disorders within cricket. Recently, cricketers have been prominent in the mainstream media describing their lived experiences of mental illness. As a result, some have withdrawn from competition and suggested there is an unmet need for mental health services within the sport. OBJECTIVES: (i) To appraise the existing evidence on mental health symptoms and disorders amongst cricketers. (ii) To provide guidance on shaping mental health research and services within cricket. DESIGN: A narrative review of the literature from inception of available databases until 26 July 2019, with analysis and recommendations. RESULTS: Five studies were included in this narrative review. Studies covered a range of mental health symptoms and disorders, including distress, anxiety, depression, sleep disturbance, suicide, adverse alcohol use, illicit drug use, eating disorders and bipolar disorder. Results indicated that cricketers are at high risk for distress, anxiety, depression and adverse alcohol use. When compared with the general population, cricketers are more likely to experience anxiety and depressive symptoms. Rates of suicide were proposed to be high for test cricketers. Overall, studies to date have been of low quality, demonstrating non-rigorous research methods. Some studies have relied on non-validated questionnaires to collect self-reported data on mental health symptoms and disorders, while others have presented biographical data obtained through searches of the media. CONCLUSIONS: The results of this narrative review highlight the lack of evidence underpinning mental health services for athletes within cricket. We suggest the following recommendations for future research and practice: (i) normalising mental health symptoms and disorders; (ii) working with and helping vulnerable demographic segments within the target population; (iii) designing and implementing early recognition systems of mental health symptoms and disorders; (iv) addressing the mental health needs of cricketers on a population basis.

Comparing Acceleration and Change of Direction Ability Between Backpedal and Cross-over Run Techniques for Use in American Football.

ABSTRACT: Angelino, D, McCabe, TJG, and Earp, JE. Comparing acceleration and change of direction ability between backpedal and cross-over run techniques for use in American football. J Strength Cond Res 35(1): 47-55, 2021-In American football, defensive backs guard receivers using either cross-over (CO) run or backpedal (BP) techniques, but the efficacy of these techniques is unknown. The purpose of this study was to compare linear acceleration (LA) and change of direction (CoD) ability when using CO and BP. Collegiate football defensive backs participated in LA (n = 13) and CoD (n = 7) testing. During LA, subjects performed CO, BP, and forward sprints with split times taken between 0-3 and 3-5 yd and ground reaction forces recorded 0 and 3 yd from the start. During CoD testing, subjects performed the CO or BP for 3 yd and then were given a cue to sprint to a gate 5 yd away in 1 of 4 directions (downfield, midfield, sideline, or upfield). In LA, CO was faster than BP between 0-3 yd (Δ -0.20 ± 0.02 seconds, p = 0.000) and 3-5 yd (Δ -0.12 ± 0.02 seconds, p = 0.000). At the start of the movement, CO demonstrated greater propulsive forces (p = 0.017). However, 3 yd from the start, CO demonstrated greater propulsive forces and reduced braking forces (p = 0.000 & 0.003). In CoD, CO was faster than BP when running in the downfield (Δ 0.21 ± 0.05 seconds, p = 0.044) and lateral directions (Δ 0.21 ± 0.08 seconds, p = 0.035), but similar in the upfield direction (Δ 0.01 ± 0.08, p = 0.986). Our results indicate that CO is superior to BP in LA, CoD ability, and movement efficiency and support the use of CO for defensive backs.

Mental health and suicide in former professional soccer players.

INTRODUCTION: There is growing recognition of an association between contact sports participation and increased risk of neurodegenerative disease, including Alzheimer's disease and chronic traumatic encephalopathy. In addition to cognitive impairment, a range of mental health disorders and suicidality are proposed as diagnostic features of traumatic encephalopathy syndrome, the putative clinical syndrome associated with chronic traumatic encephalopathy. However, to date, epidemiological data on contact sport participation and mental health outcomes are limited. METHODS: For a cohort of former professional soccer players (n=7676) with known high neurodegenerative mortality and their matched general population controls (n=23 028), data on mental health outcomes were obtained by individual-level record linkage to national electronic records of hospital admissions and death certification. RESULTS: Compared with matched population controls, former professional soccer players showed lower risk of hospital admission for anxiety and stress related disorders, depression, drug use disorders, alcohol use disorders and bipolar and affective mood disorders. Among soccer players, there was no significant difference in risk of hospitalisation for mental health disorders between outfield players and goalkeepers. There was no significant difference in rate of death by suicide between soccer players and controls. CONCLUSIONS: Among a population of former professional soccer players with known high neurodegenerative disease mortality, hospital admissions for common mental health disorders were lower than population controls, with no difference in suicide. Our data provide support for the reappraisal of currently proposed diagnostic clinical criteria for traumatic encephalopathy syndrome, in particular the inclusion of mental health outcomes.

Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening.

4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and ß with low nanomolar affinity and <20-fold selectivity for α over ß and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERß (compound 42; 170-fold selectivity).

Post-flight confusion: does flying affect the brain?

This paper describes a condition termed post-flight confusion using anecdotal and clinical observations. It reviews research from the fields of aviation and altitude medicine and how this could apply to some physiological changes that happen during commercial flights. The collection of symptoms observed is similar to those of delirium. More research is needed to validate these observations, to identify the risks of flying for older people and to consider not only how to minimise these risks but whether this situation contributes to our knowledge about the aetiologies of delirium and dementias.

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells.

Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-ß-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 M for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that ß-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-ß-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

Incorporating an Interactive Statistics Workshop into an Introductory Biology Course-Based Undergraduate Research Experience (CURE) Enhances Students' Statistical Reasoning and Quantitative Literacy Skills.

Course-based undergraduate research experiences (CUREs) provide an avenue for student participation in authentic scientific opportunities. Within the context of such coursework, students are often expected to collect, analyze, and evaluate data obtained from their own investigations. Yet, limited research has been conducted that examines mechanisms for supporting students in these endeavors. In this article, we discuss the development and evaluation of an interactive statistics workshop that was expressly designed to provide students with an open platform for graduate teaching assistant (GTA)-mentored data processing, statistical testing, and synthesis of their own research findings. Mixed methods analyses of pre/post-intervention survey data indicated a statistically significant increase in students' reasoning and quantitative literacy abilities in the domain, as well as enhancement of student self-reported confidence in and knowledge of the application of various statistical metrics to real-world contexts. Collectively, these data reify an important role for scaffolded instruction in statistics in preparing emergent scientists to be data-savvy researchers in a globally expansive STEM workforce.

A Call for Programmatic Assessment of Undergraduate Students' Conceptual Understanding and Higher-Order Cognitive Skills.

In response to empirical evidence and calls for change, individual undergraduate biology instructors are reforming their pedagogical practices. To assess the effectiveness of these reforms, many instructors use course-specific or skill-specific assessments (e.g., concept inventories). We commend our colleagues' noble efforts, yet we contend that this is only a starting point. In this Perspectives article, we argue that departments need to engage in reform and programmatic assessment to produce graduates who have both subject-matter knowledge and higher-order cognitive skills. We encourage biology education researchers to work collaboratively with content specialists to develop program-level assessments aimed at measuring students' conceptual understanding and higher-order cognitive skills, and we encourage departments to develop longitudinal plans for monitoring their students' development of these skills.

The Tigriopus CURE - A Course-Based Undergraduate Research Experience with Concomitant Supplemental Instruction.

Evidence indicates that students who participate in scientific research during their undergraduate experience are more likely to pursue careers in the STEM disciplines and to develop increased scientific reasoning and literacy skills. One avenue to increase student engagement in research is via their enrollment in course-based undergraduate research experiences (CUREs), where they are able to conduct authentic research as part of the laboratory curriculum. The information presented herein provides an example of a CURE which was developed and implemented in an introductory cell and molecular biology course at the University of Northern Colorado. In addition to describing the Tigriopus CURE curriculum itself, we also present evidence regarding the effectiveness of the CURE in promoting students' development of confidence in science process skills, quantitative reasoning skills, and written communication skills. The curricular details of the Tigriopus CURE are provided in this article to provide instructors who are interested in CUREs the opportunity to implement this specific CURE in their own course.

Synthesis, Antiproliferative and Pro-Apoptotic Effects of Nitrostyrenes and Related Compounds in Burkitt's Lymphoma.

BACKGROUND: Cancers of the lymphatic cells (lymphomas) account for approximately 12% of malignant diseases worldwide. The nitrostyrene scaffold is identified as a lead target structure for the development of particularly effective compounds targeting Burkitt's lymphoma (BL). OBJECTIVES: The aims of the curent study were to synthesise a panel of nitrostyrene compounds and to evaluate their activity in Burkitt's lymphoma (BL). METHODS: A panel of structurally varied compounds were designed and synthesised using Henry Knoevenagel condensation reactions. Single crystal X-Ray analysis confirmed the E configuration for six examples of these novel structures. A number of nitrostyrene-related compounds were also investigated including 1,3-bis(aryl)-2-nitropropenes together with heterocyclic scaffolds containing the nitrovinyl pharmacophore such as 3-nitro-2-phenyl-2H-chromenes. The antiproliferative activities of the compounds were evaluated using the BL cell lines EBV- MUTU-1 and EBV+ DG- 75 (chemoresistant) to establish preliminary structure-activity relationships. RESULTS: Lead compounds with optimized nitrostyrene scaffolds and 3-nitro-2-phenyl-2Hchromene structures were successfully established with typical IC50 values of 0.45 µM and 0.47 µM in MUTU-1 cells and 1.41 µM and 1.92 µM, respectively, in DG-75 cells. The mechanism of cell death was identified as apoptotic and the lead compound was found to elicit comparable apoptotic effects to Taxol in Burkitt's lymphoma cell lines MUTU-1 and DG-75. CONCLUSION: This class of pharmaceutically active compounds with potential for the treatment of Burkitt`s lymphoma suggest a potential role for nitrostyrene based agents in chemotherapy.

'Doc, can I fly to Australia?' A case report and review of delirium following long-haul flight.

Air travel is now a common feature of most of our elderly population's lives. There is little by way of warnings, rules or recommendations for our patients with psychiatric diagnoses, in particular dementia, who intend to travel by plane, in contrast to other specialties. In this article I highlight an adverse outcome of long-haul air travel as a result of delirium and resulting accelerated decline in overall cognitive function. I review literature related to the topic and suggest ways to minimise precipitating factors for stressors prior to and during flights. This article suggests that more thought should be given to the title question.

Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents.

Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl "A" ring and 4-phenyl "B" ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G2/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on ß-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.

Healable luminescent self-assembly supramolecular metallogels possessing lanthanide (Eu/Tb) dependent rheological and morphological properties.

Herein we present the use of lanthanide directed self-assembly formation (Ln(III) = Eu(III), Tb(III)) in the generation of luminescent supramolecular polymers, that when swelled with methanol give rise to self-healing supramolecular gels. These were analyzed by using luminescent and (1)H NMR titrations studies, allowing for the identification of the various species involved in the subsequent Ln(III)-gel formation. These highly luminescent gels could be mixed to give a variety of luminescent colors depending on their Eu(III):Tb(III) stoichiometric ratios. Imaging and rheological studies showed that these gels prepared using only Eu(III) or only Tb(III) have different morphological and rheological properties, that are also different from those determined upon forming gels by mixing of Eu(III) and Tb(III) gels. Hence, our results demonstrate for the first time the crucial role the lanthanide ions play in the supramolecular polymerization process, which is in principle a host-guest interaction, and consequently in the self-healing properties of the corresponding gels, which are dictated by the same host-guest interactions.