Budding yeast Rif1 binds to replication origins and protects DNA at blocked replication forks.

Despite its evolutionarily conserved function in controlling DNA replication, the chromosomal binding sites of the budding yeast Rif1 protein are not well understood. Here, we analyse genome-wide binding of budding yeast Rif1 by chromatin immunoprecipitation, during G1 phase and in S phase with replication progressing normally or blocked by hydroxyurea. Rif1 associates strongly with telomeres through interaction with Rap1. By comparing genomic binding of wild-type Rif1 and truncated Rif1 lacking the Rap1-interaction domain, we identify hundreds of Rap1-dependent and Rap1-independent chromosome interaction sites. Rif1 binds to centromeres, highly transcribed genes and replication origins in a Rap1-independent manner, associating with both early and late-initiating origins. Interestingly, Rif1 also binds around activated origins when replication progression is blocked by hydroxyurea, suggesting association with blocked forks. Using nascent DNA labelling and DNA combing techniques, we find that in cells treated with hydroxyurea, yeast Rif1 stabilises recently synthesised DNA Our results indicate that, in addition to controlling DNA replication initiation, budding yeast Rif1 plays an ongoing role after initiation and controls events at blocked replication forks.

Rif1 acts through Protein Phosphatase 1 but independent of replication timing to suppress telomere extension in budding yeast.

The Rif1 protein negatively regulates telomeric TG repeat length in the budding yeast Saccharomyces cerevisiae, but how it prevents telomere over-extension is unknown. Rif1 was recently shown to control DNA replication by acting as a Protein Phosphatase 1 (PP1)-targeting subunit. Therefore, we investigated whether Rif1 controls telomere length by targeting PP1 activity. We find that a Rif1 mutant defective for PP1 interaction causes a long-telomere phenotype, similar to that of rif1Δ cells. Tethering PP1 at a specific telomere partially substitutes for Rif1 in limiting TG repeat length, confirming the importance of PP1 in telomere length control. Ablating Rif1-PP1 interaction is known to cause precocious activation of telomere-proximal replication origins and aberrantly early telomere replication. However, we find that Rif1 still limits telomere length even if late replication is forced through deletion of nearby replication origins, indicating that Rif1 can control telomere length independent of replication timing. Moreover we find that, even at a de novo telomere created after DNA synthesis during a mitotic block, Rif1-PP1 interaction is required to suppress telomere lengthening and prevent inappropriate recruitment of Tel1 kinase. Overall, our results show that Rif1 controls telomere length by recruiting PP1 to directly suppress telomerase-mediated TG repeat lengthening.

GenPhilly: a strategy for improving the sustainability of aging in community initiatives.

GenPhilly is an innovative, replicable model that was developed in Philadelphia, Pennsylvania, to inspire and engage emerging leaders from a variety of disciplines to promote and sustain an aging-in-community agenda. Administrative support is provided by the Area Agency on Aging, Philadelphia Corporation for Aging, yet it was designed by its members to be peer-led. In this way, young professionals in their 20s and 30s can capitalize on popular culture to create unique professional development opportunities and get younger generations thinking about the type of city in which they themselves want to get older. The group has benefited the field of aging by building awareness of aging services in the wider community; facilitating cross-disciplinary learning and innovation around aging issues; stressing the competitive advantage for emerging leaders from all fields to know about aging issues; strengthening the aging network workforce; breaking down stereotypes about working with older adults; and introducing expertise from outside the aging network to benefit older adults. Encouraging the development of similar groups will not only benefit the field of aging, it will assist the next generation of leaders in many fields to plan better for their communities and for themselves.

Building an integrated research/policy planning age-friendly agenda.

This article describes an innovative model for integrating research into a policy and planning agenda aimed to help neighborhoods become more supportive of older adults. Philadelphia Corporation for Aging (PCA) established Age-Friendly Philadelphia (AFP) to catalyze efforts to improve the physical and social environments for seniors. The Research Program at PCA became an important part of this effort by providing multiple types of supports to PCA staff and other stakeholders. Most notably, the research program worked with planners to adopt the United States Environmental Protection Agency's Aging Initiative model for Philadelphia. That model focuses on (1) staying active, connected, and engaged; (2) development and housing; (3) transportation and mobility; and (4) staying healthy. Examples of practice efforts actualized using this research are also presented. By developing a new approach to the way research can support practice initiatives, AFP has been able to increase its effectiveness, and researchers have found better ways to work collaboratively with professionals in policy, planning, and practice. The PCA model should be considered as a framework for similar efforts aimed at creating age-friendly communities.

Semaglutide, A Long-Acting GLP-1 Analogue, for the Management of Early Onset Obesity due to MC4R defect - A Case Report.

INTRODUCTION: Childhood obesity is a global concern and has both nutritional and genetic causative factors. One of the most common monogenic causes of obesity is heterozygous mutations in the Melanocortin 4 receptor (MC4R), which are found in 5.7% to 8.6% of individuals with early-onset obesity. We report, the effect of Semaglutide, a long-acting Glucagon like peptide (GLP1) analogue, in the treatment of severe obesity in an adolescent boy with a heterozygous mutation in MC4R. CASE PRESENTATION: A 13-year-old boy with a history of excessive weight gain since infancy was referred to the specialised weight management team. He was born at full-term with a birth weight of 3.57kg (50th centile), but his weight consistently exceeded the 99.6th percentile after the age of one year. At the age of five years, he was diagnosed with autism spectrum disorder (ASD). Diagnostic investigations revealed insulin resistance, and dyslipidaemia, while genetic testing confirmed a heterozygous mutation in MC4R (E61K), inherited from his mother. Managing his condition was challenging due to his rapid weight gain, needle phobia, and behavioural difficulties. Despite intense multidisciplinary lifestyle interventions, he continued to gain weight, reaching a peak weight of 187.5kg [+16.65 standard deviation score (SDS)], body mass index (BMI) of 56.9kg/m2 (+4.19 SDS), body fat 63.9%] at the age of 13 years. Due to severe ASD and needle phobia, he was not keen on daily GLP-1 injections. He was commenced on Semaglutide subcutaneous injection at a dose of 0.25mg weekly, gradually increasing to the maximum dose of 1mg weekly. Over the course of 12 weeks, his BMI decreased to 52.2kg/m2 (+4.08SDS) and weight dropped to 176.8kg (+14.76SDS, body fat: 52.7%). At the 3-month and 12-month reviews post treatment, he achieved weight loss of 5.7% and 11% respectively. Quality of life questionnaire (QoL) showed improved scores from 35.95 to 60.36 at 12-month review indicating enhanced well-being. The CGM (continuous glucose monitor) demonstrated an improvement in TIR (time in range). CONCLUSION: Semaglutide, is approved by the FDA for weight management in adolescents aged 12 years and above in December 2022. A recent case series underscored the benefits of therapy with Liraglutide, a short-acting GLP-1 analogue, in rare genetic cases of early-onset obesity. To our knowledge, this is the first case report to highlight the efficacy and safety of Semaglutide in an adolescent with heterozygous MC4R mutation. Semaglutide could be a potential treatment option for monogenic obesity and will benefit from further research.

Application Experiences on a GPU-Accelerated Arm-based HPC Testbed.

This paper assesses and reports the experience of ten teams working to port, validate, and benchmark several High Performance Computing applications on a novel GPU-accelerated Arm testbed system. The testbed consists of eight NVIDIA Arm HPC Developer Kit systems, each one equipped with a server-class Arm CPU from Ampere Computing and two data center GPUs from NVIDIA Corp. The systems are connected together using InfiniBand interconnect. The selected applications and mini-apps are written using several programming languages and use multiple accelerator-based programming models for GPUs such as CUDA, OpenACC, and OpenMP offloading. Working on application porting requires a robust and easy-to-access programming environment, including a variety of compilers and optimized scientific libraries. The goal of this work is to evaluate platform readiness and assess the effort required from developers to deploy well-established scientific workloads on current and future generation Arm-based GPU-accelerated HPC systems. The reported case studies demonstrate that the current level of maturity and diversity of software and tools is already adequate for large-scale production deployments.

Deposits, flow characteristics, and landscape change resulting from the September 2009 South Pacific tsunami in the Samoan islands.

The September 29th 2009 tsunami caused widespread coastal modification within the islands of Samoa and northern Tonga in the South Pacific. Preliminary measurements indicate maximum runup values of around 17 m (Okal et al., 2010) and shore-normal inundation distances of up to ~ 620 m (Jaffe et al., 2010). Geological field reconnaissance studies were conducted as part of an UNESCO-IOC International Tsunami Survey Team survey within three weeks of the event in order to document the erosion, transport, and deposition of sediment by the tsunami. Data collected included: a) general morphology and geological characteristics of the coast, b) evidence of tsunami flow (inundation, flow depth and direction, wave height and runup), c) surficial and subsurface sediment samples including deposit thickness and extent, d) topographic mapping, and e) boulder size and location measurements. Four main types of sedimentary deposits were identified: a) gravel fields consisting mostly of isolated cobbles and boulders, b) sand sheets from a few to ~ 25 cm thick, c) piles of organic (mostly vegetation) and man-made material forming debris ramparts, and d) surface mud deposits that settled from suspension from standing water in the tsunami aftermath. Tsunami deposits within the reef system were not widespread, however, surficial changes to the reefs were observed.

Complex multifault rupture during the 2016 Mw 7.8 Kaikoura earthquake, New Zealand.

On 14 November 2016, northeastern South Island of New Zealand was struck by a major moment magnitude (Mw) 7.8 earthquake. Field observations, in conjunction with interferometric synthetic aperture radar, Global Positioning System, and seismology data, reveal this to be one of the most complex earthquakes ever recorded. The rupture propagated northward for more than 170 kilometers along both mapped and unmapped faults before continuing offshore at the island's northeastern extent. Geodetic and field observations reveal surface ruptures along at least 12 major faults, including possible slip along the southern Hikurangi subduction interface; extensive uplift along much of the coastline; and widespread anelastic deformation, including the ~8-meter uplift of a fault-bounded block. This complex earthquake defies many conventional assumptions about the degree to which earthquake ruptures are controlled by fault segmentation and should motivate reevaluation of these issues in seismic hazard models.

Interplay between nonsense-mediated mRNA decay and DNA damage response pathways reveals that Stn1 and Ten1 are the key CST telomere-cap components.

A large and diverse set of proteins, including CST complex, nonsense mediated decay (NMD), and DNA damage response (DDR) proteins, play important roles at the telomere in mammals and yeast. Here, we report that NMD, like the DDR, affects single-stranded DNA (ssDNA) production at uncapped telomeres. Remarkably, we find that the requirement for Cdc13, one of the components of CST, can be efficiently bypassed when aspects of DDR and NMD pathways are inactivated. However, identical genetic interventions do not bypass the need for Stn1 and Ten1, the partners of Cdc13. We show that disabling NMD alters the stoichiometry of CST components at telomeres and permits Stn1 to bind telomeres in the absence of Cdc13. Our data support a model that Stn1 and Ten1 can function in a Cdc13-independent manner and have implications for the function of CST components across eukaryotes.

Major earthquakes occur regularly on an isolated plate boundary fault.

The scarcity of long geological records of major earthquakes, on different types of faults, makes testing hypotheses of regular versus random or clustered earthquake recurrence behavior difficult. We provide a fault-proximal major earthquake record spanning 8000 years on the strike-slip Alpine Fault in New Zealand. Cyclic stratigraphy at Hokuri Creek suggests that the fault ruptured to the surface 24 times, and event ages yield a 0.33 coefficient of variation in recurrence interval. We associate this near-regular earthquake recurrence with a geometrically simple strike-slip fault, with high slip rate, accommodating a high proportion of plate boundary motion that works in isolation from other faults. We propose that it is valid to apply time-dependent earthquake recurrence models for seismic hazard estimation to similar faults worldwide.

A pain in the neck.

A 21-year-old man presented to the emergency department with pain and swelling to the right side of his neck and chest wall with associated shortness of breath. Two days earlier, while playing football, he had been involved in a minor collision with another player where he was struck on the right side of his head, but had managed to continue playing. On examination, the patient had extensive cervical surgical emphysema. There were no further positive findings on respiratory and general examination. A chest x-ray demonstrated no rib or clavicular fractures and no pneumothorax. Therefore, a CT was undertaken to ascertain the cause of the surgical emphysema. This demonstrated a pneumomediastinum, pneumopericardium and extradural air in the spinal column in addition to the subcutaneous air. The CT identified no bony trauma and no other injuries. The symptoms resolved spontaneously and follow-up radiography, 9 days later, showed no residual air.