Myosin-Vb functions as a dynamic tether for peripheral endocytic compartments during transferrin trafficking

<p>Abstract</p> <p>Background</p> <p>Myosin-Vb has been shown to be involved in the recycling of diverse proteins in multiple cell types. Studies on transferrin trafficking in HeLa cells using a dominant-negative myosin-Vb tail fragment suggested that myosin-Vb was required for recycling from perinuclear compartments to the plasma membrane. However, chemical-genetic, dominant-negative experiments, in which myosin-Vb was specifically induced to bind to actin, suggested that the initial hypothesis was incorrect both in its site and mode of myosin-Vb action. Instead, the chemical-genetic data suggested that myosin-Vb functions in the actin-rich periphery as a dynamic tether on peripheral endosomes, retarding transferrin transport to perinuclear compartments.</p> <p>Results</p> <p>In this study, we employed both approaches, with the addition of overexpression of full-length wild-type myosin-Vb and switching the order of myosin-Vb inhibition and transferrin loading, to distinguish between these hypotheses. Overexpression of full-length myosin-Vb produced large peripheral endosomes. Chemical-genetic inhibition of myosin-Vb after loading with transferrin did not prevent movement of transferrin from perinuclear compartments; however, virtually all myosin-Vb-decorated particles, including those moving on microtubules, were halted by the inhibition. Overexpression of the myosin-Vb tail caused a less-peripheral distribution of early endosome antigen-1 (EEA1).</p> <p>Conclusion</p> <p>All results favored the peripheral dynamic tethering hypothesis.</p

Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases

Immune checkpoint inhibitors (ICIs) have resulted in improved outcomes in non-small cell lung cancer (NSCLC) patients. However, data demonstrating the efficacy of ICIs in NSCLC brain metastases (NSCLCBM) is limited. We analyzed overall survival (OS) in patients with NSCLCBM treated with ICIs within 90 days of NSCLCBM diagnosis (ICI-90) and compared them to patients who never received ICIs (no-ICI). We reviewed 800 patients with LCBM who were diagnosed between 2010 and 2019 at a major tertiary care institution, 97% of whom received stereotactic radiosurgery (SRS) for local treatment of BM. OS from BM was compared between the ICI-90 and no-ICI groups using the Log-Rank test and Cox proportional-hazards model. Additionally, the impact of KRAS mutational status on the efficacy of ICI was investigated. After accounting for known prognostic factors, ICI-90 in addition to SRS led to significantly improved OS compared to no-ICI (12.5 months vs 9.1, p \u3c 0.001). In the 109 patients who had both a known PD-L1 expression and KRAS status, 80.4% of patients with KRAS mutation had PD-L1 expression vs 61.9% in wild-type KRAS patients (p = 0.04). In patients without a KRAS mutation, there was no difference in OS between the ICI-90 vs no-ICI cohort with a one-year survival of 60.2% vs 54.8% (p = 0.84). However, in patients with a KRAS mutation, ICI-90 led to a one-year survival of 60.4% vs 34.1% (p = 0.004). Patients with NSCLCBM who received ICI-90 had improved OS compared to no-ICI patients. Additionally, this benefit appears to be observed primarily in patients with KRAS mutations that may drive the overall benefit, which should be taken into account in the development of future trials

A deep learning approach to photo–identification demonstrates high performance on two dozen cetacean species

We thank the countless individuals who collected and/or processed the nearly 85,000 images used in this study and those who assisted, particularly those who sorted these images from the millions that did not end up in the catalogues. Additionally, we thank the other Kaggle competitors who helped develop the ideas, models and data used here, particularly those who released their datasets to the public. The graduate assistantship for Philip T. Patton was funded by the NOAA Fisheries QUEST Fellowship. This paper represents HIMB and SOEST contribution numbers 1932 and 11679, respectively. The technical support and advanced computing resources from University of Hawaii Information Technology Services—Cyberinfrastructure, funded in part by the National Science Foundation CC* awards # 2201428 and # 2232862 are gratefully acknowledged. Every photo–identification image was collected under permits according to relevant national guidelines, regulation and legislation.Peer reviewedPublisher PD

Documenting Deforestation at Sidd al-Ahmar, Petra Region, Jordan

This study documented the decline of the forests of the Petra Region of Jordan, as represented at Sidd al-Ahmar, within the Petra Archaeological Park. Biogeographical and anthropological methods were employed to explore the history of the forests. Archaeology and historical narratives provided a portrait of the study area from prehistory to the early 20th century. Aerial surveys from 1924 and 2002 were analyzed to quantify changes in forest cover. Mapping and inventory of indicator species measured short-term change between 2003 and 2006. Interviews, field observation and participant observation in the tourist industry provided a socio-cultural context for quantitative analysis and for recommendations for remediation of pressures on the remaining forest. The research documents a 58% decline in tree cover between 1924-2002, and a decline of 4.23% between 2003-2006. The conclusions question concepts such as "landscape integrity" and the usefulness of non-interventionist ideology in an historic and rapidly changing region

A digital collection of rare and endangered lemurs and other primates from the Duke Lemur Center.

Scientific study of lemurs, a group of primates found only on Madagascar, is crucial for understanding primate evolution. Unfortunately, lemurs are among the most endangered animals in the world, so there is a strong impetus to maximize as much scientific data as possible from available physical specimens. MicroCT scanning efforts at Duke University have resulted in scans of more than 100 strepsirrhine cadavers representing 18 species from the Duke Lemur Center. An error study of the microCT scanner recovered less than 0.3% error at multiple resolution levels. Scans include specimen overviews and focused, high-resolution selections of complex anatomical regions (e.g., cranium, hands, feet). Scans have been uploaded to MorphoSource, an online digital repository for 3D data. As captive (but free ranging) individuals, these specimens have a wealth of associated information that is largely unavailable for wild populations, including detailed life history data. This digital collection maximizes the information obtained from rare and endangered animals with minimal degradation of the original specimens

The Clinical Resource Hub Initiative: First-Year Implementation of the Veterans Health Administration Regional Telehealth Contingency Staffing Program.

Health care systems face challenges providing accessible health care across geographically disparate sites. The Veterans Health Administration (VHA) developed regional telemedicine service focusing initially on primary care and mental health services. The objective of this study is to describe the program and progress during the early implementation. In its first year, the Clinical Resource Hub program provided 244 515 encounters to 95 684 Veterans at 475 sites. All 18 regions met or exceeded minimum implementation requirements. The regionally based telehealth contingency staffing hub met early implementation goals. Further evaluation to review sustainability and impact on provider experience and patient outcomes is needed

A hierarchy of needs for achieving impact in international research for development

[Extract] In developing countries, change in environmental and socio-economic systems is occurring at unprecedented rates, driven by rapid globalisation, technological advances, modernisation and increasingly unpredictable economic and environmental shocks (Leach 2008). As a consequence, there are growing concerns that conventional international development initiatives aiming to reduce poverty, conserve or sustainably use the environment and increase resilience, are becoming less effective. Recently, Ramalingam (2013) argued that aid programs’ established assumptions of linear, simple cause-and-effect relationships which have long guided interventions and their evaluation are no longer valid. Instead, he argues for a more ‘systemic, adaptive, networked, dynamic approach ... and a fundamental shift in the mental models, strategic approaches, organisational philosophies and performance approaches of foreign aid’ (Ramalingam 2013, p. 361)

A hierarchy of needs for achieving impact in international research for development

[Extract] In developing countries, change in environmental and socio-economic systems is occurring at unprecedented rates, driven by rapid globalisation, technological advances, modernisation and increasingly unpredictable economic and environmental shocks (Leach 2008). As a consequence, there are growing concerns that conventional international development initiatives aiming to reduce poverty, conserve or sustainably use the environment and increase resilience, are becoming less effective. Recently, Ramalingam (2013) argued that aid programs’ established assumptions of linear, simple cause-and-effect relationships which have long guided interventions and their evaluation are no longer valid. Instead, he argues for a more ‘systemic, adaptive, networked, dynamic approach ... and a fundamental shift in the mental models, strategic approaches, organisational philosophies and performance approaches of foreign aid’ (Ramalingam 2013, p. 361)

Sleep Latency and Post-Traumatic Stress Disorder Among Retired Career Florida Firefighters Evidence From the Advancing Epidemiology of Retired Firefighters Aging Longitudinally Cohort

ObjectiveOur objective was to estimate the association of post-traumatic stress disorder (PTSD) and sleep latency among retired firefighters.MethodsBaseline health survey data collected from retried career Florida firefighters participating in an ongoing prospective cohort study from 2017 to 2021 were analyzed. Risk for PTSD was assessed using a four-item primary care PTSD screening construct, and sleep onset latency was assessed by self-reported length of time to fall asleep.ResultsAmong the 500 participants, 8.0% screened positive for PTSD risk and 37.6% had prolonged sleep onset latency (>= 20 minutes to fall asleep). Retired firefighters with PTSD risk were 2.7 times more likely (adjusted odds ratio, 2.70; 95% confidence interval, 1.27-5.75) to have prolonged sleep latency compared with those without PTSD risk while controlling for covariates.ConclusionsRetired firefighters who screen positive for PTSD risk are three times more likely to report delayed sleep onset latency