A novel mode of capping protein-regulation by Twinfilin

Cellular actin assembly is controlled at the barbed ends of actin filaments, where capping protein (CP) limits polymerization. Twinfilin is a conserved in vivo binding partner of CP, yet the significance of this interaction has remained a mystery. Here, we discover that the C-terminal tail of Twinfilin harbors a CP-interacting (CPI) motif, identifying it as a novel CPI-motif protein. Twinfilin and the CPI-motif protein CARMIL have overlapping binding sites on CP. Further, Twinfilin binds competitively with CARMIL to CP, protecting CP from barbed-end displacement by CARMIL. Twinfilin also accelerates dissociation of the CP inhibitor V-1, restoring CP to an active capping state. Knockdowns of Twinfilin and CP each cause similar defects in cell morphology, and elevated Twinfilin expression rescues defects caused by CARMIL hyperactivity. Together, these observations define Twinfilin as the first \u27pro-capping\u27 ligand of CP and lead us to propose important revisions to our understanding of the CP regulatory cycle

Dicarbonyl­dichloridobis(trimethyl­phosphane)iron(II)–carbonyl­dichlorido­tris(trimethyl­phosphane)iron(II)–tetra­hydro­furan (1/1/2)

The asymmetric unit of the title crystal, [FeCl2(C3H9P)3(CO)]·[FeCl2(C3H9P)2(CO)2]·2C4H8O, contains half mol­ecules of the two closely related FeII complexes lying on mirror planes and a tetra­hydro­furan solvent mol­ecule, one C atom of which is disordered over two sets of sites with site occupancy factors 0.633 (9) and 0.367 (9). In both FeII complex mol­ecules, a distorted octa­hedral coordination geometry has been observed around the Fe atoms. Weak intermolecular C—H⋯O inter­actions are observed in the crystal structure

The effects of high dose interferon-β1a on plasma microparticles: Correlation with MRI parameters

<p>Abstract</p> <p>Objectives</p> <p>We previously reported a correlation between levels of microparticles carrying CD31 (PMP ^CD31+) and disease activity in MS. However, the effects of long term (12 month) treatment with high dose, high frequency interferon-β1a (Rebif™) on plasma levels of PMP^CD31+, PMP^CD146+, and PMP^CD54+and MRI measures of disease activity have not yet been assessed.</p> <p>Methods</p> <p>During this prospective 1-year study, we used flow cytometry to measure changes in plasma microparticles (PMP) bearing CD31 (PMP^CD31+), CD146 (PMP^CD146+), and CD54/ICAM-1 (PMP^CD54+) in 16 consecutive patients with relapsing-remitting MS (RRMS) before and after 3, 6, and 12 months of subcutaneous therapy with interferon-beta1a (44 micrograms, 3X weekly). At each visit, clinical exams and expanded disability status scale (EDSS) scores were recorded.</p> <p>Results</p> <p>Plasma levels of PMP^CD31+, and PMP^CD54+were significantly reduced by treatment with IFN-β1a. PMP^CD146+appeared to decrease only at 3 months and did not persist at 6 and 12 months (p = 0.0511). In addition, the decrease in plasma levels of PMP^CD31+and PMP^CD54+levels at 12 months were associated with a significant decrease in the number and volume of contrast enhancing T1-weigthed lesions.</p> <p>Conclusion</p> <p>Our data suggest that serial measurement of plasma microparticles (PMP), particularly in the initial stages of MS (when neuro-inflammatory cascades are more intense), may serve as reliable and reproducible surrogate markers of response to IFN-β1a therapy for MS. In addition, the progressive decline in plasma levels of PMP^CD31+and PMP^CD54+further supports the concept that IFN-β1a exerts stabilizing effect on the cerebral endothelial cells during pathogenesis of MS.</p

The Chest Pain Choice trial: a pilot randomized trial of a decision aid for patients with chest pain in the emergency department

Background: Chest pain is a common presenting complaint in the emergency department (ED). Despite the frequency with which clinicians evaluate patients with chest pain, accurately determining the risk of acute coronary syndrome (ACS) and sharing risk information with patients is challenging. The aims of this study are (1) to develop a decision aid (CHEST PAIN CHOICE) that communicates the short-term risk of ACS and (2) to evaluate the impact of the decision aid on patient participation in decision-making and resource use. Methods/Design: This is a protocol for a parallel, 2-arm randomized trial to compare an intervention group receiving CHEST PAIN CHOICE to a control group receiving usual ED care. Adults presenting to the Saint Mary's Hospital ED in Rochester, MN USA with a primary complaint of chest pain who are being considered for admission for prolonged ED observation in a specialized unit and urgent cardiac stress testing will be eligible for enrollment. We will measure the effect of CHEST PAIN CHOICE on six outcomes: (1) patient knowledge regarding their short-term risk for ACS and the risks of radiation exposure; (2) quality of the decision making process; (3) patient and clinician acceptability and satisfaction with the decision aid; (4) the proportion of patients who decided to undergo observation unit admission and urgent cardiac stress testing; (5) economic costs and healthcare utilization; and (6) the rate of delayed or missed ACS. To capture these outcomes, we will administer patient and clinician surveys after each visit, obtain video recordings of the clinical encounters, and conduct 30-day phone follow-up. Discussion: This pilot randomized trial will develop and evaluate a decision aid for use in ED chest pain patients at low risk for ACS and provide a preliminary estimate of its effect on patient participation in decision-making and resource use

Androgen-Regulated Expression of Arginase 1, Arginase 2 and Interleukin-8 in Human Prostate Cancer

BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed cancer in North American men. Androgen-deprivation therapy (ADT) accentuates the infiltration of immune cells within the prostate. However, the immunosuppressive pathways regulated by androgens in PCa are not well characterized. Arginase 2 (ARG2) expression by PCa cells leads to a reduced activation of tumor-specific T cells. Our hypothesis was that androgens could regulate the expression of ARG2 by PCa cells. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we demonstrate that both ARG1 and ARG2 are expressed by hormone-sensitive (HS) and hormone-refractory (HR) PCa cell lines, with the LNCaP cells having the highest arginase activity. In prostate tissue samples, ARG2 was more expressed in normal and non-malignant prostatic tissues compared to tumor tissues. Following androgen stimulation of LNCaP cells with 10 nM R1881, both ARG1 and ARG2 were overexpressed. The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. Patients treated by ADT prior to surgery had lower ARG2 expression in both non-malignant and malignant tissues. Furthermore, ARG1 and ARG2 were enzymatically active and their decreased expression by siRNA resulted in reduced overall arginase activity and l-arginine metabolism. The decreased ARG1 and ARG2 expression also translated with diminished LNCaP cells cell growth and increased PBMC activation following exposure to LNCaP cells conditioned media. Finally, we found that interleukin-8 (IL-8) was also upregulated following androgen stimulation and that it directly increased the expression of ARG1 and ARG2 in the absence of androgens. CONCLUSION/SIGNIFICANCE: Our data provides the first detailed in vitro and in vivo account of an androgen-regulated immunosuppressive pathway in human PCa through the expression of ARG1, ARG2 and IL-8

The status of the world's land and marine mammals: diversity, threat, and knowledge

Knowledge of mammalian diversity is still surprisingly disparate, both regionally and taxonomically. Here, we present a comprehensive assessment of the conservation status and distribution of the world's mammals. Data, compiled by 1700+ experts, cover all 5487 species, including marine mammals. Global macroecological patterns are very different for land and marine species but suggest common mechanisms driving diversity and endemism across systems. Compared with land species, threat levels are higher among marine mammals, driven by different processes (accidental mortality and pollution, rather than habitat loss), and are spatially distinct (peaking in northern oceans, rather than in Southeast Asia). Marine mammals are also disproportionately poorly known. These data are made freely available to support further scientific developments and conservation action

Predicting At-Risk Opioid Use Three Months After Ed Visit for Trauma: Results from the AURORA Study

OBJECTIVE: Whether short-term, low-potency opioid prescriptions for acute pain lead to future at-risk opioid use remains controversial and inadequately characterized. Our objective was to measure the association between emergency department (ED) opioid analgesic exposure after a physical, trauma-related event and subsequent opioid use. We hypothesized ED opioid analgesic exposure is associated with subsequent at-risk opioid use. METHODS: Participants were enrolled in AURORA, a prospective cohort study of adult patients in 29 U.S., urban EDs receiving care for a traumatic event. Exclusion criteria were hospital admission, persons reporting any non-medical opioid use (e.g., opioids without prescription or taking more than prescribed for euphoria) in the 30 days before enrollment, and missing or incomplete data regarding opioid exposure or pain. We used multivariable logistic regression to assess the relationship between ED opioid exposure and at-risk opioid use, defined as any self-reported non-medical opioid use after initial ED encounter or prescription opioid use at 3-months. RESULTS: Of 1441 subjects completing 3-month follow-up, 872 participants were included for analysis. At-risk opioid use occurred within 3 months in 33/620 (5.3%, CI: 3.7,7.4) participants without ED opioid analgesic exposure; 4/16 (25.0%, CI: 8.3, 52.6) with ED opioid prescription only; 17/146 (11.6%, CI: 7.1, 18.3) with ED opioid administration only; 12/90 (13.3%, CI: 7.4, 22.5) with both. Controlling for clinical factors, adjusted odds ratios (aORs) for at-risk opioid use after ED opioid exposure were: ED prescription only: 4.9 (95% CI 1.4, 17.4); ED administration for analgesia only: 2.0 (CI 1.0, 3.8); both: 2.8 (CI 1.2, 6.5). CONCLUSIONS: ED opioids were associated with subsequent at-risk opioid use within three months in a geographically diverse cohort of adult trauma patients. This supports need for prospective studies focused on the long-term consequences of ED opioid analgesic exposure to estimate individual risk and guide therapeutic decision-making

Capacity assessment and spatial analysis of cervical cancer services in The Gambia

Abstract Background Cervical cancer is the most common cancer and the leading cause of cancer-related death in Gambian women. The Gambian Ministry of Health is striving to improve access to screening, diagnostic, and treatment services for cervical cancer, but comprehensive data on currently available services is limited making it challenging to appropriately prioritize the ideal next steps for expanding care. This study aims to describe the current services available for the prevention, screening, and treatment of cervical cancer in The Gambia and provide suggestions for expanding geographic access to care. Methods A survey aimed at assessing the availability of key cervical cancer-related services was developed and then administered in person by research assistants to all secondary and tertiary health facilities (HFs) in The Gambia. ArcGIS Pro Software and 2020 LandScan population density raster were used to visualize and quantify geographic access to care. Survey results were compared with published targets outlined by the Gambian Ministry of Health in the “Strategic Plan for the Prevention and Control of Cervical Cancer in The Gambia: 2016–2020.” Results One hundred and two HFs were surveyed including 12 hospitals, 3 major health centers, 56 minor health centers, and 31 medical centers/clinics. Seventy-eight of these HFs provided some form of cervical cancer-related service. HPV vaccination was available in all health regions. Two-thirds of the population lived within 10 km of a HF that offered screening for cervical cancer and half lived within 10 km of a HF that offered treatment for precancerous lesions. Ten HFs offered hysterectomy, but nine were located in the same region. Two HFs offered limited chemotherapy. Radiotherapy was not available. If all major health centers and hospitals started offering visual inspection with acetic acid and cryotherapy, 86.1% of the population would live within 25 km of a HF with both services. Conclusions Geographic access to cervical cancer screening, and precancer treatment is relatively widespread across The Gambia, but targeted expansion in line with the country’s “Strategic Plan” would improve access for central and eastern Gambia. The availability of treatment services for invasive cancer is limited, and establishing radiotherapy in the country should continue to be prioritized