Rapid Depletion of Target Proteins Allows Identification of Coincident Physiological Responses

Targeted protein degradation is a powerful tool that can be used to create unique physiologies depleted of important factors. Current strategies involve modifying a gene of interest such that a degradation peptide is added to an expressed target protein and then conditionally activating proteolysis, either by expressing adapters, unmasking cryptic recognition determinants, or regulating protease affinities using small molecules. For each target, substantial optimization may be required to achieve a practical depletion, in that the target remains present at a normal level prior to induction and is then rapidly depleted to levels low enough to manifest a physiological response. Here, we describe a simplified targeted degradation system that rapidly depletes targets and that can be applied to a wide variety of proteins without optimizing target protease affinities. The depletion of the target is rapid enough that a primary physiological response manifests that is related to the function of the target. Using ribosomal protein Si as an example, we show that the rapid depletion of this essential translation factor invokes concomitant changes to the levels of several mRNAs, even before appreciable cell division has occurred

Efficacy and cost-effectiveness of an outcall program to reduce carer burden and depression among carers of cancer patients (PROTECT) : rationale and design of a randomized controlled trial

Published: 6 January 2014BACKGROUND: Carers provide extended and often unrecognized support to people with cancer. The aim of this study is to test the hypothesis that excessive carer burden is modifiable through a telephone outcall intervention that includes supportive care, information and referral to appropriate psycho-social services. Secondary aims include estimation of changes in psychological health and quality of life. The study will determine whether the intervention reduces unmet needs among patient dyads. A formal economic program will also be conducted. METHODS/DESIGN: This study is a single-blind, multi-centre, randomized controlled trial to determine the efficacy and cost-efficacy of a telephone outcall program among carers of newly diagnosed cancer patients. A total of 230 carer/patient dyads will be recruited into the study; following written consent, carers will be randomly allocated to either the outcall intervention program (n = 115) or to a minimal outcall / attention control service (n = 115). Carer assessments will occur at baseline, at one and six months post-intervention. The primary outcome is change in carer burden; the secondary outcomes are change in carer depression, quality of life, health literacy and unmet needs. The trial patients will be assessed at baseline and one month post-intervention to determine depression levels and unmet needs. The economic analysis will include perspectives of both the health care sector and broader society and comprise a cost-consequences analysis where all outcomes will be compared to costs. DISCUSSION: This study will contribute to our understanding on the potential impact of a telephone outcall program on carer burden and provide new evidence on an approach for improving the wellbeing of carers.Patricia M Livingston, Richard H Osborne, Mari Botti, Cathy Mihalopoulos, Sean McGuigan, Leila Heckel, Kate Gunn, Jacquie Chirgwin, David M Ashley and Melinda William

The Vehicle, Spring 1974

Table of Contents PhotoJim Painterpage 1 Six Poems of the LandRay Schmuddepage 5 At Last to Find FreedomJann Briesacherpage 7 The Last IrisMarjorie Thoelepage 9 (Untitled)Melinda E. Recordpage 10 MenJan Schroederpage 10 ImpressionsJudy Bardpage 11 ScaredAnita Surpage 11 Loved and LostJan Schroederpage 12 Dripped-Over WaxAnita Surpage 13 The Crowded RoomWilliam E. Uteschpage 14 A River in IllinoisJames Jonespage 14 Sneeze SeasonDarlene A. Moorepage 14 ChangesMark Chianakaspage 15 PhotoJim Painterpage 16 Wedding VowsJann Briesacherpage 17 PhotoJim Painterpage 18 PhotoJim Painterpage 19 PhotoJim Painterpage 20 PhotoJim Painterpage 21 PhotoJim Painterpage 22 PhotoLarry Smyserpage 23 From Outside ColoradoRay Schmuddepage 24 Dairy QueenGayle Gleichmanpage 26 With Sunstreaks in our HairNancy Broom Brownpage 33 PhotoJim Painterpage 34 Water\u27s EdgeMarjorie Thoelepage 35 My 665th Illusion of SanityGordon Glessnerpage 36 Is it my turn to do the laundry again??? Jann Briesacherpage 38 TV Teachingbobbdoddpage 39 GuidanceWendy Diane Wielandpage 40 PhotoJim Painterpage 41 RaindropsJane Ann Beerspage 42 WaitingJan Schroederpage 42 To JonJudy Bardpage 43 One Autumn Day in 1971E. Christmanpage 43 More Surely Than Picture AlbumsMarjorie Thoelepage 44 WingspanningNancy Broom Brownpage 45 ReligionMelinda E. Recordpage 45 Rosalie StevensonMark Holleypage 46 PhotoJim Painterpage 47 WhiteShirley A. Rardinpage 48 The Beginning of a Perfect DayShirley A. Rardinpage 49 PhotoMichael Chenpage 50 Rosethorn Wall of June 17bobbdoddpage 51 ManJan Schroederpage 51 HaikuJudy Bardpage 51 You know it leaves me emptyJames Osbornepage 52 For JesseJames Osbornepage 52 EndingsMark Chianakaspage 53 ConfusionGary L. Owenspage 53 PhotoMichael Chenpage 54 PoemsJann Briesacherpage 54 Journey of just oneNancy Broom Brownpage 55 Blackbirds in IllinoisJames Jonespage 56 PoemsJann Briesacherpage 56 PhotoMichael Chenpage 57 I am a poemDarlene A. Moorepage 57 A Glimpse of ParadiseJann Briesacherpage 57 PhotoJim Painterpage 58 PoemSheila Marie Foorpage 59 In my windowBarbara S. Meyerpage 59 Section 4., Draft 3bobbdoddpage 60 PhotoJim Painterpage 61 PoemJann Briesacherpage 61 PhotoGary Deanpage 62 I amWilliam E. Uteschpage 62 To a tank-car in IllinoisJames Jonespage 63 PoemJane Ann Beerspage 63 PoemsJann Briesacherpage 63 Editor\u27s Pagepage 64https://thekeep.eiu.edu/vehicle/1031/thumbnail.jp

The Vehicle, Spring 1974

Table of Contents PhotoJim Painterpage 1 Six Poems of the LandRay Schmuddepage 5 At Last to Find FreedomJann Briesacherpage 7 The Last IrisMarjorie Thoelepage 9 (Untitled)Melinda E. Recordpage 10 MenJan Schroederpage 10 ImpressionsJudy Bardpage 11 ScaredAnita Surpage 11 Loved and LostJan Schroederpage 12 Dripped-Over WaxAnita Surpage 13 The Crowded RoomWilliam E. Uteschpage 14 A River in IllinoisJames Jonespage 14 Sneeze SeasonDarlene A. Moorepage 14 ChangesMark Chianakaspage 15 PhotoJim Painterpage 16 Wedding VowsJann Briesacherpage 17 PhotoJim Painterpage 18 PhotoJim Painterpage 19 PhotoJim Painterpage 20 PhotoJim Painterpage 21 PhotoJim Painterpage 22 PhotoLarry Smyserpage 23 From Outside ColoradoRay Schmuddepage 24 Dairy QueenGayle Gleichmanpage 26 With Sunstreaks in our HairNancy Broom Brownpage 33 PhotoJim Painterpage 34 Water\u27s EdgeMarjorie Thoelepage 35 My 665th Illusion of SanityGordon Glessnerpage 36 Is it my turn to do the laundry again??? Jann Briesacherpage 38 TV Teachingbobbdoddpage 39 GuidanceWendy Diane Wielandpage 40 PhotoJim Painterpage 41 RaindropsJane Ann Beerspage 42 WaitingJan Schroederpage 42 To JonJudy Bardpage 43 One Autumn Day in 1971E. Christmanpage 43 More Surely Than Picture AlbumsMarjorie Thoelepage 44 WingspanningNancy Broom Brownpage 45 ReligionMelinda E. Recordpage 45 Rosalie StevensonMark Holleypage 46 PhotoJim Painterpage 47 WhiteShirley A. Rardinpage 48 The Beginning of a Perfect DayShirley A. Rardinpage 49 PhotoMichael Chenpage 50 Rosethorn Wall of June 17bobbdoddpage 51 ManJan Schroederpage 51 HaikuJudy Bardpage 51 You know it leaves me emptyJames Osbornepage 52 For JesseJames Osbornepage 52 EndingsMark Chianakaspage 53 ConfusionGary L. Owenspage 53 PhotoMichael Chenpage 54 PoemsJann Briesacherpage 54 Journey of just oneNancy Broom Brownpage 55 Blackbirds in IllinoisJames Jonespage 56 PoemsJann Briesacherpage 56 PhotoMichael Chenpage 57 I am a poemDarlene A. Moorepage 57 A Glimpse of ParadiseJann Briesacherpage 57 PhotoJim Painterpage 58 PoemSheila Marie Foorpage 59 In my windowBarbara S. Meyerpage 59 Section 4., Draft 3bobbdoddpage 60 PhotoJim Painterpage 61 PoemJann Briesacherpage 61 PhotoGary Deanpage 62 I amWilliam E. Uteschpage 62 To a tank-car in IllinoisJames Jonespage 63 PoemJane Ann Beerspage 63 PoemsJann Briesacherpage 63 Editor\u27s Pagepage 64https://thekeep.eiu.edu/vehicle/1031/thumbnail.jp

Role of pathogenic oral flora in postoperative pneumonia following brain surgery

<p>Abstract</p> <p>Background</p> <p>Post-operative pulmonary infection often appears to result from aspiration of pathogens colonizing the oral cavity. It was hypothesized that impaired periodontal status and pathogenic oral bacteria significantly contribute to development of aspiration pneumonia following neurosurgical operations. Further, the prophylactic effects of a single dose preoperative cefazolin on the oral bacteria were investigated.</p> <p>Methods</p> <p>A matched cohort of 18 patients without postoperative lung complications was compared to 5 patients who developed pneumonia within 48 hours after brain surgery. Patients waiting for elective operation of a single brain tumor underwent dental examination and saliva collection before surgery. Bacteria from saliva cultures were isolated and periodontal disease was scored according to type and severity. Patients received 15 mg/kg cefazolin intravenously at the beginning of surgery. Serum, saliva and bronchial secretion were collected promptly after the operation. The minimal inhibitory concentrations of cefazolin regarding the isolated bacteria were determined. The actual antibiotic concentrations in serum, saliva and bronchial secretion were measured by capillary electrophoresis upon completion of surgery. Bacteria were isolated again from the sputum of postoperative pneumonia patients.</p> <p>Results</p> <p>The number and severity of coexisting periodontal diseases were significantly greater in patients with postoperative pneumonia in comparison to the control group (p = 0.031 and p = 0.002, respectively). The relative risk of developing postoperative pneumonia in high periodontal score patients was 3.5 greater than in patients who had low periodontal score (p < 0.0001). Cefazolin concentration in saliva and bronchial secretion remained below detectable levels in every patient.</p> <p>Conclusion</p> <p>Presence of multiple periodontal diseases and pathogenic bacteria in the saliva are important predisposing factors of postoperative aspiration pneumonia in patients after brain surgery. The low penetration rate of cefazolin into the saliva indicates that its prophylactic administration may not be sufficient to prevent postoperative aspiration pneumonia. Our study suggests that dental examination may be warranted in order to identify patients at high risk of developing postoperative respiratory infections.</p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Correction for Johansson et al., An open challenge to advance probabilistic forecasting for dengue epidemics.

Correction for “An open challenge to advance probabilistic forecasting for dengue epidemics,” by Michael A. Johansson, Karyn M. Apfeldorf, Scott Dobson, Jason Devita, Anna L. Buczak, Benjamin Baugher, Linda J. Moniz, Thomas Bagley, Steven M. Babin, Erhan Guven, Teresa K. Yamana, Jeffrey Shaman, Terry Moschou, Nick Lothian, Aaron Lane, Grant Osborne, Gao Jiang, Logan C. Brooks, David C. Farrow, Sangwon Hyun, Ryan J. Tibshirani, Roni Rosenfeld, Justin Lessler, Nicholas G. Reich, Derek A. T. Cummings, Stephen A. Lauer, Sean M. Moore, Hannah E. Clapham, Rachel Lowe, Trevor C. Bailey, Markel García-Díez, Marilia Sá Carvalho, Xavier Rodó, Tridip Sardar, Richard Paul, Evan L. Ray, Krzysztof Sakrejda, Alexandria C. Brown, Xi Meng, Osonde Osoba, Raffaele Vardavas, David Manheim, Melinda Moore, Dhananjai M. Rao, Travis C. Porco, Sarah Ackley, Fengchen Liu, Lee Worden, Matteo Convertino, Yang Liu, Abraham Reddy, Eloy Ortiz, Jorge Rivero, Humberto Brito, Alicia Juarrero, Leah R. Johnson, Robert B. Gramacy, Jeremy M. Cohen, Erin A. Mordecai, Courtney C. Murdock, Jason R. Rohr, Sadie J. Ryan, Anna M. Stewart-Ibarra, Daniel P. Weikel, Antarpreet Jutla, Rakibul Khan, Marissa Poultney, Rita R. Colwell, Brenda Rivera-García, Christopher M. Barker, Jesse E. Bell, Matthew Biggerstaff, David Swerdlow, Luis Mier-y-Teran-Romero, Brett M. Forshey, Juli Trtanj, Jason Asher, Matt Clay, Harold S. Margolis, Andrew M. Hebbeler, Dylan George, and Jean-Paul Chretien, which was first published November 11, 2019; 10.1073/pnas.1909865116. The authors note that the affiliation for Xavier Rodó should instead appear as Catalan Institution for Research and Advanced Studies (ICREA) and Climate and Health Program, Barcelona Institute for Global Health (ISGlobal). The corrected author and affiliation lines appear below. The online version has been corrected

State of the climate in 2018

In 2018, the dominant greenhouse gases released into Earth’s atmosphere—carbon dioxide, methane, and nitrous oxide—continued their increase. The annual global average carbon dioxide concentration at Earth’s surface was 407.4 ± 0.1 ppm, the highest in the modern instrumental record and in ice core records dating back 800 000 years. Combined, greenhouse gases and several halogenated gases contribute just over 3 W m−2 to radiative forcing and represent a nearly 43% increase since 1990. Carbon dioxide is responsible for about 65% of this radiative forcing. With a weak La Niña in early 2018 transitioning to a weak El Niño by the year’s end, the global surface (land and ocean) temperature was the fourth highest on record, with only 2015 through 2017 being warmer. Several European countries reported record high annual temperatures. There were also more high, and fewer low, temperature extremes than in nearly all of the 68-year extremes record. Madagascar recorded a record daily temperature of 40.5°C in Morondava in March, while South Korea set its record high of 41.0°C in August in Hongcheon. Nawabshah, Pakistan, recorded its highest temperature of 50.2°C, which may be a new daily world record for April. Globally, the annual lower troposphere temperature was third to seventh highest, depending on the dataset analyzed. The lower stratospheric temperature was approximately fifth lowest. The 2018 Arctic land surface temperature was 1.2°C above the 1981–2010 average, tying for third highest in the 118-year record, following 2016 and 2017. June’s Arctic snow cover extent was almost half of what it was 35 years ago. Across Greenland, however, regional summer temperatures were generally below or near average. Additionally, a satellite survey of 47 glaciers in Greenland indicated a net increase in area for the first time since records began in 1999. Increasing permafrost temperatures were reported at most observation sites in the Arctic, with the overall increase of 0.1°–0.2°C between 2017 and 2018 being comparable to the highest rate of warming ever observed in the region. On 17 March, Arctic sea ice extent marked the second smallest annual maximum in the 38-year record, larger than only 2017. The minimum extent in 2018 was reached on 19 September and again on 23 September, tying 2008 and 2010 for the sixth lowest extent on record. The 23 September date tied 1997 as the latest sea ice minimum date on record. First-year ice now dominates the ice cover, comprising 77% of the March 2018 ice pack compared to 55% during the 1980s. Because thinner, younger ice is more vulnerable to melting out in summer, this shift in sea ice age has contributed to the decreasing trend in minimum ice extent. Regionally, Bering Sea ice extent was at record lows for almost the entire 2017/18 ice season. For the Antarctic continent as a whole, 2018 was warmer than average. On the highest points of the Antarctic Plateau, the automatic weather station Relay (74°S) broke or tied six monthly temperature records throughout the year, with August breaking its record by nearly 8°C. However, cool conditions in the western Bellingshausen Sea and Amundsen Sea sector contributed to a low melt season overall for 2017/18. High SSTs contributed to low summer sea ice extent in the Ross and Weddell Seas in 2018, underpinning the second lowest Antarctic summer minimum sea ice extent on record. Despite conducive conditions for its formation, the ozone hole at its maximum extent in September was near the 2000–18 mean, likely due to an ongoing slow decline in stratospheric chlorine monoxide concentration. Across the oceans, globally averaged SST decreased slightly since the record El Niño year of 2016 but was still far above the climatological mean. On average, SST is increasing at a rate of 0.10° ± 0.01°C decade−1 since 1950. The warming appeared largest in the tropical Indian Ocean and smallest in the North Pacific. The deeper ocean continues to warm year after year. For the seventh consecutive year, global annual mean sea level became the highest in the 26-year record, rising to 81 mm above the 1993 average. As anticipated in a warming climate, the hydrological cycle over the ocean is accelerating: dry regions are becoming drier and wet regions rainier. Closer to the equator, 95 named tropical storms were observed during 2018, well above the 1981–2010 average of 82. Eleven tropical cyclones reached Saffir–Simpson scale Category 5 intensity. North Atlantic Major Hurricane Michael’s landfall intensity of 140 kt was the fourth strongest for any continental U.S. hurricane landfall in the 168-year record. Michael caused more than 30 fatalities and $25 billion (U.S. dollars) in damages. In the western North Pacific, Super Typhoon Mangkhut led to 160 fatalities and$6 billion (U.S. dollars) in damages across the Philippines, Hong Kong, Macau, mainland China, Guam, and the Northern Mariana Islands. Tropical Storm Son-Tinh was responsible for 170 fatalities in Vietnam and Laos. Nearly all the islands of Micronesia experienced at least moderate impacts from various tropical cyclones. Across land, many areas around the globe received copious precipitation, notable at different time scales. Rodrigues and Réunion Island near southern Africa each reported their third wettest year on record. In Hawaii, 1262 mm precipitation at Waipā Gardens (Kauai) on 14–15 April set a new U.S. record for 24-h precipitation. In Brazil, the city of Belo Horizonte received nearly 75 mm of rain in just 20 minutes, nearly half its monthly average. Globally, fire activity during 2018 was the lowest since the start of the record in 1997, with a combined burned area of about 500 million hectares. This reinforced the long-term downward trend in fire emissions driven by changes in land use in frequently burning savannas. However, wildfires burned 3.5 million hectares across the United States, well above the 2000–10 average of 2.7 million hectares. Combined, U.S. wildfire damages for the 2017 and 2018 wildfire seasons exceeded $40 billion (U.S. dollars)

An open challenge to advance probabilistic forecasting for dengue epidemics.

A wide range of research has promised new tools for forecasting infectious disease dynamics, but little of that research is currently being applied in practice, because tools do not address key public health needs, do not produce probabilistic forecasts, have not been evaluated on external data, or do not provide sufficient forecast skill to be useful. We developed an open collaborative forecasting challenge to assess probabilistic forecasts for seasonal epidemics of dengue, a major global public health problem. Sixteen teams used a variety of methods and data to generate forecasts for 3 epidemiological targets (peak incidence, the week of the peak, and total incidence) over 8 dengue seasons in Iquitos, Peru and San Juan, Puerto Rico. Forecast skill was highly variable across teams and targets. While numerous forecasts showed high skill for midseason situational awareness, early season skill was low, and skill was generally lowest for high incidence seasons, those for which forecasts would be most valuable. A comparison of modeling approaches revealed that average forecast skill was lower for models including biologically meaningful data and mechanisms and that both multimodel and multiteam ensemble forecasts consistently outperformed individual model forecasts. Leveraging these insights, data, and the forecasting framework will be critical to improve forecast skill and the application of forecasts in real time for epidemic preparedness and response. Moreover, key components of this project-integration with public health needs, a common forecasting framework, shared and standardized data, and open participation-can help advance infectious disease forecasting beyond dengue