Wall-associated kinase 1 (WAK1) is crosslinked in endomembranes, and transport to the cell surface requires correct cell-wall synthesis

The Arabidopsis thaliana wall-associated kinases (WAKs) bind to pectin with an extracellular domain and also contain a cytoplasmic protein kinase domain. WAKs are required for cell elongation and modulate sugar metabolism. This work shows that in leaf protoplasts a WAK1-GFP fusion protein accumulates in a cytoplasmic compartment that contains pectin. The WAK compartment contains markers for the Golgi, the site of pectin synthesis. The migration of WAK1-GFP to the cell surface is far slower than that of a cell surface receptor not associated with the cell wall, is influenced by the presence of fucose side chains on one or more unidentified molecules that might include pectin, and is dependent upon cellulose synthesis on the plasma membrane. WAK is crosslinked into a detergent-insoluble complex within the cytoplasmic compartment before it appears on the cell surface, and this is independent of fucose modification or cellulose synthesis. Thus, the assembly and crosslinking of WAKs may begin at an early stage within a cytoplasmic compartment rather than in the cell wall itself, and is coordinated with synthesis of surface cellulose

Implementation of the Tobacco Tactics intervention versus usual care in Trinity Health community hospitals

Abstract Background Guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) implementation framework, a National Institutes of Health-sponsored study compared the nurse-administered Tobacco Tactics intervention to usual care. A prior paper describes the effectiveness of the Tobacco Tactics intervention. This subsequent paper provides data describing the remaining constructs of the RE-AIM framework. Methods This pragmatic study used a mixed methods, quasi-experimental design in five Michigan community hospitals of which three received the nurse-administered Tobacco Tactics intervention and two received usual care. Nurses and patients were surveyed pre- and post-intervention. Measures included reach (patient participation rates, characteristics, and receipt of services), adoption (nurse participation rates and characteristics), implementation (pre-to post-training changes in nurses' attitudes, delivery of services, barriers to implementation, opinions about training, documentation of services, and numbers of volunteer follow-up phone calls), and maintenance (continuation of the intervention once the study ended). Results Reach: Patient participation rates were 71.5 %. Compared to no change in the control sites, there were significant pre- to post-intervention increases in self-reported receipt of print materials in the intervention hospitals (n = 1370, p < 0.001). Adoption: In the intervention hospitals, all targeted units and several non-targeted units participated; 76.0 % (n = 1028) of targeted nurses and 317 additional staff participated in the training, and 92.4 % were extremely or somewhat satisfied with the training. Implementation: Nurses in the intervention hospitals reported increases in providing advice to quit, counseling, medications, handouts, and DVD (all p < 0.05) and reported decreased barriers to implementing smoking cessation services (p < 0.001). Qualitative comments were very positive (“user friendly,” “streamlined,” or “saves time”), although problems with showing patients the DVD and charting in the electronic medical record were noted. Maintenance: Nurses continued to provide the intervention after the study ended. Conclusions Given that nurses represent the largest group of front-line providers, this intervention, which meets Joint Commission guidelines for treating inpatient smokers, has the potential to have a wide reach and to decrease smoking, morbidity, and mortality among inpatient smokers. As we move toward more population-based interventions, the RE-AIM framework is a valuable guide for implementation. Trial registration ClinicalTrials.gov, NCT0130921

Cdc28/Cdk1 Regulates Spindle Pole Body Duplication through Phosphorylation of Spc42 and Mps1

AbstractDuplication of the Saccharomyces cerevisiae spindle pole body (SPB) once per cell cycle is essential for bipolar spindle formation and accurate chromosome segregation during mitosis. We have investigated the role that the major yeast cyclin-dependent kinase Cdc28/Cdk1 plays in assembly of a core SPB component, Spc42, to better understand how SPB duplication is coordinated with cell cycle progression. Cdc28 is required for SPB duplication and Spc42 assembly, and we found that Cdc28 directly phosphorylates Spc42 to promote its assembly into the SPB. The Mps1 kinase, previously shown to regulate Spc42 phosphorylation and assembly, is also a Cdc28 substrate, and Cdc28 phosphorylation of Mps1 is needed to maintain wild-type levels of Mps1 in cells. Analysis of nonphosphorylatable mutants in SPC42 and MPS1 indicates that direct Spc42 phosphorylation and indirect regulation of Spc42 through Mps1 are two overlapping pathways by which Cdc28 regulates Spc42 assembly and SPB duplication during the cell cycle

Responding to the Call: Building a Training Program to Diversify the Academy in Alzheimer’s Disease Research

Alzheimer\u27s disease and related dementias (ADRD) are at the forefront of the United States (US) public health agenda due to their tremendous human and financial burden. Further, disproportionately high ADRD rates among racial/ethnic minorities require incorporating the unique perspectives of racially and ethnically diverse scientists, which will necessitate diversifying the scientific workforce that investigates disparities in aging. The purpose of this paper is to describe the training and mentorship initiatives of the National Institute on Aging (NIA)-funded Carolina Center on Alzheimer\u27s Disease and Minority Research, emphasizing lessons learned from our engagement with underrepresented minority and minoritized (URM) Scientists. We highlight three aims of the Center\u27s training and mentorship component: (1) Fund pilot projects for URM Scientists conducting research on sociocultural, behavioral, and environmental factors that influence ADRD-related health disparities; (2) Provide mentorship to build the research capacity of Center Scientists; and (3) Offer research education in Health Disparities and Minority Aging Research to Center Scientists and interested researchers at all partner institutions. Our experience may be a practical resource for others developing interdisciplinary training programs to increase the pipeline of URM Scientists conducting ADRD research

Improving Adherence to Adjuvant Hormonal Therapy Among Disadvantaged Women Diagnosed With Breast Cancer in South Carolina: Proposal for a Multimethod Study

Background: Current clinical guidelines recommend that hormone receptor-positive breast cancer survivors take adjuvant hormonal therapy (AHT) for 5 to 10 years, following the end of definitive treatment. However, fewer than half of patients adhere to the guidelines, and suboptimal adherence to AHT is associated with an increased risk of breast cancer mortality. Research has extensively documented sociodemographic and disease-specific factors associated with adherence to AHT, but very little evidence exists on behavioral factors (eg, knowledge, patient-provider communication) that can be modified and targeted by interventions. Objective: The goal of this study is to develop and test a theory-based, multilevel intervention to improve adherence to AHT among breast cancer survivors from racially and socioeconomically disadvantaged backgrounds (eg, Medicaid-insured). The specific aims are to (1) explore multilevel (eg, patient, health care system) factors that influence adherence to AHT; (2) develop a theory-based, multilevel intervention to improve adherence to AHT; and (3) pilot test and evaluate the intervention developed in Aim 2. Methods: For Aim 1, we will recruit breast cancer survivors and health care professionals to participate in semistructured interviews to gain their perspectives about barriers and facilitators to AHT use. We will conduct a directed content analysis of the Aim 1 qualitative interview data. For Aim 2, we will integrate Aim 1 findings and current literature into the design of a multilevel intervention using an Intervention Mapping approach. For Aim 3, we will recruit Medicaid-insured breast cancer survivors to assess the feasibility of the pilot intervention. Results: From May 2016 to July 2018, we completed interviews with 19 breast cancer survivors and 23 health care professionals in South Carolina. We will conduct a directed content analysis of the qualitative interview data. Results from this analysis will be used, in combination with current literature, to design (Aim 2) and pilot test a theory-based multilevel intervention (Aim 3) in Summer 2021. Results of the pilot are expected for Fall 2021. Conclusions: This study will provide a deeper understanding of how to improve adherence to AHT, using a novel and multilevel approach, among socioeconomically disadvantaged breast cancer survivors who often experience disproportionate breast cancer mortality

Algorithms, governance, and governmentality:on governing academic writing

Algorithms, or rather algorithmic actions, are seen as problematic because they are inscrutable, automatic, and subsumed in the flow of daily practices. Yet, they are also seen to be playing an important role in organizing opportunities, enacting certain categories, and doing what David Lyon calls ‘‘social sorting.’’ Thus, there is a general concern that this increasingly prevalent mode of ordering and organizing should be governed more explicitly. Some have argued for more transparency and openness, others have argued for more democratic or value-centered design of such actors. In this article, we argue that governing practices—of, and through algorithmic actors—are best understood in terms of what Foucault calls governmentality. Governmentality allows us to consider the performative nature of these governing practices. They allow us to show how practice becomes problematized, how calculative practices are enacted as technologies of governance, how such calculative practices produce domains of knowledge and expertise, and finally, how such domains of knowledge become internalized in order to enact self-governing subjects. In other words, it allows us to show the mutually constitutive nature of problems, domains of knowledge, and subjectivities enacted through governing practices. In order to demonstrate this, we present attempts to govern academic writing with a specific focus on the algorithmic action of Turnitin

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Mapping regional risks from climate change for rainfed rice cultivation in India

Global warming is predicted to increase in the future, with detrimental consequences for rainfed crops that are dependent on natural rainfall (i.e. non-irrigated). Given that many crops grown under rainfed conditions support the livelihoods of low-income farmers, it is important to highlight the vulnerability of rainfed areas to climate change in order to anticipate potential risks to food security. In this paper, we focus on India, where ~ 50% of rice is grown under rainfed conditions, and we employ statistical models (climate envelope models (CEMs) and boosted regression trees (BRTs)) to map changes in climate suitability for rainfed rice cultivation at a regional level (~ 18 × 18 km cell resolution) under projected future (2050) climate change (IPCC RCPs 2.6 and 8.5, using three GCMs: BCC-CSM1.1, MIROC-ESM-CHEM, and HadGEM2-ES). We quantify the occurrence of rice (whether or not rainfed rice is commonly grown, using CEMs) and rice extent (area under cultivation, using BRTs) during the summer monsoon in relation to four climate variables that affect rice growth and yield namely ratio of precipitation to evapotranspiration (PER), maximum and minimum temperatures (Tmax and Tmin), and total rainfall during harvesting. Our models described the occurrence and extent of rice very well (CEMs for occurrence, ensemble AUC = 0.92; BRTs for extent, Pearson's r = 0.87). PER was the most important predictor of rainfed rice occurrence, and it was positively related to rainfed rice area, but all four climate variables were important for determining the extent of rice cultivation. Our models project that 15%–40% of current rainfed rice growing areas will be at risk (i.e. decline in climate suitability or become completely unsuitable). However, our models project considerable variation across India in the impact of future climate change: eastern and northern India are the locations most at risk, but parts of central and western India may benefit from increased precipitation. Hence our CEM and BRT models agree on the locations most at risk, but there is less consensus about the degree of risk at these locations. Our results help to identify locations where livelihoods of low-income farmers and regional food security may be threatened in the next few decades by climate changes. The use of more drought-resilient rice varieties and better irrigation infrastructure in these regions may help to reduce these impacts and reduce the vulnerability of farmers dependent on rainfed cropping

Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma

Both the combination of nivolumab + ipilimumab and single-agent anti-PD- 1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD- 1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single-center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan–Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil-to- lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti-PD- 1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti-PD- 1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti-PD- 1 alone