Ecological effects of extreme drought on Californian herbaceous plant communities

Understanding the consequences of extreme climatic events is a growing challenge in ecology. Climatic extremes may differentially affect varying elements of biodiversity, and may not always produce ecological effects exceeding those of "normal" climatic variation in space and time. We asked how the extreme drought years of 2013- 2014 affected the cover, species richness, functional trait means, functional diversity, and phylogenetic diversity of herbaceous plant communities across the California Floristic Province. We compared the directions and magnitudes of these drought effects with expectations from four "pre-drought" studies of variation in water availability: (1) a watering experiment, (2) a long- Term (15-yr) monitoring of interannual variability, (3) a resampling of historic (57-yr- old) plots within a warming and drying region, and (4) natural variation in communities over a broad geographic gradient in precipitation. We found that the drought was associated with consistent reductions in species richness and cover, especially for annual forbs and exotic annual grasses, but not with changes in functional or phylogenetic diversity. Except for total cover and cover of exotic annual grasses, most drought effects did not exceed quantitative expectations based on the four pre-drought studies. Qualitatively, plant community responses to the drought were most concordant with responses to pre-drought interannual rainfall variability in the 15-yr monitoring study, and least concordant with responses to the geographic gradient in precipitation. Our results suggest that, at least in the short term, extreme drought may cause only a subset of community metrics to respond in ways that exceed normal background variability

DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose

Macroautophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. The process operates under basal conditions as a mechanism to turnover damaged or misfolded proteins and organelles. As a result, it has a major role in preserving cellular integrity and viability. In addition to this basal function, macroautophagy can also be modulated in response to various forms of cellular stress, and the rate and cargoes of macroautophagy can be tailored to facilitate appropriate cellular responses in particular situations. The macroautophagy machinery is regulated by a group of evolutionarily conserved autophagy-related (ATG) proteins and by several other autophagy regulators, which either have tissue-restricted expression or operate in specific contexts. We report here the characterization of a novel autophagy regulator that we have termed DRAM-3 due to its significant homology to damage-regulated autophagy modulator (DRAM-1). DRAM-3 is expressed in a broad spectrum of normal tissues and tumor cells, but different from DRAM-1, DRAM-3 is not induced by p53 or DNA-damaging agents. Immunofluorescence studies revealed that DRAM-3 localizes to lysosomes/autolysosomes, endosomes and the plasma membrane, but not the endoplasmic reticulum, phagophores, autophagosomes or Golgi, indicating significant overlap with DRAM-1 localization and with organelles associated with macroautophagy. In this regard, we further proceed to show that DRAM-3 expression causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Reciprocally, CRISPR/Cas9-mediated disruption of DRAM-3 impairs autophagic flux confirming that DRAM-3 is a modulator of macroautophagy. As macroautophagy can be cytoprotective under starvation conditions, we also tested whether DRAM-3 could promote survival on nutrient deprivation. This revealed that DRAM-3 can repress cell death and promote long-term clonogenic survival of cells grown in the absence of glucose. Interestingly, however, this effect is macroautophagy-independent. In summary, these findings constitute the primary characterization of DRAM-3 as a modulator of both macroautophagy and cell survival under starvation conditions

Association between fixation type and revision risk in total knee arthroplasty patients aged 65 years and older: a cohort study of 265,877 patients from the Nordic Arthroplasty Register Association 2000-2016

Background and purpose - The population of the Nordic countries is aging and the number of elderly patients undergoing total knee arthroplasty (TKA) is also expected to increase. Reliable fixation methods are essential to avoid revisions. We compared the survival of different TKA fixation concepts with cemented fixation as the gold standard. Patients and methods - We used data from the Nordic Arthroplasty Register Association (NARA) database of 265,877 unconstrained TKAs performed for patients aged ≥ 65 years with primary knee osteoarthritis between 2000 and 2016. Kaplan-Meier (KM) survival analysis with 95% confidence intervals (CI) and the Cox multiple-regression model were used to compare the revision risk of the fixation methods. Results - Cemented fixation was used in 243,166 cases, uncemented in 8,000, hybrid (uncemented femur with cemented tibia) in 14,248, and inverse hybrid (cemented femur with uncemented tibia) fixation in 463 cases. The 10-year KM survivorship (95% CI) of cemented TKAs was 96% (96 - 97), uncemented 94% (94 - 95), hybrid 96% (96 - 96), and inverse hybrid 96% (94 - 99), respectively. Uncemented TKA was associated with increased risk of revision compared with the cemented TKA; the adjusted hazard ratio was 1.3 (95% CI 1.1 - 1.4). Interpretation - Cemented, hybrid, and inverse hybrid TKAs showed 10-year survival rates exceeding 95%. Uncemented fixation was associated with an increased risk of revision in comparison with cemented fixation. As both hybrid and inverse hybrid fixation were used in only a limited number of TKAs, indicating possibility of selection bias in their favor, cemented TKA still remains the gold standard, as it works reliably in the hands of many

Implant survival of the most common cemented total hip devices from the Nordic Arthroplasty Register Association database

Background and purpose According to previous Nordic Arthroplasty Register Association (NARA) data, the 10-year implant survival of cemented total hip arthroplasties (THAs) is 94% in patients aged 65-74 and 96% in patients aged 75 or more. Here we report a brand-level comparison of cemented THA based on the NARA database, which has not been done previously.Patients and methods We determined the rate of implant survival of the 9 most common cemented THAs in the NARA database. We used Kaplan-Meier analysis with 95% CI to study implant survival at 10 and 15 years, and Cox multiple regression to assess survival and hazard ratios (HRs), with revision for any reason as endpoint and with adjustment for age, sex, diagnosis, and femoral head material.Results Spectron EF THA (89.9% (CI: 89.3-90.5)) and Elite THA (89.8% (CI: 89.0-90.6)) had the lowest 10-year survivorship. Lubinus (95.7% survival, CI: 95.5-95.9), MS 30 (96.6%, CI: 95.8-97.4), and C-stem THA (95.8%, CI: 94.8-96.8) had a 10-year survivorship of at least 95%. Lubinus (revision risk (RR)=0.77, CI: 0.73-0.81), Muller (RR =0.83, CI: 0.70-0.99), MS-30 (RR =0.73, CI: 0.63-0.86), C-stem (RR =0.70, CI: 0.55-0.90), and Exeter Duration THA (RR =0.84, CI: 0.77-0.90) had a lower risk of revision than Charnley THA, the reference implant.Interpretation The Spectron EF THA and the Elite THA had a lower implant survival than the Charnley, Exeter, and Lubinus THAs. Implant survival of the Muller, MS 30, CPT, and C-stem THAs was above the acceptable limit for 10-year survival

Hospital volume and the risk of revision in Oxford unicompartmental knee arthroplasty in the Nordic countries -an observational study of 14,496 cases

Background: High procedure volume and dedication to unicompartmental knee arthroplasty (UKA) has been suggested to improve revision rates. This study aimed to quantify the annual hospital volume effect on revision risk in Oxfordu nicompartmental knee arthroplasty in the Nordic countries.Methods: 14,496 cases of cemented medial Oxford III UKA were identified in 126 hospitals in the four countries included in the Nordic Arthroplasty Register Association (NARA) database from 2000 to 2012. Hospitals were divided by quartiles into 4 annual procedure volume groups (= 44). The outcome was revision risk after 2 and 10 years calculated using Kaplan Meier method. Multivariate Cox regression analysis was used to assess the Hazard Ratio (HR) of any revision due to specific reasons with 95% confidence intervals (CI).Results: The implant survival was 80% at 10 years in the volume group = 44 procedures per year compared to the low volume group. Log-rank test was p = 0.003. The risk of revision for unexplained pain was 40-50% higher in the low compared with other volume groups.Conclusion: Low volume hospitals performing <= 11 Oxford III UKAs per year were associated with an increased risk of revision compared to higher volume hospitals, and unexplained pain as revision cause was more common in low volume hospitals

Similar early mortality risk after cemented compared with cementless total hip arthroplasty for primary osteoarthritis: data from 188,606 surgeries in the Nordic Arthroplasty Register Association database

Background and purpose - Current literature indicates no difference in 90-day mortality after cemented compared with cementless total hip arthroplasty (THA). However, previous studies are hampered by potential selection bias and suboptimal adjustment for comorbidity confounding. Therefore, we examined the comorbidity-adjusted mortality up to 90 days after cemented compared with cementless THA performed due to osteoarthritis.Patients and methods - Using the Nordic Arthroplasty Register Association database, 2005-2013, we included 108,572 cemented and 80,034 cementless THA due to osteoarthritis. We calculated the Charlson comorbidity index of each patient based on data from national patient registers. The Kaplan-Meier method was used to estimate unadjusted all-cause mortality. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for 14, 30-, and 90-day mortality comparing cemented with cementless THA, adjusting for age, sex, comorbidity, nation, and year of surgery.Results - Cumulative all-cause mortality within 90 days was 0.41% (CI 0.37-0.46) after cemented and 0.26% (CI 0.22-0.30) after cementless THA. The adjusted HR for cemented vs. cementless fixation was 0.97 (CI 0.79-1.2), and similar risk estimates were obtained for mortality within 14 (adjusted HR 0.91 [CI 0.64-1.3]) and 30 days (adjusted HR 0.94 [CI 0.71-1.3]). We found no clinically relevant differences in mortality between cemented and cementless THA in analyses stratified by age, sex, Charlson comorbidity index, or year of surgery.Interpretation - After adjustment for comorbidity as an important confounder, we observed similar early mortality between the 2 fixation techniques

Up-regulated expression of LAMP2 and autophagy activity during neuroendocrine differentiation of prostate cancer LNCaP cells

Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE model of prostate cancer. Serum deprivation increased the expression of NE markers such as neuron-specific enolase (NSE) and βIII tubulin (βIII tub) and decreased the expression of the androgen receptor protein in LNCaP cells. Using cDNA microarrays, we compared gene expression profiles of NE cells and non-differentiated LNCaP cells. We identified up-regulation of 155 genes, among them LAMP2, a lysosomal membrane protein involved in lysosomal stability and autophagy. We then confirmed up-regulation of LAMP2 in NE cells by qRT-PCR, Western blot and confocal microscopy assays, showing that mRNA up-regulation correlated with increased levels of LAMP2 protein. Subsequently, we determined autophagy activity in NE cells by assessing the protein levels of SQSTM/p62 and LC3 by Western blot and LC3 and Atg5 mRNAs content by qRT-PCR. The decreased levels of SQSTM/p62 was accompanied by an enhanced expression of LC3 and ATG5, suggesting activation of autophagy in NE cells. Blockage of autophagy with 1μM AKT inhibitor IV, or by silencing Beclin 1 and Atg5, prevented NE cell differentiation, as revealed by decreased levels of the NE markers. In addition, AKT inhibitor IV as well as Beclin1 and Atg5 kwockdown attenuated LAMP2 expression in NE cells. On the other hand, LAMP2 knockdown by siRNA led to a marked blockage of autophagy, prevention of NE differentiation and decrease of cell survival. Taken together, these results suggest that LAMP2 overexpression assists NE differentiation of LNCaP cells induced by serum deprivation and facilitates autophagy activity in order to attain the NE phenotype and cell survival. LAMP2 could thus be a potential biomarker and potential target for NE prostate cancer

Decreased insulin-stimulated brown adipose tissue glucose uptake after short-term exercise training in healthy middle-aged men

Aims: To test the hypothesis that high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) improve brown adipose tissue (BAT) insulin sensitivity.Participants and methods: Healthy middle-aged men (n = 18, age 47 years [95% confidence interval {CI} 49, 43], body mass index 25.3 kg/m(2) [95% CI 24.1-26.3], peak oxygen uptake (VO2peak) 34.8 mL/kg/min [95% CI 32.1, 37.4]) were recruited and randomized into six HIIT or MICT sessions within 2 weeks. Insulin-stimulated glucose uptake was measured using 2-[F-18] flouro-2-deoxy-D-glucose positron-emission tomography in BAT, skeletal muscle, and abdominal and femoral subcutaneous and visceral white adipose tissue (WAT) depots before and after the training interventions.Results: Training improved VO2peak (P =.0005), insulin-stimulated glucose uptake into the quadriceps femoris muscle (P =.0009) and femoral subcutaneous WAT (P =.02) but not into BAT, with no difference between the training modes. Using pre-intervention BAT glucose uptake, we next stratified subjects into high BAT (> 2.9 mu mol/100 g/min; n = 6) or low BAT (< 2.9 mu mol/100 g/min; n = 12) groups. Interestingly, training decreased insulin-stimulated BAT glucose uptake in the high BAT group (4.0 [2.8, 5.5] vs 2.5 [1.7, 3.6]; training*BAT, P =.02), whereas there was no effect of training in the low BAT group (1.5 [1.2, 1.9] vs 1.6 [1.2, 2.0] mu mol/100 g/min). Participants in the high BAT group had lower levels of inflammatory markers compared with those in the low BAT group.Conclusions: Participants with functionally active BAT have an improved metabolic profile compared with those with low BAT activity. Short-term exercise training decreased insulin-stimulated BAT glucose uptake in participants with active BAT, suggesting that training does not work as a potent stimulus for BAT activation

The benefits of collaboration: the Nordic Arthroplasty Register Association

The Nordic Arthroplasty Register Association (NARA) was established in 2007 by arthroplasty register representatives from Sweden, Norway and Denmark with the overall aim to improve the quality of research and thereby enhance the possibility for quality improvement with arthroplasty surgery. Finland joined the NARA collaboration in 2010.NARA minimal hip, knee and shoulder datasets were created with variables that all countries can deliver. They are dynamic datasets, currently with 25 variables for hip arthroplasty, 20 for knee arthroplasty and 20 for shoulder arthroplasty.NARA has published statistical guidelines for the analysis of arthroplasty register data. The association is continuously working on the improvement of statistical methods and the application of new ones.There are 31 published peer-reviewed papers based on the NARA databases and 20 ongoing projects in different phases. Several NARA publications have significantly affected clinical practice. For example, metal-on-metal total hip arthroplasty and resurfacing arthroplasty have been abandoned due to increased revision risk based on i.a. NARA reports. Further, the use of uncemented total hip arthroplasty in elderly patients has decreased significantly, especially in Finland, based on the NARA data.The NARA collaboration has been successful because the countries were able to agree on a common dataset and variable definitions. The collaboration was also successful because the group was able to initiate a number of research projects and provide answers to clinically relevant questions. A number of specific goals, set up in 2007, have been achieved and new one has emerged in the process

Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform

The dynamics and coordination between autophagy machinery and selective receptors during mitophagy are unknown. Also unknown is whether mitophagy depends on pre-existing membranes or is triggered on the surface of damaged mitochondria. Using a ubiquitin-dependent mitophagy inducer, the lactone ivermectin, we have combined genetic and imaging experiments to address these questions. Ubiquitination of mitochondrial fragments is required the earliest, followed by auto-phosphorylation of TBK1. Next, early essential autophagy proteins FIP200 and ATG13 act at different steps, whereas ULK1 and ULK2 are dispensable. Receptors act temporally and mechanistically upstream of ATG13 but downstream of FIP200. The VPS34 complex functions at the omegasome step. ATG13 and optineurin target mitochondria in a discontinuous oscillatory way, suggesting multiple initiation events. Targeted ubiquitinated mitochondria are cradled by endoplasmic reticulum (ER) strands even without functional autophagy machinery and mitophagy adaptors. We propose that damaged mitochondria are ubiquitinated and dynamically encased in ER strands, providing platforms for formation of the mitophagosomes