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Premature aging of circulating T cells predicts all-cause mortality in hemodialysis patients
Fangfang Xiang1,2,3,
Rongyi Chen1,
Xuesen Cao1,
Bo Shen1,
Xiaohong Chen1,
Xiaoqiang Ding1,2,3,4 &
Jianzhou Zou1,2,3,4
BMC Nephrology volume 21, Article number: 271 (2020) Cite this article
Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of immune system, which is recently concerned as a significant factor for increased risk of various morbidities. Nevertheless, there are few dates explicating the relevancy of T cell senescence to mortality. In this study, we prospectively studied the predictive value of T cell senescence for mortality in hemodialysis patients.
Patients who had been on hemodialysis treatment for at least 6 months were enrolled. T cell senescence determined by differentiation status was evaluated by flow cytometry. Survival outcomes were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to evaluate the prognostic impact of T cell premature aging and other clinical factors on all-cause mortality.
A total of 466 patients (277 man and 169 women) were enrolled in this study. Decreased number of naïve T cell, as the most prominent feature of T cell senescence, did not change in parallel with age in these patients. Decreased absolute count of T cell, naïve T cell, CD4+ naïve T cell were independently associated with all-cause mortality. Decreased percentage of T cell and increased percentage of CD8+central-memory T cell were also independently associated with all-cause mortality. After including all the T cell parameters in one regression model, only decreased count of naïve T cell was significantly associated with increased mortality in these patients.
Aging-associated T cell changes are aggravated in ESRD patients. For the first time, our study demonstrates that naïve T cell depletion is a strong predictor of all-cause mortality in HD patients.
End-stage renal disease (ESRD) patients suffer from much higher mortality compared to chronological age-matched individuals, mainly due to a high risk of cardiovascular disease (CVD) and infections [1], which also prevails in elderly people. Actually, besides CVD and infection, much more aging-related complications are increased in ESRD patients including malnutrition, impaired physical function, muscle wasting, cognitive function decline and malignancies [2, 3]. This proposes the hypothesis that uremia induces premature senescence, and chronic kidney disease (CKD) may be a model of premature aging. The decline of the immune system with age is thought to be the core factor behind these manifestations since the immune system is not only involved in controlling infections and malignancies, but also in tissue homeostasis and repair [4, 5]. Focusing on aging immune system, therefore, is a priority with crucial implications to reveal pathogenic mechanism of chronic diseases such as renal failure and to improve outcomes for these patients.
Age-related changes in the immune system, which are generally referred to as immunosenescence, are well documented and concern primarily the adaptive immune responses [4]. Among which, altered T cell function has been the most dramatic and consistent change reported during aging. In this content, T cells should be a very good spot to shed light into the uremia-related immune alteration. Recent evidence suggests uremia-related immune changes resemble to aging immune system, increasing immunological age of T cells by 20–30 years [6, 7]. As compared to an age-matched healthy control, ESRD patients present a lower thymic output of naïve T cells, a decline in the T-cell telomere length and an increase in the differentiation status towards the terminal differentiated memory phenotype with a large number of CD28-negative T cells. More importantly, these changes are strongly associated with CVD and occurrence of severe infectious episodes in ESRD patients [8, 9], supporting the idea that premature senescence in T cell compartment is a critical feature in this population and will impact clinical outcomes profoundly.
Although uremic associated T cell premature aging is well documented and concerned with a significant factor for increased risk of various morbidities; there is few dates explicating the relevancy of T cell senescence to mortality. This study prospectively researched the predictive value of T cell senescence determined by differentiation status for all-cause mortality and provided reference values for both absolute number and percentage of these T cell parameters in each decade of life within hemodialysis (HD) patients.
Study populations
This current study included HD patients who had been on HD treatment for at least 6 months in Blood Purification Center, Department of Nephrology, Zhongshan Hospital, Fudan University. Patients were enrolled from august to September in 2016 and followed until death, transfer to other clinic, renal transplantation, peritoneal dialysis, or July 15, 2019. Exclusion criteria were HD patients with recent or current infections, hematological diseases, rheumatic diseases, active malignancies, history of human immunodeficiency virus infection or currently use of any immunosuppressants. For all patients met the inclusion criteria, the clinical datas were recorded, including age, gender, body mass index (BMI), smoking behavior, blood pressure, underlying kidney disease and comorbidities such as hypertension, diabetes and CVD. CVD were defined as cardiac, cerebrovascular, or peripheral vascular disease.
All methods were carried out in accordance with relevant guidelines and regulations. This study was approved by the Ethical Committee, Zhongshan Hospital, Fudan University, and all the patients provided written informed consent.
Cells preparation
Blood samples were drawn from the arterial site of the vascular access at the start of each dialysis session after a 2-day interval and stored in heparin tubules (BD Biosciences, San Diego, CA). Blood samples were lysed with red blood cell lysis solution [10 mM KHCO3, 155 mM NH4Cl (Sangon Biotech) and 0.1 mM EDTA (Sigma- Aldrich, St Louis, MO, USA)]. Subsequently, the cells were washed twice and resuspended in staining buffer containing PBS with 0.2% FBS (Invitrogen, Grand Island, NY, USA) and 0.09% NaN3 (Sigma-Aldrich).
Flow cytometry analysis
Lysed cells were acquired and subsequently stained for 30 min at 4 °C with the following fluorescein-conjugated monoclonal antibodies: CD3-PE (Bio- Legend, San Diego, CA, USA), CD4-APC (eBioscience, San Diego, CA, USA), CD8a-Percp/Cy5.5 (eBioscience), CD45RO-FITC (Miltenyi Biotec, Bergisch Gladbach, Germany) and CCR7-APC/Cy7 (BioLegend). The T cell subsets were defined as previous study reported [10]: Naive T cells being CCR7+ and CD45RO−; central memory T cells as CD45RO+ and CCR7+; effector memory T cells as CD45RO+ and CCR7−, and effector memory RA (EMRA) T cells as CD45RO− and CCR7− (Figure S1). A total of 200,000 events were acquired by the BD LSRFortessa™ flow cytometer (BD Bioscience, San Jose, CA, USA). The data analysis was carried out with Flowjo v10.1 Software (Tree Star, Ashland, OR). The absolute number of each T cell subset was calculated as follows: (percentage of each cell population among total lymphocytes) × (total lymphocytes count)/100.
All data were expressed as mean ± SD or median (interquartile range) appropriately. To analysis the correlation between T cell parameters and age, One-way ANOVA and linear analysis were used. Survival was estimated using the Kaplan–Meier curve and differences were examined using the log-rank test. Univariate Cox regression analysis was used to identify predictors of total death. Significant predictors were subsequently added to the multivariable model and backward stepwise Cox regression identified the most parsimonious model. The probability used for the stepwise regression was set at 0.05 for entry of variables and 0.1 for removal. Results of the Cox proportional hazards analysis were presented as the hazard ratio and the 95% confidence interval. P value of < 0.05 was considered statistically significant. All statistical calculations were performed with SPSS version 20.0 (SPSS Inc., Chicago, IL, USA).
A total of 446 patients (277 man and 169 women) were enrolled in this study. The average age of patients was 59.3 ± 14.4 years. The median time on HD was for 54 (28, 83) months. The underlying kidney diseases were composed of chronic glomerulonephritis (47.5%), diabetic nephropathy (16.8%), polycystic kidney disease (8.7%), hypertension renal disease (3.1%), others (11.4%), and unknown (12.3%). Of the 466 patients, 103 (23.1%) had diabetes mellitus and 395 (79.1%) had hypertension. 141 patients (31.6%) had CVD history, of which 45 had more than one CVD complication. CVD incidents included 7 myocardial infarctions, 15 angina pectoris, 60 congestive heart failures, 64 cerebral infarctions, 10 cerebral hemorrhages and 9 peripheral vascular diseases. Only 3 out of 446 ESRD patients were seronegative for CMV (99.3% seropositive). Table 1 presents baseline characteristics of the study population.
Table 1 Demographic data of the study population
CVD cardiovascular disease; CMV cytomegalovirus; BMI Body mass index; LDL-C low density lipoprotein -cholesterol; HDL-C high density lipoprotein- cholesterol; NT-proBNP N-terminal pro-brain natriuretic peptide; hsCRP high sensitivity-C reactive protein; iPTH intact parathyroid hormone
Comparison of T cell senescence in different age period among hemodialysis patients
To analyze the correlation between T cell parameters and age, patients were divided into 5 groups according to age. T cell parameters were expressed as median (interquartile range), as shown in Table 2. There was a significant difference in absolute number of CD4+T cells, CD4+naïve T cells, CD4+EMRA T cells, CD8+T cells, CD8+ naïve T cells among 5 groups (p < 0.05). However, these T subsets did not decrease in parallel with age. In the pairwise comparison, the absolute number of CD4+T cells decreased significantly with age in patients aged from 20 to 69 years old. Afterwards, there was no significant difference and even a little increase in 80–89 years old. This was mainly due to the changes of CD4+ naïve T cells, since they showed the same trend. The absolute number of CD4+ EMRA T cells was significantly higher in the 20–45 age group than other groups, and there was no significant difference in older age groups. A similar kinetics was observed in CD8+ T cell number, with a significant decrease with age in patients aged from 20 to 59 years old. CD8+ naïve T cells decreased significantly with age in a nearly parallel pattern in patients aged from 20 to 89 years old. It was presumed that CD8+ memory T cells expanded after 60 years old so that number of CD8+ T cells pools was relative remained, although statistical difference was not shown in these memory T cell parameters. Correlations between naïve T cells and age were shown in Fig. 1. When came to percentages, there was a significant difference in almost all the T cell parameters across age groups except CD4+ EMRA T cells. Linear analysis indicated percentages of naïve T cells were negatively correlated and percentages of memory T cells were positively correlated with age in both CD4+ and CD8+ compartment (p < 0.001).
Table 2 values of percentages and absolute numbers of T cell subset during aging
Correlations between naïve T cells and age. Scatter plots and regression lines demonstrated the relationship between T cell parameters with age in ESRD patients. Linear regression analysis showed that both CD4+ and CD8+ naïve T cell counts were negatively correlated to age. After dividing patients into 5 groups according to age period, CD4+ naïve T cell count decreased significantly with age in patients aged from 20 to 69 years old. Afterwards, there was no significant difference in CD4+ naïve T cell count, and even a little increase in 80–89 years old. CD8+ naïve T cell count decreased significantly with age in patients aged from 20 to 89 years old
Naïve T cell count as a predictor of all-cause mortality in hemodialysis patients
All the patients were followed weekly, and follow-up ended in July, 2019. The median follow-up was for 33 months (range, 1–34 months) corresponding to a total follow-up of 1049 patient-years. During follow-up, 103 patients died, 11 patients had renal transplantation, 2 were transferred to peritoneal dialysis and 23 were transferred to another clinic. The most common cause of mortality was cardiovascular death (death due to myocardial infarction, heart failure, cerebrovascular accident or peripheral vascular disease) (n = 54; 52.4%), followed by infection (n = 17; 16.5%), sudden death (n = 9; 8.7%), cancer (n = 7; 6.8%), gastrointestinal hemorrhage (n = 7; 6.8%) and others (n = 9; 8.7%).
We divided the patients into six groups according to age and value of naïve T cell count. The median level of naïve T cell was 190 cells/μl. Group 1 included patients younger than 46 years old (n = 84). Group 2 L included patients aged 46 to 60 years old with naïve T cell count below the median level (n = 60). Group 2H included patients aged 46 to 60 years old with naïve T cell count above the median level (n = 80). Group 3 L included patients aged 61 to 75 years old with naïve T cell count below the median level (n = 105). Group 3H included patients aged 61 to 75 years old with naïve T cell count above the median level (n = 52). Group 4 included patients older than 75 years old (n = 65). Kaplan-Meier analysis revealed that survival rate was significantly different between six age-naïve T groups (p < 0.001). In pairwise comparison, survival rate was significantly lower in the oldest group when compared with other groups. Patients aged 61–75 years old with a lower naïve T cell count had a significant lower survival rate than those in the same age period but with a higher naïve T cell count (p < 0.001). Patients aged 46–60 years old with a lower naïve T cell count also had a significant lower survival rate than those in the youngest age period (p = 0.04). Notably, patients aged 46–75 years old with a higher naïve T cell count seemed to have a similar survival rate compared to patients younger than 46 years old (Fig. 2). CD4+ and CD8+ naïve T cell count showed a similar effect in predicting all-cause mortality in these patients (Figure S2, Figure S3).
Overall survival curves according to age - naïve T group. Patients were divided into six groups according to age and value of naïve T cell count. Kaplan-Meier analysis revealed that survival rate was significantly different between six age-naïve T groups (p < 0.001). In pairwise comparison, survival rate was significantly lower in the oldest group when compared with other groups. Patients age 61–75 years old with a lower naïve T cell count had a significant lower survival rate than those in the same age period but with a higher naïve T cell count (p < 0.001). Patients aged 46–60 years old with a lower naïve T cell count also had a significant lower survival rate than those in the youngest age period (p = 0.04). Patients aged 46–75 years old with a higher naïve T cell count seemed to have a similar survival rate compared to patients younger than 46 years old
In univariate cox proportional hazard model, decreased absolute count of T cells, naïve T cells, CD4+ naïve T cells, CD8+ naïve T cells were significant predictors of mortality. Decreased percentage of T cells, naïve T cells, CD4+ naïve T cells, CD8+ naïve T cells and increased percentage of CD4+effector-memory T cells, CD8+central-memory T cells, CD8+effector-memory T cells, CD8+EMRA T cells were also significant correlated with higher mortality rate. Other mortality predictors included older age, history of CVD, diabetes mellitus, lower serum level of albumin, prealbumin, urea nitrogen, creatinine, uric acid and increased serum level of high sensitivity-C reactive protein, soluble interleukin-2 receptor, N-terminal pro-brain natriuretic peptide (Table 3). After adjusted with various conventional and unconventional risk factors related to mortality, decreased absolute count of T cells, decreased absolute count of naïve T cells, decreased absolute count of CD4+ naïve T cells, decreased percentage of T cells and increased percentage of CD8+ central-memory T cells along with older age, history of diabetes, history of CVD, decreased albumin level and elevated NT-proBNP level were independently associated with all-cause mortality. After including all the significant T cell parameters in one regression model, only decreased count of naïve T cell was significantly associated with increased mortality in those patients (Table 4).
Table 3 Univariate Cox hazard model for all-cause mortality in hemodialysis patients
Table 4 Multivariate Cox proportional hazard model for all-cause mortality
To the best of our knowledge, the present study has been the first one to evaluate differentiation status of peripheral T lymphocyte in predicting mortality in ESRD patients. The main finding was highlighted as follows: decreased naïve T cell is a strong predictor of all-cause mortality in HD patents.
In this study, we analyzed circulating T cell subsets of 466 ESRD patients for each decade of life. Our finding consisted with earlier studies that aging affected lymphocyte subpopulation profile of ESRD patients with a decrease of absolute numbers of naïve T cells and an increase of percentage of memory T cells [11, 12]. Decreased number of naïve T cell seems to be the most prominent phenomenon of T cell senescence, no matter it is caused by aging or ESRD. Chiu YL et al. posted a dramatic 40–50% reduction in CD4+ and CD8+ naïve T cell numbers in 412 ESRD patients when compared to age-matched healthy individuals [12]. Freitas et al. suggested that age and ESRD presented additive effect decreasing naïve T cells without synergic effect [11]. However, this study was based on a small sample size and patients were roughly divided into two groups if age was over 60 or not. In the current study, since we provided values for the absolute numbers and proportions of T cell subsets in each decade of life, it allowed us to analyze the trend of T cell variation with more detailed information. We found that the number of CD4+ naïve T cell didn't change in parallel with age and patients over 80 years old seemed to have a relatively increased naïve T cells in CD4+ compartment, which was not reported in healthy elderl y[13]. Although there was no statistical difference owing to the sample size, it suggested that uremia and age might affect differently to immune system in extremely old ESRD patients.
In the analysis of predictors of mortality, we discovered naïve T cell depletion was independently associated with all-cause mortality. By analyzing the influence of physiological and immunological age, we found patients presented with lower naïve T cell count were associated with a significantly lower survival compared to those in the same age period but with a higher naïve T cell count. It led to consumption that naïve T cell could be a valuable marker of presenting overall immunological age in ESRD patients. In this respect, every patient should have this test as a part of immune disturbance evaluation and risk assessment of multiple complications, even with early intervention if possible. Another dominant effect by ESRD is a significant increase in percentage of memory T cells with advanced differentiation, which is also universal in age-related immune senescence. In this study, we find increased percentage of CD8+central-memory T cell was independently associated with mortality, which can be caused by increased naïve T cell turnover [14]. While increased percentage of CD8+EMRA T cell, on the other hand, could not predict mortality independently. This also confirmed that loss of naïve T cells might be a hallmark of immune aging, while increased differentiated T cells might partly if not entirely due to the decrease of naive T cells. This is partly explained by some epigenetic studies [15, 16].
Observations over the past 10 years have concordantly indicated that the process of naïve T cell homeostasis is profoundly affected by aging, with the changes aimed to maintain naïve T cell pool eventually leading to its further depletion and demise [17, 18]. Several factors need to be considered to grasp both the quantitative and qualitative changes of the naive T cells with aging:their production by the thymus, their homeostatic proliferation and the diversity of their TCR repertoire, which are all disturbed in uremic setting. A decreased thymic output of naïve T cells was observed in both CD4 and CD8 compartment in ESRD patients and was associated with severe infection episode and cardiovascular events in these patients [6, 9]. Data of thymic function are lacking for ESRD patient. However, it was reported that renal failure could lead to involution of thymus and spleen in animal experiments [19, 20]. A recent study indicated serum PTH concentrations were related to thymus atrophy evaluated by recent thymic emigrants, indicating mineral and bone disorder might be an underling mechanism [21]. Besides thymus atrophy, malfunction of peripheral maintenance may be a profounder reason of marked decreased naïve T cell in ESRD patient. Interleukin-7, as the central factor in maintaining naïve T cells, does not decline with age but decreases in ESRD patients [22, 23], indicating there may be a relatively insufficient increase in homeostatic proliferation in these patients. However, impaired proliferation function is not the major case in naïve T cell senescence. Actually, most studies support age-related loss of naive T cells in both healthy individuals and ESRD patients associated with an increased turnover [6, 23,24,25]. The most significant factor associated with T cell turnover is inflammation. It is posted that excess cytokines and increased expression of cytokine receptors, such as those produced in inflammatory conditions, could be detrimental for homeostasis and accelerate immune aging [26, 27]. Accordingly, accelerated aging has been described in several autoimmune diseases [28, 29]. In ESRD patients, inflammation is significantly enhanced by uremia [30], which could theoretically accelerate the processes of aging. Chronic immune stimulation could also lead to clonally expanded T cell population [31, 32]. Recent studies indicated ESRD patients presented reduced T-cell receptor diversity with clonal expansions [33, 34], which may has several clinical implications as it may increase the risk for infections, malignancies and CVD [14]. In addition, TCR-mediated signaling was also disturbed among these patients [35].
CMV infection has a substantial impact on the composition and function of circulating T cells and is recognized increasingly as a significant factor for T cell aging [36]. In infected humans, CMV induces an inflation of both the CD4+ and CD8+ effector-memory T cells, followed by a dramatic shrinkage of TCR repertoire, as such may add to the increased risk of infections as well as CVD in healthy and ESRD individuals [37, 38]. In ESRD, 70–100% patients are CMV seropositive [12, 39]. According to previous research, the additional effects of CMV latency on T cell ageing parameters in young to middle-aged ESRD patients were modest and confined mainly to the CD8+ T cells [40]. While in elderly ESRD patients, CMV latency seemed to promote highly differentiation in both CD4+ and CD8+ T cells [41]. In addition, recent studies indicated a higher level of CMV-IgG was associated with advanced T-cell differentiation and coronary artery disease [42]. It is also important to note that the expansion of CD28− T cells seems only occurred in CMV-seropositive patients with ESRD [43], while CD28− T cells had significant pro-inflammatory and cytotoxic function and was highly associated with cardiovascular complications, thus CMV infection should account for increased cardiovascular morbidity in CKD patients [38]. In this study, more than 99% patients were CMV seropositive, which may confound the effect to premature T cell ageing by CMV infection and uremia itself. However, since most studies indicated CMV infection mostly affected memory T cells, while in the current study we certainly found a strong association between naïve T cells rather than memory T cells with mortality, therefore CMV may not be a major reason of unpleasant prognosis in these patients.
Other factors could also lead to immune senescence in patients with CKD. Notably, decreased kidney function per se and the uremic milieu affect most of the factors known to accelerate aging, including DNA damage, phosphate toxicity, klotho deficiency, oxidative stress and telomere shortening [2]. Accumulation of uremic toxins is another important factor inducing premature aging of the T cells [9, 12, 23]. In addition, the treatment recipe including hemodialysis and iron supplementation may further exacerbate immunological ageing of the T cell compartment in these patients [44, 45]. After renal transplantation, despite of pro-inflammatory cytokines and oxidative stress decreasing to normal levels, uremia- associated prematurely aged T-cell immune system still exists [46], indicating uremia associated T cell aging may not be reversible. Deeper mechanistic insight into the phenomena of premature ageing as well as early diagnosis of CKD might improve the application and efficacy of interventions and provide novel lead to combat CVD and infection in CKD.
Our study had several limitations. First, since the study population was composed of 99% CMV seropositive patients, it was not known if the findings could be extrapolated to CMV seronegative ESRD patients. Secondly, T cells may exhibit aging-related changes in their effector functions that were not reflected by phenotypic changes. Finally, this was a single-center study, which might potentially limit the statistical power and its external validity.
In conclusion, this study posted that naïve T cells depletion was a strong predictor of total mortality in HD patients. Assessing T-cell ageing parameters could be useful for picturing the whole immune function and early identifying patients at high risk of profound complications. Since many factors of maintaining naïve T cells are disturbed in ESRD patients, further researches are required to promulgate the underling mechanism and explore effective method of preventing or even reversing uremia associated T cell premature aging.
The datasets supporting the current study are available from the corresponding author on reasonable request.
BMI:
CKD:
Central memory
CMV:
CVD:
ESRD:
End-stage renal disease
Effector memory
EMRA:
Effector memory RA
HDL-C:
High density lipoprotein- cholesterol
hsCRP:
high sensitivity-C reactive protein
LDL-C:
Low density lipoprotein -cholesterol
NT-proBNP:
N-terminal pro-brain natriuretic peptide
iPTH:
intact parathyroid hormone
sIL-2R:
soluble interleukin-2 receptor
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Huang L, Langerak AW, Baan CC, Litjens NH, Betjes MG. Latency for cytomegalovirus impacts T cell ageing significantly in elderly end-stage renal disease patients. Clin Exp Immunol. 2016;186(2):239–48.
Yang F, Shu K, Chen H, Chen I, Lay F, Chuang Y, Wu C, Tsai W, Peng Y, Hsu S, et al. Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease. Immun Ageing. 2018;15(1):15.
Betjes MG, Huisman M, Weimar W, Litjens NH. Expansion of cytolytic CD4+CD28- T cells in end-stage renal disease. Kidney Int. 2008;74(6):760–7.
Meijers R, Litjens N, Wit E, Langerak A, Spek A, Baan C, Weimar W, Betjes M. Uremia causes premature ageing of the T cell compartment in end-stage renal disease patients. Immun Ageing. 2012;9(1):19.
Ducloux D, Legendre M, Bamoulid J, Rebibou JM, Saas P, Courivaud C, Crepin T. ESRD-associated immune phenotype depends on dialysis modality and iron status: clinical implications. Immun Ageing. 2018;15:16.
Meijers RWJ, Litjens NHR, Wit EA, Langerak AW, Baan CC, Betjes MGH. Uremia-associated immunological aging is stably imprinted in the T-cell system and not reversed by kidney transplantation. Transpl Int. 2014;27(12):1272–84.
This work was supported by the Shanghai Clinical Medical Center for Kidney Disease Project support by Shanghai Municipal Health Commission (No. 2017ZZ01015), Shanghai Municipal Hospital Frontier Technology Project supported by Shanghai Shen Kang Hospital Development Center (No. SHDC12018127) and Natural Science Foundation of China (No. 81800677).
Department of Nephrology, Zhongshan Hospital, Fudan University, NO180, Feng'lin Road, Xuhui District, Shanghai, 200032, P.R. China
Fangfang Xiang, Rongyi Chen, Xuesen Cao, Bo Shen, Xiaohong Chen, Xiaoqiang Ding & Jianzhou Zou
Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
Fangfang Xiang, Xiaoqiang Ding & Jianzhou Zou
Shanghai Institute of Kidney and Dialysis, Shanghai, China
Shanghai Medical Center for Kidney, Shanghai, China
Xiaoqiang Ding & Jianzhou Zou
Fangfang Xiang
Rongyi Chen
Xuesen Cao
Xiaohong Chen
Xiaoqiang Ding
Jianzhou Zou
XFF analyzed the data and drafted the paper; ZJZ and CXH made the diagnosis and designed the experiments; DXQ, SB and CXS revised the manuscript; XFF and CRY collected the data. All authors read and approved the final manuscript.
Correspondence to Jianzhou Zou.
The study and protocol were reviewed and approved by the Medical Ethics Committee of Zhongshan Hospital, Fudan University. Written informed consent have been obtained from participants. The study complies with the Declaration of Helsinki.
Figure S1. Flowchart of flow cytometry analysis to identify T cell subset. T cell subsets were defined by flow cytometry: Naive T cells as CCR7+ and CD45RO-; central memory T cells as CD45RO+ and CCR7+; effector memory T cells as CD45RO+ and CCR7-, and EMRA T cells as CD45RO- and CCR7-.
Additional file 2
Figure S2. Overall survival curves according to age – CD4+naïve T group. Patients were divided into six groups according to age and value of CD4+ naïve T cell count. Kaplan-Meier analysis revealed that survival rate was significantly different between six age- CD4+ naïve T groups (p < 0.001).
Xiang, F., Chen, R., Cao, X. et al. Premature aging of circulating T cells predicts all-cause mortality in hemodialysis patients. BMC Nephrol 21, 271 (2020). https://doi.org/10.1186/s12882-020-01920-8
T cell aging
naïve T cells
Submission enquiries: bmcnephrology@biomedcentral.com


text:
Jim DeLa
Jim has more than 40 years of reporting and editing experience in radio, TV, newspapers and nonprofit organizations in markets including Washington, D.C., Maryland, Colorado, Hawaii and Florida.
Jim has worked a wide variety of beats in his career, including religion, NASA and baseball. He is a graduate of the University of Maryland. He holds a private pilot certificate and is a PADI-certified Master Scuba Diver Trainer.
In his spare time, he umpires women's fastpitch softball at tournaments across the state.
Civil suit against Laundrie family moving forward, judge rules
Updated: Jun. 30, 2022 at 3:32 PM CDT
By Melissa Ratliff, Jim DeLa and Debra Worley
Circuit Court Judge Hunter Carroll denied the motion by Christopher and Roberta Laundrie to dismiss the civil suit brought by Joseph Petito and Nichole Schmidt, the parents of Gabby Petito.
Brian Laundrie confession claims Gabby Petito's death was mercy killing
Updated: Jun. 26, 2022 at 12:36 AM CDT
By Melissa Ratliff, Jim DeLa and Gray News staff
In a confession letter written prior to his death, Brian Laundrie claimed Gabby Petito's death was a mercy killing after she suffered a head injury in a fall.
Fla. class president told he couldn't speak about being gay uses hair metaphor
Updated: May. 23, 2022 at 5:36 AM CDT
By Tatyiana Hayes , Jim DeLa and Gray News staff
The senior class president was warned not to speak about his experience as a gay student or criticize the state's "Don't Say Gay" law during his graduation speech.

redpajama_set_name: RedPajamaCommonCrawl


It is this statement that causes the apostles to start to think and ponder as they left Jerusalem that day. What Jesus was referring to was the events that would transpire in 70 A.D. some forty year in the future, and only six years after the final completion of the overall temple itself.
Matthew 24:3 – Later, Jesus sat on the Mount of Olives. His disciples came to him privately and said, "Tell us, when will all this happen? What sign will signal your return and the end of the world?
Jesus mentioning the destruction of the temple led the apostles to think that the destruction of the second temple would signal his return to earth. This is why they posed the questions to Him in such a manner. Not realizing that their two questions had two completely different answers.
One point that does need to come to light here is the pattern in which are followed with respect to the first temple. When Solomon's temple was destroyed in 586 B.C. it was followed by Israel's captivity to the gentile nation of Babylon, which lasted seventy years. It is during this time period, it must be noted, that Daniel lived and wrote his prophecies.
But back on point, it is the fact the temple is destroyed and then there is exile for the Jewish people from their homeland. When the second temple is destroyed the Jewish people are spread throughout the world and do not return to Israel and re-establish the nation until 1948.
The pattern is one that is constant with the Jewish people. They have faith, they fall from their faith. They rebel, they are punished. Each time they are punished it is worse than the time before. This is God showing all that to spare the rod is to spoil the child and thus rebellion. So God never spared the rod and each punishment suited the nation as a whole, and each one worse than the last.
So if they had pondered it correctly they would not have thought that the destruction of the temple meant His return, but their rejection as a nation of God once again.
In today's climate you can see that out of all the generations before this one that is currently on the rise, there was a form of discipline. Within the last few decades though, discipline has become something discouraged and as a result the youths in all societies no longer respect their elders and in turn are rebelling. Does this not point to a coming correction form God Himself? I think it does, and woe unto to those that deny the existence of God.
So, the questions are: 1) When will the temple be destroyed? And 2) What signs will single Christ's return and the end of the world?
As I have just pointed out these are not related, but to the apostles they were. Due to their current blindness when they asked the question. The answers are covered as we progress through this series.


What a bunch of hypocrites and liars. They all need to go, and I mean every member of Congress. It is not supposed to be a career and when it becomes that, they just bend over backwards for the NRA so they can keep their jobs.


text:
Haunted Historic Homes in Jonesborough TN
Jules Corriere
Jules Corriere is a playwright and theater director. She has written over 40 plays, one of which was performed at the Kennedy Center in D.C.
Carolyn Moore's House in Jonesborough, Tennessee
photo by Jules Corriere
Tennessee's Oldest Town is One of America's Most Haunted
I've actually stayed in several of these homes. The pictures I've taken of these wonderful buildings and homes in Jonesborough certainly show how historic they are, but don't even begin to tell the stories of the people who once resided (and some say, still do reside) within the walls. The town's local restaurant, the Cranberry Thistle, home of the Storyteller's Guild as well as the best homegrown bluegrass you'll hear this side of the Appalachians, boasts right on their menu to keep an eye out for their resident ghost. Across the street from the Thistle sits the Institute for Paranormal Technology. If you are interested in a ghost tour, they offer these nightly, up and down the historic Main Street, built in 1779, which is fourteen years before Tennessee even became a state. These buildings are not reconstructions, like you'll see in so many other "historic towns". Andrew Jackson and Andrew Johnson walked the same streets you'll travel as you visit these buildings. They stayed in the Historic Chester Inn, which now houses the International Storytelling Center, as well as the newly opened museum in the basement of the building. Daniel Boone and Davey Crockett both strode these streets. In fact, Daniel Boone's famous tree carving, "D. Boone cilled a bar. on tree in year 1790" (D. Boone killed a bear on this tree in the year 1790) was discovered just on the outskirts of the town. Senator David Crocket spent years going back and forth to the historic Courthouse on Main Street. Those are some of the famous people we know about. But the real stars, according to guests of the Eureka Inn, or perhaps visitors who stop in to visit my friend Sue Henley's home at the end of Main Street, are the strange orbs of light, or the sudden cold spots that move through the room, sending goosebumps up the spines of everyone present. In this lens, I take pleasure in sharing with you the very beautiful, historic homes, and stories about the people who lived in them. I'll leave it up to you to decide if you believe. As for me...I lived in some of these homes (while working in Jonesborough on the play I wrote about the town's oral histories), and I will tell you one thing...I believe.
Carolyn Moore's Home
I Was Lucky Enough To Live Here For 6 Spooky Months
In this picture, the window immediately above the turret was where I called home for 6 months. Most of the days were uneventful. It took some time to get used to the hissing sounds of the radiator, and the odd creeks and moans of the house. I lived here while I was working on a play that I wrote for the town of Jonesborough. The woman who owned the home, and who was really a supporter of the play and the project, sadly passed away just months before we began rehearsals. I interviewed her for the play, and actually used one of her stories in the play. When the town was looking for housing for the artists working on the project, myself included, her daughters offered the home to us, and said, "Mom always hosted the storytellers who came for the National Storytelling Festival in Jonesborough. She certainly would want you to stay here." A somewhat spooky coincidence then occurred. Ray Hicks, one of America's most famous Jack Tale storytellers, stayed in the room across the hall during the storytelling festival, year after year. Well, I happened to have gathered a Ray Hicks story and used it in my play, "The Whole World Gets Well", which ended up touring in London and Edinburgh. Ray passed away a few years ago, but I would imagine his lanky 6'7" frame walking through the home. I did hear footsteps, coming up the main set of stairs, many a night. One person told me it was "Sarah". I'm not sure who or what it was, but I know that I heard the boards creek-- and I know it was NOT the radiator, no matter what anyone tries to tell me.
The Christopher Taylor House - Circa 1778: Andrew Jackson Slept Here
christopher taylor house
The Christopher Taylor House is perhaps one of the most striking buildings you will see on Main Street in downtown Jonesborough. It was built in 1778, although Main Street was not it's first location. The house was moved about a mile from it's original location and then restored. Andrew Jackson stayed in this home for several months when he lived in Jonesborough.
The house was built by Christopher Taylor, who was sent to Jonesborough from North Carolina, in order to "fend off Indian Attacks in the region."
The home is a 2 story log cabin. A small narrow stairway leads to the upstairs. A brick fireplace provided heat during the cold Jonesborough Winters. Taylor lived in this modest home with his wife and 13 children. Keep in mind that the home, in total, is about the same square footing as 2 modern day living rooms-- No more than that. I think codes compliance would have a problem allowing that many people in such a small space according to today's standards!
The Taylor house is reported to be one of the most haunted buildings in America, even after it's move. Andrew Jackson's ghost has been seen by generations of frightened visitors.
The Taylor House Before the Move - We're Talking History!
The Christopher Taylor House in its original location, about a mile and a half from main Street. This image is taken from a vintage Jonesborough postcard from over 100 years ago. Imagine, a hundred years ago, this house was already seen as an historic home and a tourist spot! It really reminds you of just how old this region is, how long it has been settled, how much history has passed through these hills.
The Historic Chester Inn Circa 1797 - One of the liveliest places for Ghosts in all of Jonesborough
The Historic Chester Inn has been in in continuous use as an inn, apartment complex or dwelling since it's beginning in 1797. It is often a site visited on the Paranormal Institute's nightly ghost tours of the town. It is one of the places where ghost hunters have been able to capture images of orbs of light, especially under the upper balcony on the left hand side of the building.
The Inn has deep roots in American History. Andrew Jackson held a reception for his friends on the upper balcony. Andrew Jackson, Andrew Johnson and James K. Polk, and John Sevier, all frequented this establishment.
Ghost Stories at Jonesborough's Festival
Ghost Stories at the Storytelling Festival
Do You Know About The Festival?
For 39 Years, Jonesborough, Tennessee, has been the host of the National Storytelling Festival. In fact, the town has been named the "Story Telling Capital of the World". Beginning the first Thursday in October, 10,000 people descend upon the town to hear some good old fashioned storytelling. It is a long tradition of the festival to have "Ghost Stories" in the evening, when the sun has gone down, and there is a chill in the air. Hundreds of people gather on the hillside near the Gazebo and just yards away from the Colonial Era Old Mill Spring. They lay out their blankets and quilts, sipping hot cocoa, apple cider, and most recently, caramel apple cider. Then, when the stars begin to twinkle, the best storytellers in the world take to the small gazebo stage and lure the audience in to their web of haunted horrors for an evening full of ghost stories.
This Halloween
Put Ghost Stories On Your Bucket List. No Pun Intended.
Put Ghost Stories on Your Bucket List - If You Dare!
If you love stories, especially ghost stories, this should definitely be a bucket-list event. Click this link to check out this event in October. Come for the Haunted Homes, and stay for the haunted stories!
Ghost Stories at the Festival
Click here to find out more about Ghost Stories at the National Storytelling Festival In Jonesborough...if you dare!
Rosolowski's Home
Lucky Luciano's Girl Friend Lived Here
This 140 year old home on College Street belongs to my good friend, Katy Rosolowski. She loves to give tours. (And she was also kind enough to allow me to spend a week there while I was in town gathering stories and holding auditions for their latest historical play, which I wrote. But I digress...) Katy loves to give tours of the home, including the basement, where you can actually see thumbprints in the plaster by workers from the middle of the last century. I love putting my hand prints on theirs, knowing that so long ago, those long gone hands carefully built this masterpiece of construction.
Katy takes delight in showing all of the hidden locations in the house, including the "Harry Potter" closet under the stairs, which is accessible only through a disguised door in the bathroom.
The claim to fame of this home is that a previous owner was a one-time friend of Lucky Luciano. Not only that--- this brave lady went against Lucky and his mob, and was instrumental in helping the police finally "get him!", as she says. It's hard to imagine now this sweet grandmotherly woman once ran around with the likes of Lucky. Makes me want to ask my grandparents who they hung around with, back in the day.
Buffalo Soldier's Home
Alfred Martin Rhea's Home
Buffalo Soldier and Great American
Alfred Martin Rhea was born a slave in the year 1849. After freedom, he joined the re-United States of America's army. He was part of the 10th Cavalry Division, known as the Buffalo Soldiers. He fought in the Spanish-American War, and it was his honor to be the man who planted the U.S. Flag on San Juan Hill. After he retired, he moved back to Jonesborough, bought property there, and built a house on Depot Street, across from the church that his great neice, Nancy, attends today. The American Dream. It didn't come to his family before him. It didn't come easy, when it came to him. But it's never easy being the first at anything.
Nancy told me her great-uncle's story, which I used in the play, "I Am Home".
I think about Alfred's story a lot, especially during times when I think I'm having it rough, and don't know if I'll make my goals, and I look at everything Alfred accomplished. He is a hero in so many ways, and I am so glad that Jonesborough has made such an effort to save his humble home. His home and lot is an example of a small but huge contribution he made to his community.
Institute For Paranormal Technology
Ghost Tours?
Right on Main Street you can walk in and sign up for a ghost tour. Really. Each night, the Paranormal Technology folks take tourists and townfolks through downtown Jonesborough in search of the many reported ghosts. My friend Brandi has gone ghost hunting with her dad, and took a very eerie photo of a glowing orb under the Historic Chester Inn. I do not want to give away other usual characters that are spotted on a regular occasion during these tours. I wouldn't want to spoil it for you. So you should definitely sign up for a ghost tour one night while you're in town. No trip to Jonesborough would be complete without it.
Book Your Own Ghost Tour
Follow this link and talk to the very folks who run the Ghost Tours in Jonesborough. Bring your cameras-- video and still. You will be AMAZED. And probably a little bit creeped out!
Paranormal Technology Company
These folks will be glad to sign your up for your very own personal ghost tour!
Ghosts are on the Menu At the Cranberry Thistle - Read For Yourself
Cranberry Thistle Menu
The folks at the Cranberry are proud of their resident ghost.
Cranberry Thistle
The Cranberry Thistle Restaurant
This restaurant is just a few doors down from the International Storytelling Center. It's one of my favorite places to grab a cup of coffee. It's on the honor system there. You put your dollar in the bucket, pick out your mug, and pour yourself a cup of joe. All the cream and sugar is there, too. You can tank up as much as you want, for a buck. While you're there, you might see a shadow. Or did you? You might feel a chill. Or did you? The Cranberry Thistle has long been known to have unseen inhabitants among them. But, they're the friendly sorts. They must love music, too, because each weekend, you'll hear the best local bluegrass music. The ghost must love stories, too, because every Tuesday evening, the Storyteller's Guild gets together and they swap stories for all to hear. Be sure to check out the back room. Your chances of spotting something spooky are much greater back there.
Davy Crockett's Home Site
Davy Crockett Slept Here
No, Really, He DID
In fact, he was born here in this log cabin, built in 1771. Senator David Crockett entered into legend even before his untimely death at the Alamo. Serving as Tennesee's Senator, Crockett was known for his down-home speech among the political set of the day, ruffling many feathers. He was the common man's (person's) Senator, and went to work at the Senate dressed like the common man. And talking like him, too. A red-head, he was also tempermental, and when he was finally fed up with the political system, he told the rest of the folks in Tennessee, "You go to hell, I'm going to Texas!". Which he did. And then...well, ever heard of the Alamo? He did too. He fought there. That's pretty much the end of the story. But this is his birth place. It's on an amazing piece of land, which is still mostly wild and free, as it was when he lived here. I walked down some fields, and then along the stream which runs in front of his home, and I imagined, "yes" I would be fierce about my home and my place if I grew up in such amazing beauty, too. He was a fighter, but this was something truly worth fighting for. The home sits a little ways away from downtown, but it is well worth the drive off the road to get there. Just be careful of the poison ivy in the summer.
A Book Worth Reading - Halloween or Anytime
type=text
Sometimes, when you're alone at night, and you hear a sound, do you think it is just the house settling, or does something more enter your imagination?
Comments - Have you ever stayed in a haunted home?
Eileen Fitch Douvarjo on December 26, 2016:
Have lived in one, saw the ghost age 8, slept in a family home where a terrific lady lived and died..she made her presence know to myself and younger brother. As an adult, in our own new home..built on the grounds of a Civil War battle site, as did all three of our children.
Guest on April 20, 2015:
I use to ghost hunt, but my side kick died. She was my best friend and I miss doing it. I was closer to the spirits then and seem to have lost it. I really hate that. My friend could see them, and would tell me when it pasted me as I was going to her side, and them to my side. We have picked up ghost hitch hikers, and I have had one go through me. The old farmhouse I live in is way over 50 yrs. old. I would say about 75 to 80 yrs. old. I would be on the computer early morning and smell coffee brewing. Bacon cooking and eggs frying. It would make me so hungry. When I first moved here, which my friend who lived here before, for 7 yrs. The first week, I had a mattress thrown down in the back bedroom. I had gone to bed, lying in the middle facing the bathroom. And as good as you talking to someone face to face, it said "Good night honey, I Love you. Talking about a shock, it did that. I have seen the bottom of a woman's gown in my bedroom. Things have been misplaced. Calls with no one on the other end, or strange noises. I have seen a man ghost wearing overralls and a checkered shirt, heading to my land lords shed where his office and farm vehicles. And he disappeared when he got to the sliding door. I also heard a woman and 2 men talking on the other side of the door. When the woman talked, the men were quite, and when they talked she was quiet. I could not understand what they were saying, its was mumbling. Like my friends Dad said, it was not meant for us to understand. I have also seen soldiers in gray, protecting the land. One on 1 side, two on the other. The one would go by the side of the house to the back and the other 2, one would go by the other side of the house, to the back, and the other one would pass me and go to the other side. I have seen a house across the road that had been torn down many, many years ago. My friend told me, he use to go over there to play. My sisters Yorkie was put to sleep 12-26-2014 of cancer he had. I have seen him, and other different kinds of dogs, laying down wagging their tails. So this is my, never a dull moment. This house I live in is a 4 room house. 2 bedrooms, a kitchen and living room. Each door lead to one of the 4 rooms. A small addition was added for a small bathroom on one end, and a small laundry room. A small porch in between. I have seen 3 women dressed in Victorian Style clothes. I see to much. LOL But i'm sorry its long, I have so many to tell. I told my Mom and she thinks I lost it and crazy until the living room fan came on by it self. Thanks for reading.
halloweenprops on September 14, 2012:
No, I've never stayed in a haunted home. Enjoyed the lens!
wheresthekarma on July 14, 2012:
Fun lens!! Love anything paranormal!
Margarita Boettcher from Morrison, Colorado on June 30, 2012:
I love! If I was an angel i'd bless it. If I were a ghost I'd haunt it!
JoshK47 on June 22, 2012:
I absolutely love haunted history - and I not only stayed in one, I'm fairly certain I lived in one. Blessed by a SquidAngel!
sheezie77 on June 09, 2012:
Nice lens, I like it! Squidlikes!
Michelle from Central Ohio, USA on June 06, 2012:
I had family that lived in Jonesboro for many years. I've seen a few of these. Pretty cool stuff. Squid Angel Blessed!
VeseliDan on June 05, 2012:
No, luckily I haven't stayed in a haunted home yet. I believe in ghosts and I find these stories very scary. *blessed*
kimmanleyort on April 26, 2012:
Not that I know of. This town sounds like quite the interesting place. Beautifully written.
anonymous on March 10, 2012:
ya, only for 2 years, but i must say it was a horrible experience.
TransplantedSoul on February 16, 2012:
Whether ghosts, imagination or other, "hauntings" can be entertaining and intriguing.
Tolovaj Publishing House from Ljubljana on January 31, 2012:
Yep, I did! But there were nice ghosts, so nothing really spooky happened... Very cool lens, thanks!
anonymous on December 16, 2011:
I love old, spooky places. I frequent Tennessee a few times a year, so I'm going to have to make Jonesborough in 2012. Thanks for sharing!
WriterJanis2 on December 05, 2011:
I would love to visit these places and stay in one of them. Very enjoyable lens!
waldenthreenet on November 18, 2011:
Appreciating your topic and enjoying your presentation. I cast my ballot for "LIke" on this one. Thanks so much.
norma-holt on November 08, 2011:
Gosh, one doesn't think of famous people living in these types of places. Featured this on Most Haunted Houses. Well done
dahlia369 on October 31, 2011:
just the right time for haunted homes lens. Great job, congratulations! :)
Vicki from USA on October 31, 2011:
Fascinating lens! I envy you for getting to live in some of these beautiful, spooky houses!! ;-) I enjoyed this lens about haunted historic homes in Jonesborough, TN.
Vikk Simmons from Houston on October 31, 2011:
Great idea for a Halloween subject. My friend was telling me about a ghost tour she went on a few weeks ago here in Houston. Congratulations on making it to the top 50 in the Halloween contest finals, too.
BeyondRoses on October 31, 2011:
As a child, I lived in a Haunted Historic Home for 7 years. I know enough about it to know that today, if someone offered to pay me to stay overnight in the house, I would not do it. It's kind of like an old movie, where some one comes up with the idea, to pay a million dollars to anyone that can last the night alive in a haunted house.
MariaMontgomery from Coastal Alabama, USA on October 20, 2011:
A really (spooky) nice lens that I enjoyed reading. Keep up the good work.
APackageAtTheDoor on October 17, 2011:
No, but now we know where to go if the urge to stay in a haunted home strikes. Nice lens, thanks!
mothersdayflowersmacon on October 15, 2011:
There are a ton of haunted homes in Savannah GA as well.
JoyfulReviewer on October 15, 2011:
Congratulations on your lens being included on the "It Was a Dark and Stormy Night"
monsterboard!
Jellyrolldesigns on October 13, 2011:
Boy, this is giving me the creeps! Great lens and the ghost story tellling festival sounds like so much fun!
anonymous on October 09, 2011:
Your "I believe" got my attention for sure! I've never stayed in a haunted home that I'm aware of but have had spiritual encounters that can't be explained in the natural. Nicely done!
iWriteaLot on October 07, 2011:
I used to live in a small town in Ohio and we had a Ghost Story Festival every Halloween. So much fun! I live in Kentucky now. Jonesborough TN would be a neat weekend trip. Thanks for the info.
Candace Bacon from Mad Laboratories on October 04, 2011:
These are spooky places. Jonesborough is just down the road from me. I love to go to the ghost stories during the Storytelling Festival. Happy Halloween!
Mary Norton from Ontario, Canada on October 01, 2011:
I used to get scared when alone in our century old home so I would not be able to stay in those houses.
GypsyPirate LM on September 30, 2011:
No, I don't really think that I have. I'm not sure what I would do...as it is, I can get pretty jumpy just at regular house noises. But, I really enjoyed reading about them here. Thanks for sharing!
NevermoreShirts on September 30, 2011:
Great spooky lens! Awesome work!
Kevin Lerner from Washington, DC on September 27, 2011:
Good lens. (makes me want to avoid Jonesborough!). How about something about top 10 haunted homes in America?
Donnette Davis from South Africa on September 08, 2011:
Lovely lens, thank you..
Jennie Hennesay from Lubbock TX on September 07, 2011:
Great history of haunted houses. Thanks for sharing.
LissaKlar LM on September 07, 2011:
Cool Halloween lens! I learned a lot...thanks!!
darciefrench lm on August 17, 2011:
Yes, I lived in one for a year - we got quite used to it :) Loved this article, many thanks.


The European Union is preparing a new list of American goods to hit with protective measures, according to a person familiar with the move, in case a mission to Washington next week fails to persuade U.S. President Donald Trump not to raise car tariffs.
The European Commission briefed EU ambassadors Wednesday on trade relations with the U.S., and said it was working on so-called rebalancing measures that would be ready immediately if the U.S. imposes levies on European car exports, said the person, who asked not to be named because the meeting was private.
When Commission President Jean-Claude Juncker meets with Trump on July 25, he'll bring two main negotiating proposals in an effort to tamp down the escalating trade tensions: an offer to discuss the reduction of levies on cars and car parts among all major auto-exporting countries in a so-called plurilateral deal; and the possibility of broaching a limited free-trade agreement, according to a separate official familiar with the EU's thinking.
The U.S. is in the midst of a probe into whether car imports damage national security, which could trigger the 20 per cent tariff on autos that Trump has threatened. Washington has already hit the EU with duties on its steel and aluminum exports using the same national-security justification, which led to European levies on 2.8 billion euros (US$3.3 billion) of American goods.
The EU isn't allowed under global rules to reduce its 10 per cent tariff on American cars unless it either does so for all WTO members or reaches a bilateral accord with the U.S. that covers "substantially all" two-way trade. A plurilateral deal modeled after the Information Technology Agreement, which abolished tariffs on some IT products traded between its signatories, is allowed under WTO rules.
Plurilateral accords involve a group of like-minded countries that are typically limited to specific sectors of goods or services. The WTO permits these types of negotiations as long as the benefits are provided to all WTO members on a most-favored nation basis. It is faster and less burdensome to negotiate these accords rather than multilateral deals because they don't require the approval of all 164 WTO members.
EU member states are divided on the next course of action, according to a separate official. Germany, which shipped 640,000 cars to the U.S. last year, is eager to negotiate a solution with the U.S. administration.
The French are less enthusiastic and consider the new auto tariffs a foregone conclusion, according to another official. They want Juncker to approach the Trump meeting with options, but say now isn't the time to negotiate.
--With assistance from Nikos Chrysoloras.


Look down from Schauer's vineyards - one of Europe's highest winemaking locations - and imagine: 300 million years ago, everything you see below lay beneath a prehistoric ocean; and where you're standing was an island. Mindblowing how things evolve.
This wine is testament to that. Sauvignon Blanc from Austria! Planted on severe slate slopes, with uncompromising character. Minerality, Alpine herbs; and crisp and clean as mountain air. An extraordinary meeting of modern and ancient. Who said time travel is impossible? Just take a sip!
The Schauer Winery in Kitzeck, South Styria has roots in winemaking leading back to 1757. Since 2010 the family business has been run by Stefan and Bernhard Schauer, passed down to them from their father, Karl. The wines from Kitzeck are significantly different than other wines of the region due to a unique geological history. The incredibly steep vineyard slopes of Kitzeck once rose out of an ancient prehistoric sea and the slate soil allows for the wines to have an inimitable mineral character. The Family Schauer cultivates fifteen hectares around Gaisriegel. The typical Styrian varieties are grown here as well and next to the traditional wines there is also a broad assortment of single vineyard wines from very steep sites. The young winemaker Stefan strives to highlight the unique character of each vineyard. The family's wine tavern is situated in the middle of idyllic vineyards right next to the wine cellar where you are able to enjoy their wines with tasty regional speciailities.


It is important that you are familiar with the JEE Main 2019 Syllabus because you can not get ahead with the preparation without knowing the chapters that you have to deal with. JEE Main 2019 is not an impossible exam to crack. You can do so with an extra effort and a well-tuned preparation timetable.
Here we will let you know what are the important chapters, subject wise, that you will need to cover for JEE Main 2019. There are no changes in the syllabus as of now. According to the trends of the examination, this year too, the syllabus will remain the same. We have provided here the JEE Main 2019 syllabus in an easy to understand format. Go through it so that you can start your IIT JEE 2019 preparations as early as possible.
As for the candidates applying in the month of January, the application procedure starts from September 2018, itself. It becomes crucial for every candidate to be well aware of the exam pattern and the syllabus for JEE Main 2019. Candidates can keep this page out, for more detailed information on JEE Main 2019 Syllabus.
According to the press release, the MHRD confirmed that there won't be any changes in the JEE Main 2019 Syllabus. So, candidates can start preparing as per the syllabus listed the last year. The JEE Main 2019 Syllabus will be available in the information brochure on the official website of NTA. Candidates can check the important date and can start their preparation n full swing!
It will be a computer based online test.
It will be an objective type (MCQ ) question paper.
English and Hindi languages will be the medium available to appear for the exam. Although, in test centers across Daman, Diu, Gujarat, and Nagar Haveli – Gujarati will be also given as a language option.
30 questions each shall be asked from Physics, Chemistry, and Mathematics section for Paper 1(BE/BTech), whereas 50 questions will be asked from the aptitude section while 30 questions from Mathematics section and 2 questions from the drawing part for candidates appearing for Paper B(B.Arch/B.Plan).
Marking Scheme will be as follows – For every correct answer, 4 marks will be awarded and for an incorrect answer, there will be a negative marking of 1 mark.
No marks will be deducted if an answer is left unanswered.
Once we are clear with the JEE Main 2019 Exam Pattern, without further ado let's start discussing the JEE Main 2019 Syllabus! We will also suggest you to go through the eligibility criteria.
The paper will basically consist of 3 sections of candidates appearing for BE/BTech courses and one section more, that of drawing for candidates appearing for B.Arch / B.Plan.
The IIT JEE Main 2019 syllabus will be pretty much the same as the NCERT syllabus of class 11 and 12. So if you are following the same in your school, you have an advantage. The subjects that JEE Main 2019 Syllabus will cover are Physics, Chemistry and Mathematics for Paper 1, and for Paper 2, there is a separate syllabus. We have listed down the syllabus for you in the table below.
The above were the chapters that you will need to cover to prepare for JEE Main 2019. Below we are providing you with the detailed description of the topics that you will need to cover under each chapter of the subjects. The syllabus is of JEE Main 2019. There is no changes are announced in JEE Main 2019 Syllabus till now.
JEE Main 2019 will have 2 papers as every year. There are certain frequently asked question about these two papers, which we clear below. You must be clear about the papers as it will help you to sketch out a proper JEE Main 2019 Timetable for preparation.
Q: Do I have to clear Paper 1 to apply for Paper 2?
A: No. Paper 1 is for B.Tech/B.E Candidates and Paper 2 is for B.Arch./B.Planning Candidates. Both are not related, merit lists and results for the both will be seperate. You may need to take both the Papers if you select courses that fall under both B.E./B.Tech. and B.Arch/B.Planning.
Q: Are Syllabus for both the Papers different?
A: Yes, they are different. As clearly listed above in the table and in the official syllabus of JEE Main, the syllabus for both the Papers will be different.
Q: Which Paper is tougher?
A: Experienced candidates of JEE Main say that both paper have their own level of difficulties, but one may find Paper 2 a bit easier than Paper 1. But it all comes down to your preparation.
How to cover the entire syllabus?
The syllabus may seem a bit lengthy and overwhelming. But the good thing is you are already in flow with the syllabus as you are studying the same in your schools, especially the students of CBSE Board whos are following the NCERT pattern. But to catch up with JEE Main 2019 Syllabus which is a mix of both class 11 and class 12, you will need to stay ahead of your school.
Prepare a timetable of your own that will help you cover the JEE Main 2019 Syllabus by December, so that you have plenty of time for revision and previous years' question paper practise. Or, you can save time, and refer to the JEE Main 2019 Timetable that we have prepared for you.
Stick to the timetable and follow it without fail.
To cover all the chapter from each subject, divide the time equally among all. Give few extra hours to the chapters that you are weak in.
Avoid procrastination and concentrate while you are preparing.
Don't go beyond the syllabus. Sticking to the JEE Main 2019 Syllabus will be enough if you cover the whole of it.
Lastly, start now, so that you don't just complete your syllabus but you can have plenty of time for rigorous practise and revisions.
I have taken exam of class 12 in 2018 From BSEB but due to low marks i decided to give improvement in 2019 so sir pls help during filling the jee mains form fill which year of passing i have to choose sir pls help….
sir kya ap paper upload karrnge mtlab practice papers?
can we know that how many questions put up from each chapter to P.C.M.
officially there is no chapter wise topic distribution. if you want we can provide important topics article.
You need not to give JEE Main 2019 examination to apply for B.Sc courses.
Will paper 2 be available for jee mains practice test by nta? ???
Not confirmed yet, may be available for question other than drawing test.
Sir , Is level of papers in all shifts maintain at single level by nta ?
Sir, Differential Calculus is not given in the syllabus though it is a major topic of Mathematics. As per my understanding Differential Calculus and Differential Equations are two different topics. Plz clear my doubts.
there will be no maths in the jee paper 2?
It is now required. In question paper aptitude test contains mathematical questions.
will paper pattern be remain same for the candidates studying both selfly & by coaching resrectively????
Sir If i want to do Computer engineering which paper should i apply for??


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The first victim was found inside a crashed car.
Police say the found the second victim a short distance away.
Investigators believe the robbery was a targeted attack.
Two men died after an attempted robbery in District Heights, Maryland, early Wednesday ended in gunfire.
Loved ones gathered near the scene Wednesday morning, collapsing to the ground in tears.
Kevin Muse, 26, and Samuel Paige, 27, died after a car Paige was found inside crashed into a tree, Prince George's County police said.
Officers found Paige, of Suitland, inside the crashed car near Aztec Drive and Gateway Boulevard about 4:30 a.m. He was pronounced dead on the scene. Muse, of District Heights, was found a short distance away. He was taken to a hospital, where he died.
2 Found Shot to Death After Attempted Robbery in Md.
Two people are dead after an attempted robbery in District Heights, Maryland, ended in gunfire.
Investigators do not believe the incident was random.
"This car and the individuals in the car were targeted," District Heights Police Chief Elliott Gibson said.
Sources said a third person is believed to have been in the car and survived the shooting.
Muse was a father, neighbor Randy Thomas said.
"Real good guy. He never caused no problem. He never give anybody any kind of problems," he said. "It's sad to see him go like that, knowing that he just got a baby and stuff like that at home."
No information on a suspect was released immediately.
"Our investigation is continuing, and as events present themselves, we'll share them," Gibson said.
In 2016 thus far, 32 people have been murdered in Prince George's County. Nine of the killings occurred in the past two weeks. Nine of the killings were categorized as domestic in nature.
Anyone with information for police is asked to call 301-772-4925, or to remain anonymous, 1-866-411-TIPS. Information also can be sent in a text message to CRIMES that includes PGPD, or by visiting www.pgcrimesolvers.com. A reward is offered.


text:
Xiangqi Greats :
Zhao Xinxin 赵鑫鑫
Name: 赵鑫鑫 1988-present
Birthplace: Zhejiang province
Titles: GM
Summary of achievements:
1. 2000 runner up in the under 12 Chinese National Youth Xiangqi Singles Championship.
2. 2001 champion of the under 14 Chinese National Youth Xiangqi Singles Championship.
3. 4th board on the Shenzhen team when they came in 2nd place in the Chinese National Xiangqi Team Championships in 2002. Many had considered the Shenzhen team to be underdogs. Zhao had a recored of 7 wins, 2 draws and zero losses!
4. Champion of the Youth under 16 section of the Chinese National Youth Xiangqi Singles Championship. He was bestowed the title of Master for this achievement. He won the tournament with a record of 9W1D1L.
5. Represented China in the 2002 Asian Xiangqi Championship Youth Section, and was champion.
6. Made Grandmaster in 2007 after winning the 伊泰杯 Yi Tai Cup, defeating GM Zhao Guorong, Lv Qin along the way. He was only 19 years old when he became grandmaster.
7. Won the 嘉洲杯 Jiazhou Cup in 2008 on his very first try. Only National champions and grandmasters were allowed to participate in this competition.
Nickname: 小天王 which translated means young heavenly king.
Zhao Xinxin was born in 1988 and is a native of Zhejiang province. His father was instrumental in encouraging him to play Xiangqi. Early in his childhood, he received pointers from various masters, amongst them 陈寒锋. He game rapidly improved and by the time he was 12 years old, he was making headlines on the national scene by coming in runner up in the under 12 section of the National Xiangqi Youth Championships.
He improved by becoming champion in the under 14 section of the same event one year later. For his achievements, he was recruited to the Shenzhen team and played 4th board in the 2002 Chinese National Xiangqi Team Championships. What was amazing was his 7W2D0L record! Imagine, he was only 14 at that time when he went up against accomplished adult masters. His contribution was instrumental in allowing Shenzhen to come in runner up in that tournament. Shenzhen was very much the underdog, whereby Guangzhou, Shanghai and many other teams were favorited. The world was beginning to take this young player seriously.
Zhao continued his winning ways, representing China in the Asian Xiangqi Championships in December 2002. He was champion of the youth section.
He continued blazing in the Chinese Xiangqi scene and was very much active.
In 2005, he was invited to take part in the Chinese National Masters Tournament, where he became champion. He was to be eligible for the title of Grandmaster but was punished for inappropriate conduct by the Chinese authorities for accusations of false play. He was also banned from taking part in further competition for one year. It was a severe blemish in his career.
A year later, after his ban was lifted, he roared back in the Xiangqi scene and proceeded to win the coveted Yang Guanlin Tournament with an undefeated record of 8W3D.
Zhao continued his hardworking ways and was finally awarded the title of Grandmaster in 2007, after winning 伊泰杯 Yi Tai Cup, beating Zhao Guorong (no relation) and Lv Qin along the way and was allowed to participate in the 5 Rams Cup the following year. He came in 3rd place on his first attempt which was quite a feat for a 19 year old!
Since then, Zhao has had very good results in the various tournaments. Currently, in the latter half standings of 2011, he was placed third.
More, much more is to be expected from Zhao!
First created: 13th September 2011
Last updated: 13th September 2011
Acknowledgements: None yet
1. In chinese, <<大师棋路 赵鑫鑫>> by 童本平 郑平平
2. In chinese, http://www.dpxq.com/hldcg/qishou_4.html


text:
LNU Algotesters— перша в Україні школа мистецтва розв'язування алгоритмічно складних задач, переможець півфіналу світу у південно-східному європейському регіоні з алгоритмічного програмування серед студентських команд SEERC 2016.

Спортивне програмування як прогресивний технологічний різновид спорту стрімко набуває популярності в Україні. У цьому немала заслуга аспіранта факультету прикладної математики та інформатики ЛНУ ім. Івана Франка Василя Білецького. За рейтингом TopCoder ranking, Василь Білецький увійшов до десятки найкращих алгоритмічних програмістів світу. Вже п'ятий рік Василь організовує змагання зі спортивного програмування. Навчання відбувається у головному корпусі львівського національного університету імені Івана Франка.

До складу коледжу також входить команда «LNU Penguins». Команда Penguins відома насамперед через те, що привозить призові місця з найвідомішого у світі чемпіонату зі спортивного програмування ACM-ICPC, де беруть участь майже три тисячі університетів.

Досягнення коледжу
Яким є сьогодні рівень спортивного програмування у Львові, в Україні загалом? Чи відбулися суттєві зміни у спортивному програмуванні в нашій країні після того, як команда ЛНУ ім. Івана Франка здобула золоту медаль на чемпіонаті світу? Коли я почав займатися спортивним програмуванням, у Львові про нього ще ніхто не знав. На різноманітні всеукраїнські турніри з програмування скеровували команди, але про завдання учасники не мали жодного уявлення, дізнавалися про них уже на самих змаганнях. Учасників зі Львова ніхто не готував, не тренував. У півфіналах чемпіонату України, які з 2001 р. традиційно відбувалися щороку в чотирьох регіонах — західному, східному, північному, південному — перемогу здобували команди з Рівного, Хмельницького. І тільки 2005 р. уперше у півфіналі перемогла команда нашого Університету, відтоді у півфіналах 9 з 10-ти команд, що потрапляли в першу десятку, — львівські. У цьому аспекті Львів зробив великий крок уперед. Найбільша заслуга — те, що відбуваються змагання, заняття зі школярами, студентами, створено гуртки, коледжі. Звісно, коли команда ЛНУ ім. Івана Франка у 2008 р. на чемпіонаті світу здобула золото, це стало хорошим прикладом для іншим команд і поштовхом працювати ще більше. Як наслідок, у півфіналі чемпіонату світу, що його традиційно проводять у Бухаресті, у 2007 р. українські команди здобули перші 3 місця, у 2008 р. — перші 5 місць, а у 2009 р. — перші 7 місць.Щодо змагань, які проходять у нашому Університеті, то їх я організував уже понад 30. Пригадую, на найперших, що відбулися 2005 р., рівень задач був дуже низьким. Тобто ми розв'язували елементарні задачі, наші студенти приходили заради цікавості. Поступово ми ускладнювали задачі, географія учасників розширювалася. Долучалися програмісти і з інших навчальних закладів Львова, і з інших міст — Ужгорода, Києва, Донецька тощо. Тепер рівень задач, що їх розв'язують учасники змагань, відповідає всеукраїнським змаганням. Рівень справді високий, потенціал хороший.

Коледж зробив чималий вклад, щоб розвинути програмування в Україні на світовому рівні, тому півфінал світу тепер проходить саме у нас.

Викладачі
 Білецький Василь
 Чайка Тарас
 Білий Роман
 Макар Андрій
 Пилип Михайло
 Герасимів Віталій
 Засоба Євген
 Медвідь Андрій
 Чіх Володимр

та інші

Змагання

2015 рік

КРІ-OPEN2015
Команда студентів факультету прикладної математики та інформатики «LNU Penguins» виборола першість на ювілейній Х Міжнародній відкритій студентській олімпіаді з програмування ім. С. О. Лебедєва та В. М. Глушкова «КРІ-OPEN2015»

Близько 100 команд із 46 вищих навчальних закладів України, Польщі, Литви, Естонії та Росії змагалися за звання кращих на найвідомішому у Східній Європі й одному з найбільших у світі турнірі серед найперспективніших молодих програмістів.

Львівський університет на олімпіаді представляла команда «LNU Penguins» у складі студентів факультету прикладної математики та інформатики: Тараса Савіцького, Віталія Герасиміва, Романа Білого (тренер — Василь Білецький).

За підсумками двох турів змагань перше місце виборола команда студентів факультету прикладної математики та інформатики «LNU Penguins» Львівського національного університету імені Івана Франка, яка отримала головний приз турніру «KPI-OPEN» — кришталеву вежу КПІ, прикрашену символікою олімпіади.

Друге місце розділили команди Київського національного університету імені Тараса Шевченка «Flawless» та «Frogs». Третє місце посіли команди «MAI#1» Московського авіаційного інституту (Національний дослідницький університет), (Російська Федерація), «Looksery 1 2/3» Одеського національного університету імені І. І. Мечникова і «ZNTU_SetUp» Запорізького національного технічного університету. Дипломи переможців і призи — ноутбуки MacBook Air, окуляри віртуальної реальності Oculus Rift, комп'ютери Raspberry Pi, а також ліцензії на ПЗ CleanMyMac, подарункові сертифікати на відео курси від компанії ITVDN та набори для очищення мобільних пристроїв та оргтехніки від компанії ColorWay вручив представникам команд та їх тренерам Іван Плотніков.

Міжнародний чемпіонат «Challenge24»

Після участі в Чемпіонаті світу студенти, не зупиняючись на досягнутому, продемонстрували свої знання, вміння та витривалість і на Міжнародних змаганнях із програмування «Challenge24», під час яких упродовж 24 годин безперервно працювали над виконанням поставлених завдань. Із-поміж 233 команд-учасників із 35 країн світу 14 — представляли Україну

«LNU Penguins» зайняли 8 місце.

LNU Penguins у фіналі міжнародної олімпіади з програмування в Марокко

У команді ЛНУ, яка називається Пінгвіни, є представники 3, 4 та 5 курсів. Ми беремо участь в різноманітних онлайн-змаганнях від компаній Google, Microsoft, Facebook. Це найкращий тренажер. Наймолодший серед учасників львівської команди, третьокурсник Герасимів Віталій розповів про свої перші дитячі спроби програмування та неабиякий досвід у олімпіадах. «Я з дитинства мріяв стати інженером і у 6 класі мені купили перший комп'ютер. З того часу, програмування — моє улюблене заняття», — розповів Віталій. В 9 класі Віталій поїхав на першу олімпіаду з програмування у своєму житті. Це були всеукраїнські змагання і хлопець виборов перше місце"

2016 рік — ігри розуму
Згідно з правилами чемпіонату команда повинна складатися з трьох учасників, які представляють один університет. Кожен студент може двічі взяти участь у змаганнях. Гравець не може бути страшим 24 років

Студенти прикладної математики ЛНУ імені І.Франка LNU Penguins отримали бронзу на чемпіонаті світу з програмування у Таїланді. Це найпрестижніші змагання з алгоритмічного програмування у світі, де за п'ять годин учасники повинні розв'язати понад 10 завдань з реального життя. Вони визначають місця найбільших покладів нафти, пишуть програми для прокладання найкоротшої дороги для екскурсії, вираховують кількість солодощів на день для людини з низьковуглеводною дієтою. У чемпіонаті беруть участь більше 13 тисяч команд.

Цього року львівську команду обігнали тільки університети Санкт-Петербурга, Варшави, Шанхаю, Гарварду та Массачусетсу.

Фіналістам чемпіонату вручають грошову нагороду. Для бронзових призерів — це майже 100 тисяч гривень. Щоправда самі математики запевняють, що це зовсім не головне, найголовніше для них у цій грі — здобутий престиж. Кожна ІТ — компанія в Україні хотіла б мати у команді фіналіста світового чемпіонату з програмування.

2017
Команда LNU_AlgoTesters у складі Андрій Макар, Тарас Чайка, Михайло Пилип (тренер Віталій Герасимів) з 2-им місцем Чемпіонату України (4-им у півфіналі чемпіонату світу) з командного програмування.

турнірна таблиця — http://acm.ro/results.htm

Основні теми вивчення у коледжі
 Динамічне програмування
 Бінарний та тернарний пошук
 Алгоритми на орієнтованих графах
 Алгоритми знаходження максимального потоку в мережі
 Алгоритми знаходження найменшого спільного предка в дереві
 Система неперетинних множин
 Швидке перетворення Фур'є
 Елементарні алгоритми на рядках
 Елементарна теорія чисел
 Обчислювальна геометрія
 Теорія Ігор
 Довга арифметика
 Алгоритм Дейкстра
 Елементарні структури даних

Посилання
 http://acm.ro/results.htm
 https://www.facebook.com/lnu.fami/
 http://kameniar.lnu.edu.ua/?p=1203
 https://softserve.ua/ua/press-center/news/lviv-students-in-olimpiad-final/
 https://zaxid.net/igri_rozumu_n1394296
 http://www.lnu.edu.ua/komanda-studentiv-fakultetu-prykladnoji-matematyky-ta-informatyky-lnu-penguins-vyborola-pershist-na-yuvilejnij-h-mizhnarodnij-vidkrytij-studentskij-olimpiadi-z-prohramuvannya-im-s-o-lebedjeva-ta-v/
 http://ami.lnu.edu.ua/en/academics/contests
 http://algotester.com/en/

redpajama_set_name: RedPajamaWikipedia


text:
Science Fiction, Fantasy & Horror Authors
Pierre Boulle
Full Name: Pierre Francois Marie Louis Boulle
Born: February 20, 1912
Died: January 30, 1994
Occupation: Novelist
Pierre Boulle was born in 1912 at Avignon. Boulle spent the Second World War fighting in Yunnan, Calcutta and Indo-Chine, where he was captured by the Japanese. After the war he lived in Malaya, the Cameroons and, finally, Paris, where he settled until his death in 1994.
Works in the WWEnd Database
Non Series Works
The Good Leviathan
Desperate Games
Because It Is Absurd
The Marvelous Palace
Garden on the Moon
Time Out of Mind: and Other Stories
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This is a question that I have been asked many times. It's not a simple yes or no question. It depends. Matching an owner to a dog is essential to a good relationship. The more the potential owner knows about the breed and the dog, the better the chances that they will have a long happy life together.
Border collies, like many working breeds, were developed to do a specific job. It didn't matter much what they looked like - long haired, short-haired, straight coat, wavy coat, black and white, tri-color, blue merle, flopped ears, prick ears, wide head, narrow head, long nose, shorter nose - as long as they could do the job. Of course a dog that was poorly structured, would not have been able to work all day on the hills and in the fields. The typical border collie may have varied in looks but they were sound and healthy.
Before too long, organizations sprang up to record the breeding of dogs. Most working dogs in the United States were, and still are registered with the American Border Collie Association. Their only requirement was that the dog could herd and was breed from parents who were registered with the ABCA or related working dog registry. What the dog looked like was not taken into consideration.
Border collies are smart and most are driven to work at some sort of job. They are also agile and fast. For these reasons they became a favorite with people who like to compete in dog sports such as obedience, agility or flyball. Many of these competitors like a dog who is a bit hyperactive as they are fast and very competitive.
As border collies became more popular, the American Kennel Club (AKC) began a campaign to include them in their registry.
The AKC has always focused primarily on the breed ring. That is showing a class of dogs and selecting the one that comes closest to the ideal dog in appearance. The most popular show, the Westminster, is a prime example of this type of show. There is no consideration given for the ability of the dog to do the job it was bred for. Some feel the dogs have suffered as a result of the breeding of dogs to win in the breed ring. Common complaints are that hunting dogs no longer can hunt. Herding dogs no longer herd. Some are too fat or bred with extreme features that inhibit normal activity because that is what is winning in the show ring. If you take a look at a picture of almost any breed in the 1900s you can see what the dog originally looked like and how much they have changed.
The folks with working border collies were appalled. They fought to keep their breed out of the AKC but lost the battle. A committee somewhere sat down and determined what a proper border collie should look like. They determined the size, the colors, the coat type, the size of the head and nose, the shape of the feet, and how a border collie should move.
The border collie breed, like some other working breeds, has began to split into several lines. A good working farm dog has plenty of energy to work all day, but can come home and relax by the hearth. He has a natural talent for herding and needs a job to keep him happy and calm. Without a job to engage his body and mind, he may develop some behaviors that are less than desirable. He may take to herding other dogs, or children and even nip at them if they don't go the way he thinks they should. He may develop obsessive behaviors that are difficult, if not impossible to correct.
Sometimes there are pups in a litter that have less desire to work. Some are hardly interested in livestock at all. These pups make excellent pets and just need exercise and training like any other breed. Breeders usually can tell which dogs will work best as a family pet when they get a bit older.
Dogs bred for high-energy dog sports may be too active for most families. They might be fine for a dedicated active person or someone who wants to try out these sports.
I've read some suggestions that the best border collies for pets are those bred from show lines. That may be true, but I would suggest that anyone looking for a border collie as a pet, check out a border collie rescue organization first. Most do an excellent job of evaluating each dog for their activity level and can recommend a dog that will fit with the potential owner. They often have dogs of all ages available.
Both do a great job matching the right dog to the right family.
But there are many other rescues out there. Doing a search online will bring up many to pick from.
And there are many border collies in need. Because of their popularity, they have become subject to the seamy side of dog breeding; puppy mills, hoarders, backyard breeders and just generally greedy people. These dogs just need a good chance at a good life.
So do border collies make good pets? The answer is yes and no.
No if you want a dog just to hang out in the back yard. They need training, exercise and time with the family. They are a breed who can get into trouble when bored and left to their own devices. They can learn to chase cars, kids and bicycles among other things. They can develop obsessive behaviors. And some need more attention than others.
The answer may be yes for the right person. Border collies are smart, funny and each one is unique. They can be good with children and other animals if they are raised with them. They are loyal and want to please. It takes some work to keep them happy but I can't imagine life without one.