Gene polymorphisms and serum levels of TL1A in patients with rheumatoid arthritis

Recent findings showed elevated expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) in rheumatoid arthritis (RA) patients and arthritis mice. However, whether TL1A gene polymorphisms may correlate with RA susceptibility needs to be discussed. This case-control study was performed on 350 RA patients and 556 healthy subjects to identify TL1A genetic variants (rs3810936, rs6478109, and rs7848647) and their possible association with TL1A levels, susceptibility to and severity of RA. Odds ratio and 95% confidence interval were calculated to represent the correlation between TL1A polymorphisms and RA. The TL1A serum levels were evaluated. Results showed that frequencies of TC, TT + TC genotypes of rs3810936, rs7848647 in RA patients were significantly lower in RA patients compared with controls. Patients with C allele showed more severe disease course (disease activity index: erythrocyte sedimentation rate, rheumatoid factor) than in carriers of T allele. However, the allele or genotype frequencies of rs6478109 were not associated with RA. In addition, TL1A genetic variants conferred higher TL1A levels in RA patients compared with controls. In conclusion, these findings indicated an association between TL1A rs3810936, rs7848647 variation and the susceptibility of RA in a sample of Chinese individuals, and TL1A may correlate with severity of RA.     

The convergent validity between two objective methods for quantifying training load in young taekwondo athletes

Various studies used objective heart rate (HR)-based methods to assess training load (TL). The common methods were Banister's Training Impulse (TRIMP; weights the duration using a weighting factor) and Edwards' TL (a summated HR zone score). Both the methods use the direct physiological measure of HR as a fundamental part of the calculation. To eliminate the redundancy of using various methods to quantify the same construct (i.e., TL), we have to verify if these methods are strongly convergent and are interchangeable. Therefore, the aim of this study was to investigate the convergent validity between Banister's TRIMP and Edwards' TL used for the assessment of internal TL. The HRs were recorded and analyzed during 10 training weeks of the preseason period in 10 male Taekwondo (TKD) athletes. The TL was calculated using Banister's TRIMP and Edwards' TL. Pearson product moment correlation coefficient was used to evaluate the convergent validity between the 2 methods for assessing TL. Very large to nearly perfect relationships were found between individual Banister's TRIMP and Edwards' TL (r values from 0.80 to 0.99; p < 0.001). Pooled Banister's TRIMP and pooled Edwards' TL (pooled data n = 284) were nearly largely correlated (r = 0.89; p < 0.05; 95% confidence interval: 0.86-0.91). In conclusion, these findings suggest that these 2 objective methods, measuring a similar construct, are interchangeable.     

Ultralong telomeres shorten with age in nestling great tits but are static in adults and mask attrition of short telomeres

Telomere length (TL) is increasingly being used as a biomarker of senescence, but measuring telomeres remains a challenge. Within tissue samples, TL varies between cells and chromosomes. Class I telomeres are (presumably static) interstitial telomeric sequences, while terminal telomeres have been divided in shorter (Class II) telomeres and ultralong (Class III) telomeres, and the presence of the latter varies strongly between species. Class II telomeres typically shorten with age, but little is known of Class III telomere dynamics. Using multiple experimental approaches, we show great tits to have ultralong telomeres, and we investigated age effects on Class II and III telomeres using a longitudinal approach (our method excludes Class I telomeres). In adults, TL averaged over the whole distribution did not significantly change with age. However, more detailed analyses showed that Class II TL did shorten with age, and, as in other species, the longest Class II telomeres within individuals shortened more quickly with age. In contrast, Class III TL did not shorten with age within individual adults. Surprisingly, we found the opposite pattern in nestlings: Class III TL shortened significantly with age, while the age effect on Class II TL was close to zero. Thus, Class III TL may provide information on developmental history, while Class II TL provides information on telomere dynamics in adulthood. These findings have practical implications for telomere studies and raise the interesting question of what causes variation in TL dynamics between chromosomes within individuals and how this is related to development.     

TNF superfamily member, TL1A, is a potential mucosal vaccine adjuvant

The identification of cytokine adjuvants capable of inducing an efficient mucosal immune response against viral pathogens has been long anticipated. Here, we attempted to identify the potential of tumor necrosis factor superfamily (TNFS) cytokines to function as mucosal vaccine adjuvants. Sixteen different TNFS cytokines were used to screen mucosal vaccine adjuvants, after which their immune responses were compared. Among the TNFS cytokines, intranasal immunization with OVA plus APRIL, TL1A, and TNF-α exhibited stronger immune response than those immunized with OVA alone. TL1A induced the strongest immune response and augmented OVA-specific IgG and IgA responses in serum and mucosal compartments, respectively. The OVA-specific immune response of TL1A was characterized by high levels of serum IgG1 and increased production of IL-4 and IL-5 from splenocytes of immunized mice, suggesting that TL1A might induce Th2-type responses. These findings indicate that TL1A has the most potential as a mucosal adjuvant among the TNFS cytokines.     

General Stress Protein CTC from Bacillus subtilis Specifically Binds to Ribosomal 5S RNA

Two recombinant proteins of the CTC family were prepared: the general stress protein CTC from Bacillus subtilis and its homolog from Aquifex aeolicus. The general stress protein CTC from B. subtilis forms a specific complex with 5S rRNA and its stable fragment of 60 nucleotides, which contains internal loop E. The ribosomal protein TL5 from Thermus thermophilus, which binds with high affinity to 5S rRNA in the loop E region, was also shown to replace the CTC protein from B. subtilis in its complexes with 5S rRNA and its fragment. The findings suggest that the protein CTC from B. subtilis binds to the same site on 5S rRNA as the protein TL5. The protein CTC from A. aeolicus, which is 50 amino acid residues shorter from the N-terminus than the proteins TL5 from T. thermophilus and CTC from B. subtilis, does not interact with 5S rRNA.     

Telomere shortening correlates with harsh weather conditions in the bat species Myotis myotis

The relationship of telomere shortening and cellular ageing in cultured cells such as fibroblasts is straightforward: telomeres shorten with an increasing number of cell divisions until they trigger replicative senescence which prevents further mitotic cycles. But studies investigating the relationship between telomere shortening and ageing in whole organisms show contrasting results: while there is a clear decline in telomere length (TL) with chronological age in some species such as humans, no such decline is observed in others. In this issue of Molecular Ecology, Foley et al. (2020) show that experiencing harsh weather conditions correlates with longitudinal telomere shortening in the bat species Myotis myotis, whereas chronological age does not (Foley et al., 2020). Further, the authors investigated whether genetics influence TL and find a low heritability (h² = 0.01–0.06) again suggesting that environmental effects are the dominant drivers of variation in TL in this species. These are important findings as there is disagreement in the literature about the relative magnitude of genetic and environmental effects contributing to TL variation in different species. This paper investigating the impact of environmental effects makes a novel and important contribution to the literature on TL in free‐living mammals.     

Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections

Background

Declining telomere length (TL) is associated with T cell senescence. While TL in naïve and memory T cells declines with increasing age, there is limited data on TL dynamics in virus-specific memory CD4⁺ T cells in healthy adults. We combined BrdU-labeling of virus-stimulated T cells followed with flow cytometry-fluorescent in situ hybridization for TL determination. We analyzed TL in T cells specific for several virus infections: non-recurring acute (vaccinia virus, VACV), recurring-acute (influenza A virus, IAV), and reactivating viruses (varicella-zoster virus, VZV, and cytomegalovirus, CMV) in 10 healthy subjects. Additionally, five subjects provided multiple blood samples separated by up to 10 years.

Results

VACV- and CMV-specific T cells had longer average TL than IAV-specific CD4⁺ T cells. Although most virus-specific cells were CD45RA^-, we observed a minor population of BrdU+ CD45RA⁺ T cells characterized by long telomeres. Longitudinal analysis demonstrated a slow decline in average TL in virus-specific T cells. However, in one subject, VZV reactivation led to an increase in average TL in VZV-specific memory T cells, suggesting a conversion of longer TL cells from the naïve T cell repertoire.

Conclusions

TLs in memory CD4⁺ T cells in otherwise healthy adults are heterogeneous and follow distinct virus-specific kinetics. These findings suggests that the distribution of TL and the creation and maintenance of long TL memory T cells could be important for the persistence of long-lived T cell memory.

     

Endotoxemia,vitamin D and premature biological ageing in Arab adults with different metabolic states

There are limited studies on the association of endotoxin, a potent mediator of gut-derived inflammation and telomere length (TL). We investigated (1) the influence of adiposity on endotoxin and TL amongst Saudi adults according to type 2 diabetes mellitus (T2DM) status and (2) the influence vitamin D may have on TL attrition. Anthropometric data and fasting blood samples were taken from 775 Saudi adults visiting different primary care centers in Riyadh [387 T2DM and 388 non-T2DM]. TL, derived from peripheral blood mononuclear cells, was analyzed by Quantitative real-time polymerase chain reaction and circulating endotoxin levels by Limulus Amebocyte Lysate assay. Subjects were stratified based on obesity and T2DM status. A significant lower TL was observed in the non-obese T2DM group as compared with their non-obese, non-T2DM counterparts (p = 0.002). Significant inverse associations between TL, endotoxin and endotoxin activity were observed in the cohort with obesity. Regression analysis showed that endotoxin was a significant predictor for TL in all subjects and even after stratification according to subgroups; with variances perceived in circulating TL stronger among non-T2DM obese (10%; p = 0.003) than non-T2DM non-obese (12%; p = 0.007). Also, in the non-T2DM group, TL and HDL-cholesterol predicted 29% of the variances perceived in 25(OH)D (p < 0.001). Taken together these findings show that circulating endotoxin and 25(OH)D are associated with premature biological ageing influenced by adiposity and metabolic state; suggesting future intervention studies to manipulate gut microbiome and or vitamin D levels may offer ways to mitigate premature TL attrition.     

KCl:Dy phosphor for thermoluminescence dosimetry of ionizing radiation

The thermoluminescence (TL) characterizations of γ‐irradiated KCl:Dy phosphor for radiation dosimetry are reported. All phosphors were synthesized via a wet chemical route. Minimum fading of TL intensity is recorded in the prepared material. TL in samples containing different concentrations of Dy impurity was studied at different γ‐irradiation doses. Peak TL intensities varied sublinearly with γ‐ray dose in all samples, but were linear between 0.08 to 0.75 kGy for the KCl:Dy (0.1 mol%) sample. This material may be useful for dosimetry within this range of γ‐ray dose. TL peak height was found to be dependant on the concentration (0.05–0.5 mol%) of added Dy in the host. Copyright © 2012 John Wiley & Sons, Ltd.     

Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease

Evidence assembled over the last decade shows that average telomere length (TL) acts as a biomarker for biological aging and cardiovascular disease (CVD) in particular. Although essential for a more profound understanding of the underlying mechanisms, little reference information is available on TL. We therefore sought to provide baseline TL information and assess the association of prevalent CVD risk factors with TL in subjects free of overt CVD within a small age range. We measured mean telomere restriction fragment length of peripheral blood leukocytes in a large, representative Asklepios study cohort of 2509 community-dwelling, Caucasian female and male volunteers aged approximately 35-55 years and free of overt CVD. We found a manifest age-dependent telomere attrition, at a significantly faster rate in men as compared to women. No significant associations were established with classical CVD risk factors such as cholesterol status and blood pressure, yet shorter TL was associated with increased levels of several inflammation and oxidative stress markers. Importantly, shorter telomere length was associated with an increasingly unhealthy lifestyle, particularly in men. All findings were age and gender adjusted where appropriate. With these cross-sectional results we show that TL of peripheral blood leukocytes primarily reflects the burden of increased oxidative stress and inflammation, whether or not determined by an increasingly unhealthy lifestyle, while the association with classical CVD risk factors is limited. This further clarifies the added value of TL as a biomarker for biological aging and might improve our understanding of how TL is associated with CVD.     

The non-synonymous SNP, R1150W, in SCN9A is not associated with chronic widespread pain susceptibility

Background

Chronic pain conditions are characterized by significant individual variability complicating the identification of pathophysiological markers. Leukocyte telomere length (TL), a measure of cellular aging, is associated with age-related disease onset, psychosocial stress, and health-related functional decline. Psychosocial stress has been associated with the onset of chronic pain and chronic pain is experienced as a physical and psychosocial stressor. However, the utility of TL as a biological marker reflecting the burden of chronic pain and psychosocial stress has not yet been explored.

Findings

The relationship between chronic pain, stress, and TL was analyzed in 36 ethnically diverse, older adults, half of whom reported no chronic pain and the other half had chronic knee osteoarthritis (OA) pain. Subjects completed a physical exam, radiographs, health history, and psychosocial questionnaires. Blood samples were collected and TL was measured by quantitative polymerase chain reaction (qPCR). Four groups were identified characterized by pain status and the Perceived Stress Scale scores: 1) no pain/low stress, 2) no pain/high stress, chronic pain/low stress, and 4) chronic pain/high stress. TL differed between the pain/stress groups (p = 0.01), controlling for relevant covariates. Specifically, the chronic pain/high stress group had significantly shorter TL compared to the no pain/low stress group. Age was negatively correlated with TL, particularly in the chronic pain/high stress group (p = 0.03).

Conclusions

Although preliminary in nature and based on a modest sample size, these findings indicate that cellular aging may be more pronounced in older adults experiencing high levels of perceived stress and chronic pain.     

斑鰶仔、稚鱼形态发育及异速生长模式研究

运用光学显微镜技术和实验生态学方法, 对斑鰶(Konosirus punctatus)早期形态发育观察、异速生长模式及其生态学意义进行了研究。结果表明: 在水温(21.5±0.5)℃下, 初孵仔鱼全长(3.18±0.52) mm, 斑鰶仔鱼期从孵化出膜到43日龄棱鳞开始出现前, 稚鱼期从44日龄棱鳞出现到55日龄全身覆满鳞片。斑鰶的形态变化和器官分化主要发生在仔鱼期。斑鰶的吻长、躯干长、肠道长、胸鳍长、腹鳍长等重要形态学指标均存在异速生长现象, 其生长拐点依次为 42日龄(TL: 26.41 mm)、24日龄(TL: 15.57 mm)、31日龄(TL: 21.41 mm)、41日龄(TL: 25.47 mm)、42日龄(TL: 26.41 mm)。相对于全长、吻长和胸鳍长在拐点前后由正异速生长变为等速生长, 腹鳍长由正异速生长转为负异速生长, 这为呼吸、摄食和成功逃避捕食者提供有利条件; 而肠道长由负异速生长变为等速生长, 这可能与斑鰶的食性转化有关。综上所述, 为适应复杂多变的生存环境, 斑鰶在早期发育阶段优先发育对生长生存起关键作用的器官, 这对提高仔、稚鱼的存活率具有重要的生态学意义。研究将为今后进一步人工繁育和苗种培育提供理论依据。     

Fine needle aspiration of toxoplasmic (Piringer-Kuchinka) lymphadenitis: a cytohistologic correlation study

OBJECTIVE: To define the cytomorphologic features of toxoplasmic lymphadenitis (TL) and to establish the diagnostic sensitivity and specificity of the cytologic diagnosis. STUDY DESIGN: A cytohistologic correlation study of 11 patients in which a histologic diagnosis of TL was available. These cases were analyzed in a blind study among other cases of nonneoplastic lymphadenopathies. The results of the study are expressed in terms of diagnostic sensitivity and specificity. Although not included in the study, 3 other cases of TL with serologic confirmation were also reviewed. RESULTS: Microgranulomas were a characteristic finding in TL. They consisted of small clusters of epithelioid histiocytes, each with abundant cytoplasm and an eccentric, oval nucleus. Diff-Quik-stained smears had cytoplasm with particularly pale staining and a homogeneous appearance. Most microgranulomas had a monotonous appearance with a few, small lymphocytes accompanying the epithelioid cells. No necrosis, suppurative changes or giant cells were present. Blind examination by 4 reviewers led to a correct diagnosis of TL in 9 of the 11 cases. Eight of the 9 cases were recognized by each of the 4 reviewers. One false positive diagnosis was made by 1 of the reviewers. The sensitivity of the diagnosis was 72.7-81.8% and the specificity 98.8-100%. CONCLUSION: This study showed high sensitivity and specificity for the cytologic diagnosis of TL. Given the appropriate clinical context, the presence of characteristic epithelioid microgranulomas permits a diagnosis of TL. The cytologic diagnosis can be easily confirmed with serologic studies, thereby avoiding biopsy.     

Dalesconols B inhibits lipopolysaccharide induced inflammation and suppresses NF-κB and p38/JNK activation in microglial cells

Therapeutic strategies designed to inhibit the activation of microglia may lead to significant advancement in the treatment of most neurodegenerative diseases. Dalesconols B, also termed as TL2, is a newly found polyketide from a mantis-associated fungus and has been reported to exert potent immunosuppressive effects. In the present study, the anti-inflammatory effects of TL2 was investigated in lipopolysaccharide (LPS)-treated BV2 microglia and primary microglia cells. Our observations indicated that pretreatment with TL2 significantly inhibited the production of NO and PGE2 and suppressed the expression of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), COX-2, TNF-α, IL-1β, IL-6, MCP-1 and MIP-1α in LPS-stimulated BV2 microglia. The nuclear translocation of NF-κB and the phosphorylation level of Akt, p38 and JNK MAP kinase pathways were also inhibited by TL2 in LPS-treated BV2 microglia. Moreover, TL2 also decreased Aβ-induced production of TNF-α, IL-1β and IL-6 in BV2 microglia. Additionally, TL2 protected primary cortical neurons against microglia-mediated neurotoxicity. Overall, our findings suggested that TL2 might be a promising therapeutic agent for alleviating the progress of neurodegenerative diseases associated with microglia activation.     

Impact of the training program on lipid profile and cardiac health

The aim of this study was to investigate the effects of training programs on serum lipid profile and myocardial oxidative stress. Male Wistar rats (2 mo-old) were divided into three groups (n = 8): sedentary (S), loadless trained (T) and trained-overload 2% body weight (TL). T and TL were trained through swimming for 9 weeks. T and TL rats had increased myocardial lipoperoxide (TBA) and lipid hydroperoxide (HP), whereas HP was higher in TL than in T animals. Superoxide dismutase (SOD) activities were lowest in TL. Myocardial glutathione peroxidase (GSH-Px) was lower in TL than in T and S rats. TL decreased HDL-cholesterol and increased LDL-cholesterol. The serum lactate dehydrogenase and TBA were increased, while SOD and GSH-Px activities were decreased in TL rats. Loadless training was able to improve HDL-cholesterol and to reduce LDL-cholesterol. In conclusion, the loadless training program induced beneficial effects on lipid profile, while overload training induced dyslipidemic profile that was associated with serum oxidative stress. The overload training program was deleterious relative to loadless training program, increasing myocardial oxidative stress.     

Biochemical genetics of TL antigens

TL antigens are class I glycoproteins which are expressed on thymocytes and which are coded by the Tla region of the major histocompatibility complex of the mouse. Biochemical analysis of TL molecules from different strains of mice revealed structural variation determined by the Tla region which is detectable by peptide mapping, isoelectric focusing, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, two-dimensional gels, and by differential reactivity of allelic forms of TL molecules with a panel of anti TL reagents. The quantity of TL expressed on thymocytes is also influenced by the Tla region; three quantitative phenotypes were identified: high (Tla ^a, Tla ^d, Tla ^c), intermediate (Tla ^c, Tla ^f), and low (Tla ^b). (Relative amounts: 1000 : 100 : 1.) Some thymic leukemias arising in (Tla ^b, Tla ^c, Tla ^c) mice with genetically determined reduced levels of thymic TL were found to express TL molecules which were structurally indistinguishable from TL isolated from thymocytes but were present in larger amounts. This suggests that TL structural genes are intrinsically capable of full expression in all mice but that the Tla region of mice expressing an intermediate or low quantity of TL is marked by some feature which causes the thymocyte to express less than the full amount of TL possible.     

Tryptase TL2 in the membrane of human T4+ lymphocytes is a novel binding protein of the V3 domain of HIV-1 envelope glycoprotein gp 120.

A novel membrane-bound serine esterase in cultured human T4+ lymphocytes, recently purified and named tryptase TL2, binds specifically to the external envelope protein gp 120 of HIV-1, interacting with its V3 domain. This binding was selectively blocked by inhibitors of tryptase TL2 with a GPCR sequence in their reactive site, synthetic peptides corresponding with the sequences of the V3 domains of various HIV-1 strains with the GPGR sequence, and antibody against tryptase TL2, or neutralizing antibody against the V3 domain of HTLV-IIIB. These findings suggest that tryptase TL2 is a binding protein of the V3 domain of HIV-1 envelope glycoprotein.     

Oligomeric state of lipocalin-1 (LCN1) by multiangle laser light scattering and fluorescence anisotropy decay

Multiangle laser light scattering and fluorescence anisotropy decay measurements clarified the oligomeric states of native and recombinant tear lipocalin (lipocalin-1, TL). Native TL is monomeric. Recombinant TL (5-68 microM) with or without the histidine tag shows less than 7% dimer formation that is not in equilibrium with the monomeric form. Fluorescence anisotropy decay showed a correlation time of 9-10 ns for TL (10 microM-1 mM). Hydrodynamic calculations based on the crystallographic structure of a monomeric TL mutant closely concur with the observed correlation time. The solution properties calculated with HYDROPRO and SOLPRO programs from the available crystallographic structure of a monomeric TL mutant concur closely with the observed fluorescence anisotropy decay. The resulting model shows that protein topology is the major determinant of rotational correlation time and accounts for deviation from the Stokes-Einstein relation. The data challenge previous gel filtration studies to show that native TL exists predominantly as a monomer in solution rather than as a dimer. Delipidation of TL results in a formation of a complex oligomeric state (up to 25%). These findings are important as the dynamic processes in the tear film are limited by diffusional, translational as well as rotational, properties of the protein.     

IBD-Associated TL1A Gene (TNFSF15) Haplotypes Determine Increased Expression of TL1A Protein

Background

The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-γ production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn''s disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts.

Methodology and Principal Findings

Here we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P≤0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcγR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype.

Conclusions and Significance

These findings suggest that TL1A gene variation exacerbates induction of TL1A in response to FcγR stimulation in Jewish CD patients and this may lead to chronic intestinal inflammation via overwhelming T cell responses. Thus, TL1A may provide an important target for therapeutic intervention in this subgroup of IBD patients.