美国国家骨髓库20年回顾:成人无关供者造血干细胞移植

自1987年起,美国国家骨髓库(NMDP)提供了>30 000份URD-HCT,其中70%以上的受者是患有恶性血液病或获得性血液疾病的成人.在此期间发生很大变化,包括无偿捐献队伍的扩大、PBSCs采集、脐血库(UCB)的加入、HLA分型技术的进步、新药物的使用、低强度预处理(RIC)以及移植后免疫调节等.本文就过去20年NMDP成人受者HCT的数据及分析作一介绍.     

A Role for Protease Activated Receptor Type 3 (PAR3) in Nociception Demonstrated Through Development of a Novel Peptide Agonist

The protease activated receptor (PAR) family is a group of G-protein coupled receptors (GPCRs) activated by proteolytic cleavage of the extracellular domain. PARs are expressed in a variety of cell types with crucial roles in homeostasis, immune responses, inflammation, and pain. PAR3 is the least researched of the four PARs, with little known about its expression and function. We sought to better understand its potential function in the peripheral sensory nervous system. Mouse single-cell RNA sequencing data demonstrates that PAR3 is widely expressed in dorsal root ganglion (DRG) neurons. Co-expression of PAR3 mRNA with other PARs was identified in various DRG neuron subpopulations, consistent with its proposed role as a coreceptor of other PARs. We developed a lipid tethered PAR3 agonist, C660, that selectively activates PAR3 by eliciting a Ca²⁺ response in DRG and trigeminal neurons. In vivo, C660 induces mechanical hypersensitivity and facial grimacing in WT but not PAR3^?/? mice. We characterized other nociceptive phenotypes in PAR3^?/? mice and found a loss of hyperalgesic priming in response to IL-6, carrageenan, and a PAR2 agonist, suggesting that PAR3 contributes to long-lasting nociceptor plasticity in some contexts. To examine the potential role of PAR3 in regulating the activity of other PARs in sensory neurons, we administered PAR1, PAR2, and PAR4 agonists and assessed mechanical and affective pain behaviors in WT and PAR3^?/? mice. We observed that the nociceptive effects of PAR1 agonists were potentiated in the absence of PAR3. Our findings suggest a complex role of PAR3 in the physiology and plasticity of nociceptors.PerspectiveWe evaluated the role of PAR3, a G-protein coupled receptor, in nociception by developing a selective peptide agonist. Our findings suggest that PAR3 contributes to nociception in various contexts and plays a role in modulating the activity of other PARs.     

美国国家骨髓库20年回顾:成人无关供者造血干细胞移植

自1987年起,美国国家骨髓库(NMDP)提供了>30 000份URD-HCT,其中70%以上的受者是患有恶性血液病或获得性血液疾病的成人.在此期间发生很大变化,包括无偿捐献队伍的扩大、PBSCs采集、脐血库(UCB)的加入、HLA分型技术的进步、新药物的使用、低强度预处理(RIC)以及移植后免疫调节等.本文就过去20年NMDP成人受者HCT的数据及分析作一介绍.     

美国国家骨髓库20年回顾:成人无关供者造血干细胞移植

自1987年起,美国国家骨髓库(NMDP)提供了>30 000份URD-HCT,其中70%以上的受者是患有恶性血液病或获得性血液疾病的成人.在此期间发生很大变化,包括无偿捐献队伍的扩大、PBSCs采集、脐血库(UCB)的加入、HLA分型技术的进步、新药物的使用、低强度预处理(RIC)以及移植后免疫调节等.本文就过去20年NMDP成人受者HCT的数据及分析作一介绍.     

Survey of conformational role of ester bonds in a cyclic depsipeptide

The effect of ester bond on the conformation of peptide molecule was studied by designing and synthesizing a model tetradepsipeptide cyclo(-l -Ala-l -Hmb-)z and by analyzing the conformation both theoretically and experimentally. Theoretical analysis showed that both ester and peptide bonds in the calculated low-energy conformations within 3 kcal/mol of the global minimum take a trans but distorted configuration. The distortion is larger in ester bonds than in peptide bonds. Further, the four carbonyls project from one side of the plane of the cyclic backbone, whereas the side chains project from the other side. These results are consistent with the experimental results obtained by NMR measurement; first, the coupling constant deduced from ¹H-NMR species in DMSO-d₆ is consistent with the dihedral angles of the calculated low-energy conformations; second, results of NOE measurement can reproduce the calculated configuration of the carbonyls and side chains. From the consistency between theoretical and experimental results, it is concluded that this model tetradepsipeptide takes an all-trans backbone conformation in solution and this backbone conformation is stabilized by large distortion in the ester bond, which compensates the strain resulted from the 12-membered cyclic backbone structure consisting only of L-residues.     

mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK

Mammalian target of rapamycin complex 1 (mTORC1) inhibitors are extensively used as immunosuppressants to prevent transplant rejection and in treatment of certain cancers. In patients, chronic treatment with rapamycin or its analogues (rapalogues) has been reported to lead to sensory hypersensitivity and pain conditions via an unknown mechanism. Here, we show that pharmacological or genetic inhibition of mTORC1 activates the extracellular signal-regulated kinase (ERK) pathway in sensory neurons via suppression of S6K1 to insulin receptor substrate 1 negative feedback loop. As a result, increased ERK activity induces sensory neuron sensitization, mechanical hypersensitivity, and spontaneous pain. The clinically available adenosine monophosphate-activated protein kinase activator, metformin, which is an antidiabetic drug, prevents rapamycin-induced ERK activation and the development of mechanical hypersensitivity and spontaneous pain. Taken together, our findings demonstrate that activation of the ERK pathway in sensory neurons as a consequence of mTORC1 inhibition leads to the development of pain. Importantly, this effect is abolished by co-treatment with metformin, thus providing a potential treatment option for rapalogue-evoked pain. Our findings highlight the physiological relevance of feedback signaling through mTORC1 inhibition and have important implications for development of pain therapeutics that target the mTOR pathway.     

Awareness of Menstrual Abnormality Amongst College Students in Urban Area of Ile-Ife, Osun State, Nigeria

Background:

Disturbances of menstrual bleeding are major social and medical problem for women and account for high percentage of gynecological visit.

Objectives:

The objective of the study was to document menstrual abnormalities experienced by female college students, their awareness and health seeking behavior.

Materials and Methods:

A cross-sectional survey was undertaken, 400 students were selected using stratified sampling technique and interviewed using semi-structured self-administered questionnaire. Inferential statistical analysis such as Chi-square test and logistic regressions were carried out.

Results:

The mean age at menarche was 14.18 years. Irregular menstrual cycles were reported in 9.0%. Dysmenorrhea was present in 62.5%, and 12.5% reported school absenteeism. Students'' awareness of menstrual abnormalities was poor (29%). A few of them (10.5%) decided to seek help for menstrual abnormalities. The awareness of students on menstrual abnormalities was significantly influenced by their age (OR = 2.33, P = 0.03); however, age at menarche and level of study did not influence their awareness (OR = 0.45, P = 0.24 and OR = 1.42, P = 0.12). History of dysmenorrheal (OR = 10.2, P = 0.001) and academic disturbance (OR = 5.45, P = 0.001) had significant influence on the health seeking behavior of the students.

Conclusion:

There was a general lack of information about menstrual issues and when to seek help. There is a need to educate female college students about menstrual issues in order to improve their health seeking behavior as regards menstrual abnormalities.     

Markoffian description of the process of protein folding

A long record of computer simulation of folding-unfolding transition in a two-dimensional lattice model of protein as monitored by one conformational order parameter was studied to see if it could be approximated by a markoffian process. For this purpose the normalized time correlation functions of the order parameter were calculated (i) directly from the record of simulation and (ii) by assuming the markoffian behavior of the record. Both of them can be well approximated by a sum of two simple exponential terms. The relaxation time of the slow relaxing term, which corresponds to the overall folding-unfolding transition, becomes very short when the markoffian assumption is made. From this observation we conclude that intermediate states defined by one more-or-less arbitrarily chosen conformational parameter are, in general, collections of very heterogeneous conformations and therefore transitions between them cannot be markoffian. This indicates the importance of multi-parameter observation of dynamic process of folding. Characteristic features of the method of trapping disulfide intermediates are discussed.