注射胸腺依赖和非胸腺依赖抗原雄性黑线毛足鼠的内分泌状态和气味吸引力

作者研究了胸腺依赖抗原 (SRBC) (羊红血细胞 ,sheepredbloodcells ,SRBC)和非胸腺依赖抗原 (细菌脂多糖 ,lipopolysaccharide ,LPS)的免疫活化对黑线毛足鼠气味信号和内分泌状态的影响。成年雄鼠注射SRBS5天后 ,其气味的性吸引力下降 ,这种结果伴随着粪便中睾酮含量的下降。SRBC处理后 ,雄性气味吸引力降低 ,这在体液免疫反应低的雄性个体中最明显。与SRBC的作用相反 ,注射LPS的雄性个体的气味吸引力增加 ,成熟雌性个体用于嗅闻嗅觉刺激上的时间差异与经LPS和盐处理过的雄鼠的粪便中睾酮浓度的差异呈正相关。作者讨论了这两种相反的嗅觉效应的适应性意义     

Low-frequency component of photoplethysmogram reflects the autonomic control of blood pressure

The question of how much information the photoplethysmogram (PPG) signal contains on the autonomic regulation of blood pressure (BP) remains unsolved. This study aims to compare the low-frequency (LF) and high-frequency components of PPG and BP and assess their correlation with oscillations in interbeat (RR) intervals at similar frequencies. The PPG signal from the distal phalanx of the right index finger recorded using a reflective PPG sensor at green light, the BP signal from the left hand recorded using a Finometer, and RR intervals were analyzed. These signals were simultaneously recorded within 15 min in a supine resting condition in 17 healthy subjects (12 males and 5 females) aged 33 ± 9 years (mean ± SD). The study revealed the high coherence of LF components of PPG and BP with the LF component of RR intervals. The high-frequency components of these signals had low coherence. The analysis of the signal instantaneous phases revealed the presence of high-phase coherence between the LF components of PPG and BP. It is shown that the LF component of PPG is determined not only by local myogenic activity but also reflects the processes of autonomic control of BP.     

Grimelysin, a novel metalloprotease from Serratia grimesii, is similar to ECP32

Limited actin proteolysis is the hallmark of bacterial metalloprotease ECP32. While ECP32 has long been considered an Escherichia coli protein, the N-terminal amino acid sequence of the active enzyme described previously, could not been retrieved in the E. coli genome. We cloned, sequenced and characterized Serratia grimesii protease grimelysin and show that grimelysin is similar to the previously described protease ECP32.     

Functional characterization of ProSAAS: similarities and differences with 7B2.

Prohormone convertases (PC) 1 and 2, enzymes found primarily in neuroendocrine tissues, are thought to mediate the proteolytic cleavage of many peptide precursors. To date, endogenous binding proteins for both PC2 (7B2) and PC1 (proSAAS) have been identified. Although 7B2 represents a potent inhibitor of PC2, the most important function of 7B2 as regards this enzyme appears to be the absolute requirement of PC2 for 7B2 in the generation of active enzyme, recently corroborated through production of a null animal that lacks PC2 activity. The purpose of the present study was to determine whether proSAAS exerts effects on PC1 other than inhibition, and to establish functional similarities and differences between 7B2 and proSAAS. We first asked whether the N-terminal domain of proSAAS (proSAAS-(1-180)) could stabilize PC1 activity, similar to the effect of the N-terminal domain of 7B2 on PC2. Recombinant His-tagged proSAAS-(1-180) had no effect on PC1 activity in vitro and was unable to protect PC1 from thermal denaturation. Transient cotransfection of proSAAS-(1-225) cDNA with PC1 cDNA into HEK 293 cells reduced the amount of PC1 activity detected in the medium. Surprisingly, cotransfection of proSAAS-(1-180) cDNA, encoding a protein that lacks the inhibitory C-terminal domain peptide, also reduced the activity of PC1 detected in the medium, but the mass of PC1 secreted into the medium was increased, suggesting a proSAAS-mediated inactivation reaction. Similar results were observed in CHO/PC1 cells stably transfected with pro-SAAS-(1-180). Stable transfection of SAAS cDNAs into AtT-20 cells was used to examine the role of proSAAS in a neuroendocrine setting. Unlike 7B2, proSAAS-(1-225) was able to slow convertase-mediated processing of proopiomelanocortin and proenkephalin; however, similarly to 7B2, proSAAS expression did not result in any accumulated differences in the content of cellular processed peptide. In summary, although both proSAAS and 7B2 potently inhibit PC enzymes via a C-terminal peptide, their intracellular interactions with PCs appear to differ significantly, with each binding protein exhibiting unique properties.     

A Comparative Study on the Cleavage of Stereoisomeric Uridylyl (3',5')Uridines [D,D-, D,L- and L,D-UPU] by Acid,Base and Metal Ion Catalysts

Stereoisomeric uridylyl(3',5')uridines D,L-UpU andL,D-UpU were synthesised. Their cleavage was followed in thepresence of acid, base and metal ion catalysts to studywhether the stereochemistry affects the inherent reactivity ofthe internucleosidic phosphodiester bond, and whether the lowmolecular weight catalysts can distinguish between thesubstrates. The rate constants obtained were compared to thoseof D,D-UpU. The comparison shows that the stability of thephosphodiester bond does not depend on the stereochemistry ofthe sugar rings. In contrast slight reactivity differences areobserved in the presence of metal ion catalysts, whichsuggests that selective cleavage of stereoisomeric substrateseven by small molecular weight chemical catalysts may bepossible.     

Essential Role of the m2R-RGS6-IKACh Pathway in Controlling Intrinsic Heart Rate Variability

Normal heart function requires generation of a regular rhythm by sinoatrial pacemaker cells and the alteration of this spontaneous heart rate by the autonomic input to match physiological demand. However, the molecular mechanisms that ensure consistent periodicity of cardiac contractions and fine tuning of this process by autonomic system are not completely understood.Here we examined the contribution of the m₂R-I_KACh intracellular signaling pathway, which mediates the negative chronotropic effect of parasympathetic stimulation, to the regulation of the cardiac pacemaking rhythm. Using isolated heart preparations and single-cell recordings we show that the m₂R-I_KACh signaling pathway controls the excitability and firing pattern of the sinoatrial cardiomyocytes and determines variability of cardiac rhythm in a manner independent from the autonomic input. Ablation of the major regulator of this pathway, Rgs6, in mice results in irregular cardiac rhythmicity and increases susceptibility to atrial fibrillation. We further identify several human subjects with variants in the RGS6 gene and show that the loss of function in RGS6 correlates with increased heart rate variability. These findings identify the essential role of the m₂R-I_KACh signaling pathway in the regulation of cardiac sinus rhythm and implicate RGS6 in arrhythmia pathogenesis.     

Posttranslational Regulation of Human DNA Polymerase ι

Human DNA polymerases (pols) η and ι are Y-family DNA polymerase paralogs that facilitate translesion synthesis past damaged DNA. Both polη and polι can be monoubiquitinated in vivo. Polη has been shown to be ubiquitinated at one primary site. When this site is unavailable, three nearby lysines may become ubiquitinated. In contrast, mass spectrometry analysis of monoubiquitinated polι revealed that it is ubiquitinated at over 27 unique sites. Many of these sites are localized in different functional domains of the protein, including the catalytic polymerase domain, the proliferating cell nuclear antigen-interacting region, the Rev1-interacting region, and its ubiquitin binding motifs UBM1 and UBM2. Polι monoubiquitination remains unchanged after cells are exposed to DNA-damaging agents such as UV light (generating UV photoproducts), ethyl methanesulfonate (generating alkylation damage), mitomycin C (generating interstrand cross-links), or potassium bromate (generating direct oxidative DNA damage). However, when exposed to naphthoquinones, such as menadione and plumbagin, which cause indirect oxidative damage through mitochondrial dysfunction, polι becomes transiently polyubiquitinated via Lys¹¹- and Lys⁴⁸-linked chains of ubiquitin and subsequently targeted for degradation. Polyubiquitination does not occur as a direct result of the perturbation of the redox cycle as no polyubiquitination was observed after treatment with rotenone or antimycin A, which both inhibit mitochondrial electron transport. Interestingly, polyubiquitination was observed after the inhibition of the lysine acetyltransferase KATB3/p300. We hypothesize that the formation of polyubiquitination chains attached to polι occurs via the interplay between lysine acetylation and ubiquitination of ubiquitin itself at Lys¹¹ and Lys⁴⁸ rather than oxidative damage per se.