Metabolipidomic profiling reveals an age‐related deficiency of skeletal muscle pro‐resolving mediators that contributes to maladaptive tissue remodeling

Specialized pro‐resolving mediators actively limit inflammation and support tissue regeneration, but their role in age‐related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography‐tandem mass spectrometry and tested whether treatment with the pro‐resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro‐resolving mediators 8‐oxo‐RvD1, resolvin E3, and maresin 1, as well as many anti‐inflammatory cytochrome P450‐derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro‐inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E₂) and 12‐lipoxygenase (e.g., 12‐hydroxy‐eicosatetraenoic acid), but aged mice produced fewer markers of pro‐resolving mediators including the lipoxins (15‐hydroxy‐eicosatetraenoic acid), D‐resolvins/protectins (17‐hydroxy‐docosahexaenoic acid), E‐resolvins (18‐hydroxy‐eicosapentaenoic acid), and maresins (14‐hydroxy‐docosahexaenoic acid). Similar absences of downstream pro‐resolving mediators including lipoxin A₄, resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro‐resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non‐steroidal anti‐inflammatory drugs.     

Gastrointestinal stress as innate defence against microbial attack

The human gastrointestinal (GI) tract has been bestowed with the most difficult task of protecting the underlying biological compartments from the resident commensal flora and the potential pathogens in transit through the GI tract. It has a unique environment in which several defence tactics are at play while maintaining homeostasis and health. The GI tract shows myriad number of environmental extremes, which includes pH variations, anaerobic conditions, nutrient limitations, elevated osmolarity etc., which puts a check to colonization and growth of nonfriendly microbial strains. The GI tract acts as a highly selective barrier/platform for ingested food and is the primary playground for balance between the resident and uninvited organisms. This review focuses on antimicrobial defense mechanisms of different sections of human GI tract. In addition, the protective mechanisms used by microbes to combat the human GI defence systems are also discussed. The ability to survive this innate defence mechanism determines the capability of probiotic or pathogen strains to confer health benefits or induce clinical events respectively.     

Biomonitoring of environmental tobacco smoke (ETS)-related exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

The exposure of non-smokers to the tobacco-specific N-nitrosamine 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a rodent lung carcinogen, was determined in the air of various indoor environments as well as by biomonitoring of non-smokers exposed to environmental tobacco smoke (ETS) under real-life conditions using the urinary NNK metabolites 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and [4-(N-methylnitrosamino)-1-(3-pyridyl)but-1-yl]-beta-O-D-glucosiduronic acid (NNAL-Gluc). NNK was not detectable (<0.5 ng m^-3) in 11 rooms in which smoking did not occur. The mean NNK concentration in 19 rooms in which smoking took place was 17.5 (2.4-50.0) ng m^-3. The NNK levels significantly correlated with the nicotine levels (r=0.856; p< 0.0001). Of the 29 non-smokers investigated, 12 exhibited no detectable NNAL and NNAL-Gluc excretion (<3 pmol day) in their urine. The mean urinary excretion of NNAL and NNAL-Gluc of the 17 remaining non-smokers was 20.3 (<3-63.2) and 22.9 (<3-90.0) pmol day^-1, respectively. Total NNAL excretion (NNAL+NNAL-Gluc) in all non-smokers investigated significantly correlated with the amount of nicotine on personal samplers worn during the week prior to urine collection (r=0.88; <0.0001) and with the urinary cotinine levels (r=0.40; p=0.038). No correlation was found between NNAL excretion and the reported extent of ETS exposure. Average total NNAL excretion in the non-smokers with detectable NNAL levels was 74 times less than in 20 smokers who were also investigated. The cotinine/total NNAL ratios in urine of smokers (9900) and non-smokers (9300) were similar. This appears to be at variance with the ratios of the corresponding precursors (nicotine/NNK) in mainstream smoke (16400) and ETS (1000). Possible reasons for this discrepancy are discussed. The possible role of NNK as a lung carcinogen in non-smokers is unclear, especially since NNK exposure in non-smokers is several orders of magnitude lower than the ordinary exposure to exogenous and endogenous N-nitrosamines and the role of NNK as a human lung carcinogen is not fully understood.     

多元化互动优化医学免疫学课堂教学

根据医学免疫学的特点和我国教学现状,设计了多种互动式教学方式,通过创设问题情境,建立激励机制,创建团队,组织小组活动等,在课堂教学中创造愉快、和谐、平等、探究的气氛,最大限度的激发学生学习主动性、创造性,提高学生的综合素质,同时促进医学基础课的教学质量。为保证多元化互动式教学模式的顺利实施,尝试建立适合该教学模式的全新考核评价体系,在新的评价体系里,期末成绩（100％）=基础理论（50％）＋出勤及课堂表现（15％）＋实验操作与技能（20％）＋小组活动（15％）。在本项研究实施过程中设置了信息反馈环节,针对提高学习兴趣、强化基础知识、促进思考能力、创新能力、语言表达能力等方面设立问卷调查,及时获得信息反馈。多元化互动式教学模式还存在许多细节性的问题急待解决,还需要反复的推敲、探索与实践。     

Basic concepts of fluid responsiveness

Predicting fluid responsiveness, the response of stroke volume to fluid loading, is a relatively novel concept that aims to optimise circulation, and as such organ perfusion, while avoiding futile and potentially deleterious fluid administrations in critically ill patients. Dynamic parameters have shown to be superior in predicting the response to fluid loading compared with static cardiac filling pressures. However, in routine clinical practice the conditions necessary for dynamic parameters to predict fluid responsiveness are frequently not met. Passive leg raising as a means to alter biventricular preload in combination with subsequent measurement of the change in stroke volume can provide a fast and accurate way to guide fluid management in a broad population of critically ill patients.     

Amyloid precursor protein is a restriction factor that protects against Zika virus infection in mammalian brains

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer''s diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.     

The potential for biological control of stoats (Mustela erminea)

Abstract

Accelerating the mortality of stoats (Mustela erminea) using biological agents, or reducing their fertility using chemosterilants or biological agents, are increasingly seen as more sustainable and more humane than trapping and poisoning. Obligate delayed implantation in fertilised female stoats of all ages allows 10–11 months for an applied biological agent or chemosterilant to interfere with gestation. Two chemosterilants (cabergoline and mifepristone) disrupt pregnancy in some species and may be effective on stoats, although they are not species‐specific and are probably more expensive than poisoning. For the longer term, more recent fertility control research has explored potentially more species‐specific options for other species based on inducing an immune response to an animal's own reproductive hormones, gametes, or products from embryos. Conception will be difficult to disrupt in stoats because females are sexually mature and are mated in the nest during a short period before they are weaned. A large research effort will be required to determine which of the immunosterilants being developed could be suitable candidates for stoat control. There are fewer options apparent for using biological agents to increase stoat mortality, although species‐specific strains of canine distemper virus may be effective against stoats.

The greatest impediment to controlling stoat fertility will be effective delivery of sterilants. For the foreseeable future, it will probably be necessary to rely on baits, but they are unlikely to put all target stoats at risk, and will be incapable of delivery over larger scales than at present.

Before undertaking expensive field trials and development of anti‐fertility and biological agents, the effects of putative compensatory changes in demographics that may be associated with changes in stoat density should be modelled to see if the sterilisation and mortality rates that are required to achieve a given level of population control are realistic targets. Also, population control should be defined in terms of accrued benefit for wildlife by establishing the relationships between stoat densities and the viability of prey populations.

Biological control of fertility or mortality may never be suitable as stand‐alone control options for stoats, particularly when some native fauna survive only if stoats are reduced to very low densities. Biological control may have greater potential when integrated with conventional control.     

Phylogenetic implications and diagenetic stability of macromolecules from pleistocene and recent shells of Mercenaria mercenaria (mollusca,bivalvia)

The phylogeny and diagenesis of Pleistocene and Recent bivalves were studied immunologically by use of a conventional antiserum elicited against an EDTA‐soluble macromolecular extract from shells of the modern bivalve mollusc Mercenaria mercenaria. ELISA tests of the antiserum with shell fragments of a wide range of modern bivalves gave taxonomically significant results. The antiserum reacted with palaeoheterodonts and heterodonts but not with representatives of other bivalve subclasses. This phylogenetic reactivity was also apparent in tests with fossil shells, although the specificity and overall strength of the reaction were both reduced. Absorption of the antiserum with etched shell powders of various (palaeo)heterodonts yielded more specific antibody preparations.

Investigations of shell matrix diagenesis, using the anti‐Mercenaria serum, demonstrated that small amounts of original determinants could be detected even in fossils over one million years old. The reactivity of the serum with extracts of fossil Mercenaria decreased with sample age. The relationship between serum reactivity and the degree of amino acid racemization was almost linear. Clearly, the various determinants to which antibodies were elicited were being destroyed at different rates.