MicroPhenoDB Associates Metagenomic Datawith Pathogenic Microbes,Microbial Core Genes,and Human Disease Phenotypes

Microbes play important roles in human health and disease. The interaction between microbes and hosts is a reciprocal relationship, which remains largely under-explored. Current computational resources lack manually and consistently curated data to connect metagenomic data to pathogenic microbes, microbial core genes, and disease phenotypes. We developed the MicroPhenoDB database by manually curating and consistently integrating microbe-disease association data. MicroPhenoDB provides 5677 non-redundant associations between 1781 microbes and 542 human disease phenotypes across more than 22 human body sites. MicroPhenoDB also provides 696,934 relationships between 27,277 unique clade-specific core genes and 685 microbes. Disease phenotypes are classified and described using the Experimental Factor Ontology (EFO). A refined score model was developed to prioritize the associations based on evidential metrics. The sequence search option in MicroPhenoDB enables rapid identification of existing pathogenic microbes in samples without running the usual metagenomic data processing and assembly. MicroPhenoDB offers data browsing, searching, and visualization through user-friendly web interfaces and web service application programming interfaces. MicroPhenoDB is the first database platform to detail the relationships between pathogenic microbes, core genes, and disease phenotypes. It will accelerate metagenomic data analysis and assist studies in decoding microbes related to human diseases. MicroPhenoDB is available through http://www.liwzlab.cn/microphenodb and http://lilab2.sysu.edu.cn/microphenodb.     

Slender,Older Women Appear to Be More Susceptible to Nontuberculous Mycobacterial Lung Disease

Background: Nontuberculous mycobacteria (NTM) are environmental microbes that are associated with a variety of human diseases, particularly chronic lung infections. Over the past several decades, NTM lung disease has been increasingly seen in postmenopausal women with slender body habitus.Objective: This article reviewed the clinical and experimental evidence that supports the observation that thin older women (aged 50–80 years) are predisposed to NTM lung disease. We posited 3 potential pathways for this predisposition: relative estrogen deficiency, abnormal levels of adipokines that alter immune responses, and abnormal expression of transforming growth factor-β (TGF-β) related to fibrillin anomalies similar to Marfan syndrome (MFS).Methods: Using the PubMed database, a literature search was performed (all publications up to July 2009) by pairing the key phrase nontuberculous mycobacteria with weight, malnutrition, female gender, body habitus, leptin, adipokines, estrogen, menopause, postmenopausal, or body mass index. Non-English-language articles were included if their abstracts were in English. Relevant articles were also identified from the abstracts.Results: Published case reports and series indicate that in the past 20 years, NTM lung disease has been recognized in disproportionately increased numbers in postmenopausal women. Among these patients, slender body habitus and thoracic cage abnormalities, such as pectus excavatum and scoliosis, are commonly described. Notably, no long-term prospective clinical studies exist to corroborate that low weight is an independent risk factor for NTM lung disease. However, based on the findings of a limited number of experimental studies, we hypothesize that decreased leptin, increased adiponectin, and/or decreased estrogen in older women with slender body habitus may account for their increased susceptibility to NTM infections. We further speculate that in some patients with features mindful of MPS (slender, scoliosis, pectus excavatum, or mitral valve prolapse), there may be anomalies of fibrillin, similar to MFS, that lead to the expression of the immunosuppressive cytokine TGP-β further increasing their susceptibility to NTM.Conclusions: It is likely that both sufficient environmental exposure and host susceptibility are required for the establishment of NTM lung disease. The observation that NTM lung infections are more common in slender, older women without any overt immune defects suggests that abnormal expression of adipokines, sex hormones, and/or TGF-β may play an important role in their susceptibility.     

Consistent Alterations of Human Fecal Microbes After Transplantation into Germ-free Mice

Fecal microbiota transplantation (FMT) of human fecal samples into germ-free (GF) mice is useful for establishing causal relationships between the gut microbiota and human phenotypes. However, due to the intrinsic differences between human and mouse intestines and the different diets of the two organisms, it may not be possible to replicate human phenotypes in mice through FMT; similarly, treatments that are effective in mouse models may not be effective in humans. In this study, we aimed to identify human gut microbes that undergo significant and consistent changes (i.e., in relative abundances) after transplantation into GF mice in multiple experimental settings. We collected 16S rDNA-seq data from four published studies and analyzed the gut microbiota profiles from 1713 human–mouse pairs. Strikingly, on average, we found that only 47% of the human gut microbes could be re-established in mice at the species level, among which more than 1/3 underwent significant changes (referred to as “variable taxa”). Most of the human gut microbes that underwent significant changes were consistent across multiple human–mouse pairs and experimental settings. Consequently, about 1/3 of human samples changed their enterotypes, i.e., significant changes in their leading species after FMT. Mice fed with a controlled diet showed a lower enterotype change rate (23.5%) than those fed with a noncontrolled diet (49.0%), suggesting a possible solution for rescue. Most of the variable taxa have been reported to be implicated in human diseases, with some recognized as the causative species. Our results highlight the challenges of using a mouse model to replicate human gut microbiota-associated phenotypes, provide useful information for researchers using mice in gut microbiota studies, and call for additional validations after FMT. An online database named FMT-DB is publicly available at http://fmt2mice.humangut.info/#/.     

Endocytosis in plant–microbe interactions

Plants encounter throughout their life all kinds of microorganisms, such as bacteria, fungi, or oomycetes, with either friendly or unfriendly intentions. During evolution, plants have developed a wide range of defense mechanisms against attackers. In return, adapted microbes have developed strategies to overcome the plant lines of defense, some of these microbes engaging in mutualistic or parasitic endosymbioses. By sensing microbe presence and activating signaling cascades, the plasma membrane through its dynamics plays a crucial role in the ongoing molecular dialogue between plants and microbes. This review describes the contribution of endocytosis to different aspects of plant–microbe interactions, microbe recognition and development of a basal immune response, and colonization of plant cells by endosymbionts. The putative endocytic routes for the entry of microbe molecules or microbes themselves are explored with a special emphasis on clathrin-mediated endocytosis. Finally, we evaluate recent findings that suggest a link between the compartmentalization of plant plasma membrane into microdomains and endocytosis.     

Design,synthesis and in vitro study of densely functionalized oxindoles as potent α-glucosidase inhibitors

Diabetes a non-communicable disease occurs either due to the lack of insulin or the inability of the human body to recognize it. The recent data indicated an increase in the trend of people diagnosed with type 2 diabetes mainly due to unhealthy life style. Here in we report a new class of oxindole derivatives 6a-kvia scaffold hopping of known α-glucosidase inhibitors 1–4. When molecular docking was performed against a homology model of α-glucosidase the resulting compound 6d revealed binding interactions comparable to 1–4. The compounds were accessed through a unique condensation-ring opening protocol of pyridofuranone building blocks. Overall the compounds exhibited decent binding to the yeast α-glucosidase, where the most potent compound 6h, inhibited the enzyme with IC₅₀ of 0.6?µM. This was nearly threefold improvement from the original known compounds 1–4, selected to design the newer analogs. The reaction kinetics of 6h indicated competitive inhibition.     

2型糖尿病肠道菌群研究进展

2型糖尿病是一种常见的慢性消耗性疾病,其发病机制十分复杂,流行病学研究表明,肥胖、高热量饮食、体力活动不足及年龄增大是2型糖尿病最主要的环境因素。它是一种以胰岛素抵抗和胰岛素分泌不足为特征的代谢性疾病。肠道菌群作为进入人体的一个重要环境因素,肠道微生物的菌群变化影响宿主能量物质的吸收,调节肠道的分泌功能和非特异性免疫功能,从营养、代谢、疾病等各方面与我们生命活动相关。肠道菌群已成为我们身体的一部分,影响宿主的免疫,在肥胖、糖尿病、代谢综合征等疾病中都具有非常重要的作用。     

Structure–activity relationships of pyrazole derivatives as potential therapeutics for immune thrombocytopenias

Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure–activity relationship of the bis-pyrazole class of molecules with –C–C–, –C–N– and –C–O– linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC₅₀ of 14 ± 9 μM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N¹ positions of the bivalent pyrazole core to be important for the inhibitory activity.     

Role of the enteric microbiota in intestinal homeostasis and inflammation

The mammalian intestine encounters many more microorganisms than any other tissue in the body thus making it the largest and most complex component of the immune system. Indeed, there are greater than 100 trillion (10¹⁴) microbes within the healthy human intestine, and the total number of genes derived from this diverse microbiome exceeds that of the entire human genome by at least 100-fold. Our coexistence with the gut microbiota represents a dynamic and mutually beneficial relationship that is thought to be a major determinant of health and disease. Because of the potential for intestinal microorganisms to induce local and/or systemic inflammation, the intestinal immune system has developed a number of immune mechanisms to protect the host from pathogenic infections while limiting the inflammatory tissue injury that accompanies these immune responses. Failure to properly regulate intestinal mucosal immunity is thought to be responsible for the inflammatory tissue injury observed in the inflammatory bowel diseases (IBD; Crohn disease, ulcerative colitis). An accumulating body of experimental and clinical evidence strongly suggests that IBD results from a dysregulated immune response to components of the normal gut flora in genetically susceptible individuals. The objective of this review is to present our current understanding of the role that enteric microbiota play in intestinal homeostasis and pathogenesis of chronic intestinal inflammation.     

The microbiota,a necessary element of immunity

The intestinal microbiota is essential for digestion, the production of physiological metabolites, and defense. More than 10¹³ bacteria are present in the intestine, inspiring awe as well as fear of potential infections. By definition, the immune system protects us from infection, and is given the task to recognize dangerous pathogens from useful mutualists. Nevertheless, the definition of pathogens and mutualists is often contextual, and the immune system reacts to all types of microbes. In fact, immune reactivity to microbiota is necessary for the development of the immune system. If the host-microbe cross-talk is perturbed before birth or weaning, the immune system develops “pathological imprinting” and increased susceptibility to inflammatory pathology later in life. Reactivity to microbiota is also important in adulthood to regulate immune responses and maintain homeostasis.     

Allometric and ontogenetic larval development of common barbel during rearing under optimal conditions

The rearing of finfish larvae is a key element in their further culture. Improper breeding protocols may result in high mortality rates, body deformation and growth rate decreases in both the larval and fattening periods. These errors can be avoided by thorough exploration of various aspects of early larvae biology, at least in model fish species. In this study, anatomical and morphological developments were analysed using allometric growth patterns of common barbel, Barbus barbus, larvae reared under optimal controlled conditions. Larvae of common barbel, which is a model species for fish of the genus Barbus, were reared for 30 days at 25 °C in the recirculated aquaculture system (RAS). Four periods of the barbel larval development were identified: pre-flexion (0–5 days post hatching – DPH; total length – TL: 9.5 ± 0.3 to 12.3 ± 0.3 mm), flexion (6–11 DPH; TL 12.4 ± 0.3–15.4 ± 0.3 mm), post-flexion (12–21 DPH; TL 16.1 ± 0.5–21.2 ± 0.8 mm) and juvenile (from 22 DPH; TL from 21.4 ± 1.7 mm). The largest changes in barbel growth were observed during the first two periods of their life (pre-flexion and flexion), which resulted in the frequency of noted flexion points (64.3% flexion points) and was also associated with intensive morphometric growth, primarily the head and tail parts of the body. Despite a low degree of growth progress upon hatching (e.g. no eye pigment, no distinct liver or pancreas, no unobstructed alimentary tract), barbel larvae pass through the larval periods very quickly in comparison to other cyprinids and enter the juvenile period (22 days).     

Natural neuroprotective alkaloids from Stephania japonica (Thunb.) Miers

Modulating inflammatory responses after stroke can prevent brain injury and, therefore, improve neurological outcome. Stephania japonica (Thunb.) Miers is a Chinese folk medicine with the function of dispelling the “wind and blockage” in the human body according to the Chinese medicine theory, in which the symptoms of stroke are caused by the “wind and blockage” in the body. In this paper, we for the first time linked S. japonica to stroke by clarifying fifteen alkaloidal constituents including five undescribed (1–5) ones and screening out six hasubanan type alkaloids (1–4, 7, 15) that elicited stronger anti-neuroinflammatory activities than the positive drug. Moreover, the total alkaloid fraction (ASJ) with previously undescribed 3 as the main component was subject to the in vivo evaluation of the protective effect in the MCAO-induced brain injury. The results showed that ASJ exhibited potent protective effect against brain injury in the MCAO rat model. The results reported in this paper suggested that the hasubanan alkaloids from S. japonica would be an important molecular source for discovering novel therapeutic agents for neuroinflammation-related diseases, such as stroke diseases.     

Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of Keap1-Nrf2 protein-protein interaction

The Keap1–Nrf2–ARE system represents a crucial antioxidant defense mechanism that protects cells against reactive oxygen species. Targeting Keap1–Nrf2 protein–protein interaction (PPI) has become a promising drug target for several oxidative stress-related and inflammatory diseases including pulmonary fibrosis, chronic obstructive pulmonary disorder (COPD) and cancer chemoprevention. For the development of a potential therapeutic agent, drug-like properties and potency are important considerations. In this work, we focused on the modification of 4 as a lead through a molecular dissection strategy in an effort to improve its metabolic stability, leading to the discovery of a series of new disubstituted xylylene derivatives. The preliminary SAR of 9a indicated that compound 21a containing S-methylated acetate moieties exhibited comparable potency to the lead compound 4 in a fluorescent polarization assay but with improved metabolic stability in the presence of human liver microsomes.     

The intrauterine origins of Hodgkin's lymphoma

Background: Both small and large body size at birth are now known to predict a range of chronic disorders in adult life, including certain cancers. These associations are thought to reflect “fetal programming.” This may lead to impairment of a small number of key systems including the immune system. Hodgkin's lymphoma is a disease of the immune system. We have therefore examined the association between Hodgkin's lymphoma and early development. Our hypothesis was that the disease would be associated with markers of poor fetal growth, specifically small body size or small placental size at birth. Methods: Using the Finnish Cancer Registry we identified patients with Hodgkin's disease in a cohort of 20,431 people born in Helsinki during 1924–44. Each person has a detailed birth record. Results: There were 12 patients with Hodgkin's disease, giving an incidence comparable to international rates. The disease was associated with prolonged gestation. For every additional week of gestation the hazard ratio was 1.37 (95% CI 1.00–1.87; p = 0.05). The disease was also associated with a short placental surface. After allowing for gestation, for each centimetre increase in surface length, the hazard ratio was 0.70 (0.53–0.92; p = 0.01). The disease was not associated with birth weight or length or maternal body size. Conclusions: We have shown that Hodgkin's lymphoma is associated with prolonged gestation and a short length of the placental surface. We speculate that Hodgkin's lymphoma is initiated by two events in fetal life. One, which is an immune event, is associated with prolonged gestation, while the other is associated with growth faltering.     

Legal Rights in Human Bodies, Body Parts and Tissue

This paper outlines the current common law principles that protect people’s interests in their bodies, excised body parts and tissue without conferring the rights of full legal ownership. It does not include the recent statutory amendments in jurisdictions such as New South Wales and the United Kingdom. It argues that at common law, people do not own their own bodies or excised bodily material. People can authorise the removal of their bodily material and its use, either during life or after their death, for medical or scientific purposes. Researchers who acquire human bodies, body parts or tissue pursuant to such an authority have a right to possess and use them according to the authorisation they have been given, but their rights fall short of full ownership because they are limited in the way that they can use the material. The legal rights of researchers who develop intellectual property and biological products from excised human tissue can be adequately protected by existing common law principles without the need for a new legal principle that people own body parts and tissue removed from their bodies.

A decreased expression of interferon stimulated genes in peri-implantation endometrium of embryo transfer recipient sows could contribute to embryo death

Pig pregnancy succeeds thanks to a well-coordinated system ruling both maternal immune activation and embryonic antigen tolerance. In physiological pregnancies, the maternal immune system should tolerate the presence of hemi-allogeneic conceptuses from the pre-implantation phase to term, while maintaining maternal defence against pathogens. Allogeneic pregnancies, as after embryo transfer (ET), depict high embryo mortality during the attachment phase, calling for studies of the dynamic modifications in immune processes occurring at the maternal-foetal interface, for instance, of interferon (IFN)-stimulated genes (ISGs). These ISGs are generally activated by IFN secreted by the conceptus during the process of maternal recognition of pregnancy (MRP) and responsible for recruiting immune cells to the site of embryo attachment, thus facilitating cell-antigen presentation and angiogenesis. We performed RNA-Seq analysis in peri-implantation (days 18 and 24) endometrial samples retrieved from artificially inseminated sows (hemi-allogeneic embryos (HAL) group) or sows subjected to ET (allogeneic embryos (AL) group) to monitor alterations of gene expression that could be jeopardising early pregnancy. Our results showed that endometrial gene expression patterns related to immune responses differed between hemi- or allogeneic embryo presence, with allogeneic embryos apparently inducing conspicuous modifications of immune-related genes and pathways. A decreased expression (P < 0.05; FC < ?2) of several interferon ISGs, such as CXCL8, CXCL10, IRF1, IRF9, STAT1, and B2M, among others was detected in the endometrium of sows carrying allogeneic embryos on day 24 of pregnancy. This severe downregulation of ISGs in allogeneic pregnancies could represent a failure of ET-embryos to signal IFN to the endometrium to warrant the development of adequate immunotolerance mechanisms to facilitate embryo development, thus contributing to elevated embryo death.     

(+)-Altholactone exhibits broad spectrum immune modulating activity by inhibiting the activation of pro-inflammatory cytokines in RAW 264.7 cell lines

An evaluation of Indonesian plants to identify compounds with immune modulating activity revealed that the methanolic extract of an Alphonsea javanica Scheff specimen possessed selective anti-inflammatory activity in a nuclear factor-kappa B (NF-κB) luciferase and MTT assay using transfected macrophage immune (Raw264.7) cells. A high-throughput LC/MS-ELSD based library approach of the extract in combination with the NF-κB and MTT assays revealed the styryl lactone (+)-altholactone (2) was responsible for the activity. Compound 2, its acetylated derivate (+)-3-O-acetylaltholactone (3), and the major compound of this class, (+)-goniothalmin (1), were further evaluated to determine their anti-inflammatory potential in the NF-κB assay. Concentration–response studies of 1–3 indicated that only 2 possessed NF-κB based anti-inflammatory activity. Compound 2 reduced the LPS-induced NO production, phosphorylation of IκBα, and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) using Western blot analysis. Further studies using qPCR indicated 2 reduced the expression of eight pro-inflammatory cytokines/enzymes (0.8–5.0 μM) which included: COX-2, iNOS, IP-10, IL-1β, MCP-1, GCS-F, IL-6 and IFN-β. These results indicated that 2 displays broad spectrum immune modulating activity by functioning as an anti-inflammatory agent against LPS-induced NF-κB signaling. Conversely the selective cytotoxicity and in vivo anti-tumor and anti-inflammatory activity previously reported for 1 do not appear to arise from a mechanism that is linked to the NF-κB immune mediated pathway.     

Systemic features of immune recognition in the gut

The immune system, to protect the body, must discriminate between the pathogenic and non-pathogenic microbes and respond to them in different ways. How the mucosal immune system manages to make this distinction is poorly understood. We suggest here that the distinction between pathogenic and non-pathogenic microbes is made by an integrated system rather than by single types of cells or single types of receptors; a systems biology approach is needed to understand immune recognition.     

The potential for probiotic manipulation of the gastrointestinal microbiome

Multiple internal and external sites of the healthy human body are colonized by a diversity of symbiotic microbes. The microbial assemblages found in the intestine represent some of the most dense and diverse of these human-associated ecosystems. Unsurprisingly, the enteric microbiome, that is the totality of microbes, their combined genomes, and their interactions with the human body, has a profound impact on physiological aspects of mammalian function, not least, host immune response. Lack of early-life exposure to certain microbes, or shifts in the composition of the gastrointestinal microbiome have been linked to the development and progression of several intestinal and extra-intestinal diseases, including childhood asthma development and inflammatory bowel disease. Modulating microbial exposure through probiotic supplementation represents a long-held strategy towards ameliorating disease via intestinal microbial community restructuring. This field has experienced somewhat of a resurgence over the past few years, primarily due to the exponential increase in human microbiome studies and a growing appreciation of our dependence on resident microbiota to modulate human health. This review aims to review recent regulatory aspects related to probiotics in food. It also summarizes what is known to date with respect to human gastrointestinal microbiota - the niche which has been most extensively studied in the human system - and the evidence for probiotic supplementation as a viable therapeutic strategy for modulating this consortium.     

Microbial programming of health and disease starts during fetal life

The pioneer microbiota of the neonatal gut are essential for gut maturation, and metabolic and immunologic programming. Recent research has shown that early bacterial colonization may impact the occurrence of disease later in life (microbial programming). Despite early conflicting evidence, it has long been considered that the womb is a sterile environment and human microbial colonization begins at birth. In the last few years, several findings have reiterated the presence of microbes in infant first stool (meconium) and pointed to the existence of in utero microbial colonization of the infant gut. The dominant bacterial taxa detected in meconium specimens belong to the Enterobacteriaceae family (Escherichia genus) and lactic acid bacteria (notably members of the genera Leuconostoc, Enterococcus, and Lactococcus). Maternal atopy promotes dominance of Enterobacteriaceae in newborn meconium, which in turn may lead to respiratory problems in the infant. This microbial interaction with the host immune system may in fact, originate during fetal life. Our review evaluates the evidence for an intrauterine origin of meconium microbiota, their composition and influences, and potential clinical implications on infant health. Birth Defects Research (Part C) 105:265–277, 2015. © 2015 Wiley Periodicals, Inc.     

Design and synthesis of novel nitrogen mustard-evodiamine hybrids with selective antiproliferative activity

A series of novel nitrogen mustard-evodiamine hybrids were synthesized and evaluated for their antitproliferative properties. The antiproliferative activities of 10a–d, 11a–d, and 12a–d against four different kinds of human cancer cell lines (PC-3, HepG2, THP-1 and HL-60) and human normal peripheral blood mononuclear cells (PBMC) were determined. The results showed that all the target hybrid compounds exhibited antiproliferative activities against tested human tumor cell lines to some extent and no antiproliferative activities (>200?μM) against human normal PBMC cells. The antiproliferative selectivity between tumorous and normal cells was very useful for further antitumor drug development. Among the target compounds, 12c showed the strongest cytotoxicity against two tumor cell lines (THP-1 and HL-60) with IC₅₀ values of 4.05?μM and 0.50?μM, respectively, and selected for further mechanism study in HL-60 cells. The results showed that 12c could induce HL-60 cells apoptosis and arrest at G₂ phase at low sub-micromolar concentrations via mitochondria-related pathways.