BACKGROUND & AIMS: :In order to provide accurate prognosis and developmental intervention to newborns, new methods of assessing cerebral functions are needed. The non-invasive technique of functional magnetic resonance imaging (fMRI) can be considered as the leading technique for functional exploration of the infant's brain. Several studies have previously applied fMRI in both healthy and diseased newborns with different sensory and cognitive tasks. In this chapter, the methodological issues that are proper to the use of fMRI in the newborn are detailed. In addition, an overview of the major findings of previous fMRI studies is provided, with a focus on notable differences from those in adult subjects. More specifically, the functional responses and the localization of cortical activations in healthy and diseased newborns are discussed. We expect a rapid expansion of this field and the establishment of fMRI as a valid clinical diagnostic tool in the newborn.

背景与目标： ：为了给新生儿提供准确的预后和发育干预，需要评估脑功能的新方法。功能性磁共振成像（fMRI）的非侵入性技术可以被认为是婴儿大脑功能性探索的主要技术。先前有几项研究将功能磁共振成像应用于具有不同感觉和认知任务的健康和患病新生儿。在本章中，将详细介绍适合于新生儿使用fMRI的方法学问题。此外，提供了以前的功能磁共振成像研究的主要发现的概述，重点是与成人受试者的显着差异。更具体地说，讨论了健康和患病新生儿的功能反应和皮质激活的定位。我们期望这一领域的快速发展和功能磁共振成像作为新生儿有效的临床诊断工具的建立。

BACKGROUND & AIMS: :Assessment of wound healing is a complex task, especially when the lesion is associated to significant (full thickness) loss of the skin. The clinical observation, essentially subjective and highly dependent on the observer's experience, creates difficulties in the comparison of results. Scoring scales were introduced in the clinical practice to create comparable semi-quantitative data and promote better management of resources, but its usefulness in a clinical perspective is still limited. New non-invasive biometric methodologies, although infrequently used, have opened new possibilities. While complementing the clinical observation and contributing to therapeutic decisions and prognosis, they may also help to look further into the pathophysiological mechanisms of scarring drugs rehabilitation. Following previous work in this arena, the authors review, the state-of-the-art of cutaneous wound healing clinical and biometric follow up, proposing a diagnosis correlation for the most relevant descriptors found in both strategies in order to fully characterise the different stages of the healing process.

背景与目标： ：伤口愈合的评估是一项复杂的任务，尤其是当病变与皮肤的严重（全层）损失有关时。临床观察本质上是主观的，并且高度依赖观察者的经验，因此在比较结果时会遇到困难。在临床实践中引入了评分量表，以创建可比较的半定量数据并促进更好的资源管理，但其在临床上的实用性仍然有限。尽管不经常使用新的非侵入式生物统计方法，但也开辟了新的可能性。在补充临床观察并有助于治疗决策和预后的同时，它们还可能有助于进一步研究疤痕药物康复的病理生理机制。在此领域的先前工作之后，作者回顾了最新的皮肤伤口愈合临床和生物测定学随访情况，提出了两种策略中最相关的描述符的诊断相关性，以全面表征不同的阶段愈合过程。

BACKGROUND & AIMS: :Tumor-infiltrating stroma cells (TISC) as well as tumors themselves are thought to be involved in tumor-related immunosuppression, which is one of the critical mechanisms of tumor escape from immune surveillance. However, preparation of TISC is difficult because of the small proportion of TISC in established tumors. Thus, the cells thought to be involved in tumor-related immunosuppression are generally prepared from spleens or draining lymph nodes in tumor-bearing mice. In this study, we developed a method for directly preparing TISC from established tumors in order to analyze their function. Using green fluorescent protein (GFP) transgenic (Tg) mice and C57BL/6 mice transplanted with bone marrow (BM) cells of GFPTg mice, we detected three subpopulations of TISC: one is compatible with immature myeloid cells (ImC) derived from BM and the two other subpopulations, CD11b(+) cells and CD11b(-) cells, do not originate from BM. The TISC including these subpopulations but not each subpopulation independently after culturing with tumors in the presence of GM-CSF could suppress T cell proliferation induced by anti-CD3. In our system, tumors did not inhibit T cell responses directly, but unknown factors from tumors affected immunosuppression by TISC.

背景与目标： ：肿瘤浸润基质细胞（TISC）以及肿瘤本身都被认为与肿瘤相关的免疫抑制有关，这是肿瘤逃避免疫监视的关键机制之一。然而，由于在已建立的肿瘤中TISC的比例很小，因此TISC的制备是困难的。因此，通常被认为与肿瘤相关的免疫抑制有关的细胞是从荷瘤小鼠的脾脏或引流淋巴结中制备的。在这项研究中，我们开发了一种从已建立的肿瘤中直接制备TISC的方法，以分析其功能。使用绿色荧光蛋白（GFP）转基因（Tg）小鼠和移植有GFPTg小鼠骨髓（BM）细胞的C57BL / 6小鼠，我们检测到TISC的三个亚群：一个与源自BM的未成熟髓样细胞（ImC）相容。其他两个亚群CD11b（）细胞和CD11b（-）细胞并非源自BM。在存在GM-CSF的情况下与肿瘤培养后，TISC包括这些亚群，但并非每个亚群独立地抑制由抗CD3诱导的T细胞增殖。在我们的系统中，肿瘤并未直接抑制T细胞反应，但来自肿瘤的未知因素影响了TISC的免疫抑制。

BACKGROUND & AIMS: :We investigated the functional significance of extraradical mycorrhizal networks produced by geographically different isolates of the arbuscular mycorrhizal fungal (AMF) species Glomus mosseae and Glomus intraradices. A two-dimensional experimental system was used to visualize and quantify intact extraradical mycelium (ERM) spreading from Medicago sativa roots. Growth, phosphorus (P) and nitrogen (N) nutrition were assessed in M. sativa plants grown in microcosms. The AMF isolates were characterized by differences in extent and interconnectedness of ERM. Phenotypic fungal variables, such as total hyphal length, hyphal density, hyphal length per mm of total or colonized root length, were positively correlated with M. sativa growth response variables, such as total shoot biomass and plant P content. The utilization of an experimental system in which size, growth rate, viability and interconnectedness of ERM extending from mycorrhizal roots are easily quantified under realistic conditions allows the simultaneous evaluation of different isolates and provides data with a predictive value for selection of efficient AMF.

背景与目标： ：我们调查了丛枝菌根真菌（AMF）物种Glomus mosseae和Glomus intraradices的地理上不同的分离物产生的自由基外菌根网络的功能意义。二维实验系统用于可视化和量化从紫花苜蓿根部传播的完整的根外菌丝体（ERM）。在微观世界中评估了苜蓿植物的生长，磷（P）和氮（N）营养。 AMF分离株的特征是ERM的程度和相互连接性不同。表型真菌变量，例如总菌丝长度，菌丝密度，每毫米总或定殖根长度的菌丝长度，与苜蓿生长反应变量（如总枝生物量和植物P含量）呈正相关。在实际条件下容易量化从菌根根延伸的ERM的大小，生长速度，生存力和相互联系的实验系统，可以同时评估不同的分离物，并为选择有效AMF提供具有预测价值的数据。

BACKGROUND & AIMS: :The site-1 determinant of the hemagglutinin molecule of influenza virus (A/PR/8/34) is one of several immunodominant sites in the BALB/c Th cell response to Ha. A synthetic peptide comprising this T cell site (HA110-120), a panel of analogs containing single substitutions in this determinant, and homologs truncated at the amino- or carboxyl-terminal were used to examine the fine specificities of 15 T cells specific for site-1 in the context of I-Ed. The results indicate that every residue within the minimal determinant plays a role in the T cell recognition process, as single substitutions at any of these positions affected the ability of the peptide to stimulate at least some site 1-specific T cells. For the majority of the residues examined, substitutions had dissimilar effects on distinct T cells, indicating that the substituted residues were affecting recognition in a receptor-specific manner. Each of the 15 T cells examined had a distinct fine specificity pattern, suggesting that the BALB/c T cell repertoire for this site is likely to exceed 100 distinct clonotypes.

背景与目标： 流感病毒血凝素分子（A / PR / 8/34）的1位点决定簇是BALB / c Th细胞对Ha的免疫应答中的几个免疫优势位点之一。包含该T细胞位点的合成肽（HA110-120），在该决定簇中包含单个取代基的一组类似物以及在氨基或羧基端被截短的同源物用于检查15个对该位点特异性的T细胞的精细特异性在I-Ed中为-1。结果表明，最小决定簇内的每个残基都在T细胞识别过程中起作用，因为这些位置中任何一个的单取代都会影响肽刺激至少一些位点1特异性T细胞的能力。对于所检查的大多数残基，取代对不同的T细胞的影响不同，表明取代的残基以受体特异性方式影响识别。检查的15个T细胞中的每一个都有独特的精细特异性模式，这表明该位点的BALB / c T细胞库可能超过100种不同的克隆型。

BACKGROUND & AIMS: How an increase in blood pressure, in and of itself, induces hypertensive nephrosclerosis is unclear. In an earlier study we found that leukocyte infiltration, proximal tubular cell proliferation, matrix deposition and interstitial fibrosis occur in the unclipped kidney of 2 K 1 C Goldblatt hypertensive rats. In this study we tested the hypothesis that the cell surface adhesion molecule ICAM-1 is expressed on the vascular endothelium and tubular epithelium of unclipped kidneys at 4 weeks. As a positive control, we examined the clipped kidney as well. We found that systolic blood pressure was significantly elevated in renovascular hypertensive rats compared to sham-operated controls after 4 weeks (198 +/- 5 mmHg vs 121 +/- 2 mmHg, P < 0.001). Furthermore, quantitative (densitometry) measurements showed that ICAM-1 expression on vascular endothelium and on tubular cells was significantly increased in unclipped kidneys compared to controls (P < 0.05). The same was true for monocyte and granulocyte infiltration (P < 0.05). These same variables were even more prominent in the clipped kidneys, compared to unclipped and control kidneys (P < 0.05). Our data show that ICAM-1 is expressed in unclipped kidneys exposed to hypertension as well as in clipped kidneys exposed to ischemia. We suggest that mechanical injury induced by increased blood pressure is responsible for an inflammatory adhesion molecule-mediated response and concomitant renal injury.

背景与目标： 血压升高本身如何引起高血压性肾硬化尚不清楚。在较早的研究中，我们发现2 K 1 C Goldblatt高血压大鼠的未切除肾脏中发生白细胞浸润，近端肾小管细胞增殖，基质沉积和间质纤维化。在这项研究中，我们测试了以下假设：第4周，细胞表面粘附分子ICAM-1在未切除的肾脏的血管内皮和肾小管上皮细胞中表达。作为阳性对照，我们还检查了修剪的肾脏。我们发现，与假手术对照组相比，肾血管性高血压大鼠的收缩压在4周后显着升高（198 /-5 mmHg与121 /-2 mmHg，P <0.001）。此外，定量（密度测定）测量结果显示，与对照相比，未切除的肾脏在血管内皮和肾小管细胞上的ICAM-1表达显着增加（P <0.05）。单核细胞和粒细胞浸润也是如此（P <0.05）。与未修剪的和对照的肾脏相比，这些相同的变量在修剪的肾脏中甚至更为突出（P <0.05）。我们的数据表明，ICAM-1在暴露于高血压的未切除的肾脏以及暴露于缺血的切除的肾脏中表达。我们认为，血压升高引起的机械损伤是炎症粘附分子介导的反应和伴随的肾损伤的原因。

BACKGROUND & AIMS: :Cyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

背景与目标： ：循环性和先天性中性粒细胞减少症是由人中性粒细胞弹性蛋白酶（HNE）基因（ELA2）突变引起的，导致免疫缺陷，其特征是血液中中性粒细胞水平降低或振荡。 HNE突变可能导致酶活性下降，因此导致免疫系统功能受损。为了了解该疾病的结构基础，我们采用了生物信息学的方法来分析序列和结构水平上所有已知的HNE错义突变。我们的结果表明，这32种不同的突变对HNE的结构和功能有多种影响，影响结构异常和聚集趋势，保持接触的稳定性以及静电性质。很大一部分突变位于保守氨基酸上，这通常是决定蛋白质结构和功能所必需的。大多数引起疾病的HNE错义突变会导致主要的结构变化和蛋白质稳定性的损失。一些突变也影响功能性残基，导致催化活性降低或配体结合改变。我们的分析揭示了HNE中所有已知错义突变的推定作用，从而阐明了周期性和先天性中性粒细胞减少症的结构基础。我们已经采用并分析了一组约30种不同的方法来预测氨基酸取代的影响。我们提供了对这些方法在众多基因，蛋白质和疾病分析中的适用性进行分析的结果和经验，以揭示蛋白质结构与功能的关系以及疾病的基因型与表型的相关性。

BACKGROUND & AIMS: Transgenic mice expressing high levels of the BclxL or Bcl2 proteins in the male germinal cells show a highly abnormal adult spermatogenesis accompanied by sterility. This appears to result from the prevention of an early and massive wave of apoptosis in the testis, which occurs among germinal cells during the first round of spermatogenesis. In contrast, sporadic apoptosis among spermatogonia, which occurs in normal adult testis, is not prevented in adult transgenic mice. The physiological early apoptotic wave in the testis is coincident, in timing and localization, with a temporary high expression of the apoptosis-promoting protein Bax, which disappears at sexual maturity. The critical role played by the intracellular balance, probably hormonally controlled, of the BclxL and Bax proteins (Bcl2 is apparently not expressed in normal mouse testis) in this early apoptotic wave is shown by the occurrence of a comparable testicular syndrome in mice defective in the bax gene. The apoptotic wave appears necessary for normal mature spermatogenesis to develop, probably because it maintains a critical cell number ratio between some germinal cell stages and Sertoli cells, whose normal functions and differentiation involve an elaborate network of communication.

背景与目标： 在雄性生殖细胞中表达高水平BclxL或Bcl2蛋白的转基因小鼠表现出高度异常的成年精子发生并伴有不育。这似乎是由于防止了睾丸早期大量凋亡的结果，这种情况发生在第一轮精子发生过程中的生发细胞之间。相反，在成年转基因小鼠中，不能阻止正常成年人睾丸中发生的精原细胞中的偶发性细胞凋亡。睾丸中的生理性早期凋亡波在时间和位置上是一致的，具有促凋亡的蛋白Bax的临时高表达，该蛋白在性成熟时消失。 BclxL和Bax蛋白的细胞内平衡（可能是激素控制的）（在正常小鼠的睾丸中显然不表达Bcl2）在细胞内平衡中起着至关重要的作用，这是由于在小鼠中出现了类似的睾丸综合征所致。 bax基因。凋亡波似乎是正常成熟精子发生发展所必需的，这可能是因为它在某些生细胞阶段和支持细胞之间维持了关键的细胞数比，其正常功能和分化牵涉到复杂的交流网络。

BACKGROUND & AIMS: :Cyclic AMP levels in rabbit carotid bodies incubated under control conditions, 100% O2- or 95% O2/5% CO2- equilibrated medium, are close to 1 pmol/mg wet tissue (range 0.4-2.43 pmol/mg). Isobutylmethylxanthine (0.5 mM) increases cyclic AMP levels by a factor of 14 and 8 in HEPES- and CO2/CH3O(-)-buffered medium, respectively. Forskolin (0.5-10 microM) applied during 30 min increases cyclic AMP levels in a dose-dependent manner. Incubation of carotid bodies at low O2 tensions resulted in an elevation of cyclic AMP levels both in the absence and in the presence of isobutymethylxanthine. In the latter conditions cyclic AMP increase was maximum at an O2 tension of 46 mm Hg and tended to decrease at extremely low PO2. In isobutylmethylxanthine-containing Ca2(+)-free medium, cyclic AMP increased linearly with decreasing PO2 from 66 to 13 mm Hg; the absolute cyclic AMP levels attained in Ca2(+)-free medium were smaller than those observed in Ca2(+)-containing medium at any PO2. The differences between Ca2(+)-free and Ca2(+)-containing media appear to be due to the action of released neurotransmitters in the latter conditions, because dopamine and norepinephrine, which are known to be released by hypoxia in a Ca2(+)-dependent manner, increase cyclic AMP in the carotid body. Low pH/high PCO2 and high [K+]e increase cyclic AMP levels only in Ca2(+)-containing medium. Forskolin potentiates the release of catecholamines induced by low PO2. These results suggest that cyclic AMP plays an important role in the modulation of the chemoreception process.

背景与目标： ：在对照条件下，100％O2-或95％O2 / 5％CO2平衡的培养基中孵育的兔颈动脉体中的循环AMP水平接近1 pmol / mg湿组织（0.4-2.43 pmol / mg范围）。在HEPES-和CO2 / CH3O（-）缓冲的培养基中，异丁基甲基黄嘌呤（0.5 mM）将循环AMP的水平分别提高14和8倍。在30分钟内施用的Forskolin（0.5-10 microM）以剂量依赖性方式增加循环AMP的水平。在不存在和存在异丁甲基黄嘌呤的情况下，在低O2张力下孵育颈动脉都会导致环AMP含量升高。在后一种情况下，循环AMP的增加在O2张力为46 mm Hg时最大，而在极低的PO2下趋于减少。在不含异丁基甲基黄嘌呤的不含Ca2（）的介质中，环状AMP随着PO2从66 mmHg降低到13 mm Hg而线性增加。不含Ca2（）的培养基中获得的绝对循环AMP水平要小于任何PO2含Ca2（）的培养基中观察到的绝对值。不含Ca2（）和含Ca2（）的培养基之间的差异似乎是由于后者条件下释放的神经递质的作用所致，因为已知多巴胺和去甲肾上腺素在依赖Ca2（）的情况下会通过低氧释放。方式，增加颈动脉体中的循环AMP。低pH /高PCO2和高[K] e仅在含Ca2（）的培养基中会增加循环AMP的水平。 Forskolin增强了低PO2诱导的儿茶酚胺释放。这些结果表明，环状AMP在化学感受过程的调节中起重要作用。

BACKGROUND & AIMS: :Despite the successful identification of several relevant genomic loci, the underlying molecular mechanisms of schizophrenia remain largely unclear. We developed a computational approach (NETBAG+) that allows an integrated analysis of diverse disease-related genetic data using a unified statistical framework. The application of this approach to schizophrenia-associated genetic variations, obtained using unbiased whole-genome methods, allowed us to identify several cohesive gene networks related to axon guidance, neuronal cell mobility, synaptic function and chromosomal remodeling. The genes forming the networks are highly expressed in the brain, with higher brain expression during prenatal development. The identified networks are functionally related to genes previously implicated in schizophrenia, autism and intellectual disability. A comparative analysis of copy number variants associated with autism and schizophrenia suggests that although the molecular networks implicated in these distinct disorders may be related, the mutations associated with each disease are likely to lead, at least on average, to different functional consequences.

背景与目标： ：尽管成功鉴定了几个相关的基因组位点，但精神分裂症的潜在分子机制仍不清楚。我们开发了一种计算方法（NETBAG），该方法可以使用统一的统计框架对与疾病相关的多种遗传数据进行综合分析。使用无偏倚的全基因组方法获得的这种方法用于精神分裂症相关遗传变异的应用，使我们能够鉴定出与轴突导向，神经元细胞移动性，突触功能和染色体重塑有关的几个内聚基因网络。形成网络的基因在大脑中高度表达，在产前发育过程中大脑表达更高。所确定的网络在功能上与先前与精神分裂症，自闭症和智力障碍有关的基因有关。对与自闭症和精神分裂症有关的拷贝数变异的比较分析表明，尽管与这些独特疾病有关的分子网络可能是相关的，但与每种疾病有关的突变可能至少平均而言导致不同的功能后果。

BACKGROUND & AIMS: :The Shozu Herpes Zoster (SHEZ) Study was designed to clarify the incidence of and predictive and immunological factors for herpes zoster in a defined community-based Japanese population. As part of this series, a total of 5683 residents aged ≥50 years received a varicella-zoster virus (VZV) skin test with VZV antigen, and 48 h later, the erythema and oedema were assessed by measuring the longest diameter. The diameters of both the erythema and oedema decreased with the increasing age of the subject. Sixty-three subjects contracted herpes zoster within a year after receiving the VZV skin test. Analysis of the herpes zoster incidence rate vs. the skin test reaction revealed that the shorter the diameter of erythema or oedema, the greater the likelihood of herpes zoster. These results demonstrated that the VZV skin test is an excellent surrogate marker for predicting the risk of herpes zoster.

背景与目标： ：Shozu疱疹带状疱疹（SHEZ）研究旨在阐明在特定的以社区为基础的日本人群中带状疱疹的发病率以及预测性和免疫学因素。作为该系列的一部分，共有5683名年龄≥50岁的居民接受了带有VZV抗原的水痘-带状疱疹病毒（VZV）皮肤测试，并且48小时后，通过测量最长直径来评估红斑和浮肿。红斑和水肿的直径随受试者年龄的增加而减小。接受VZV皮肤测试后一年内，六十三名受试者患了带状疱疹。带状疱疹发病率与皮肤试验反应的关系分析表明，红斑或水肿的直径越短，带状疱疹的可能性就越大。这些结果表明，VZV皮肤测试是预测带状疱疹风险的出色替代指标。

BACKGROUND & AIMS: OBJECTIVES:We evaluated the functional and oncological outcomes of transoral laser microsurgery (TLM) in patients with previously untreated supraglottic carcinoma compared with the outcomes in salvage cases after radiation-based treatment. METHODS:We conducted a retrospective case-control study at a single academic tertiary care institution. The functional outcomes were stratified by prior irradiation and were assessed at baseline, less than 1 week after operation, and at last follow-up. RESULTS:Five patients underwent TLM for previously untreated disease, and 5 previously irradiated patients underwent salvage TLM for local failure. No patient required tracheostomy. There was no local recurrence after TLM as primary therapy, and none of those patients required radiotherapy. One salvage patient developed local recurrence. The duration of feeding tube dependence (p = 0.049) and the rates of chronic aspiration (more than 1 month after operation; p = 0.048) were significantly higher in the salvage TLM cases than in the previously untreated cases. The median scores on the PSS-HN Understandability of Speech were 75 ("usually understandable") in the salvage group and 100 ("always understandable") in the previously untreated group. CONCLUSIONS:Both local control and function were better in the previously untreated patients than in the salvage patients. Our findings provide support for the use of TLM as a primary treatment modality for selected supraglottic carcinomas, but also suggest a potential for functional recovery in both previously untreated and salvage cases.

背景与目标： 目的：我们评估了先前未经治疗的声门上癌患者经口激光显微外科手术（TLM）的功能和肿瘤学结果，与基于放射治疗的抢救病例的结果相比。
方法：我们在一家单一的三级学术机构中进行了一项回顾性病例对照研究。功能结局通过事先照射进行分层，并在基线，手术后不到1周和最后一次随访时进行评估。
结果：5例接受过TLM的患者先前未接受过治疗，而5例接受过放射线的患者则接受了TLM进行局部衰竭治疗。没有患者需要气管切开术。 TLM作为主要疗法后没有局部复发，而且这些患者均不需要放疗。一名抢救患者出现局部复发。抢救性TLM病例的进食管依赖性持续时间（p = 0.049）和慢性误吸率（术后1个月以上； p = 0.048）显着高于先前未治疗的病例。挽救组的PSS-HN语音可理解性中位数为75（“通常可理解”），以前未治疗的组为100（“始终可理解”）。
结论：先前未治疗的患者的局部控制和功能均优于抢救患者。我们的发现为TLM作为选定的声门上癌的主要治疗手段提供了支持，但也暗示了先前未治疗和挽救病例的功能恢复潜力。

BACKGROUND & AIMS: OBJECTIVES:Patients with heartburn and normal upper gastrointestinal endoscopy, normal oesophageal acid exposure, no symptom-reflux association and who fail to respond to a proton-pump inhibitor are classified as having functional heartburn (FH). This study aimed (i) to characterize the symptoms and functional abnormalities of patients with FH and (ii) to describe their clinical outcome. MATERIALS AND METHODS:Among all patients referred for 24 h multichannel intraluminal impedance-pH (MII-pH), patients with FH were identified. The clinical characteristics and high-resolution oesophageal pressure topography recordings of FH patients were analyzed at the time of the 24-h MII-pH test. A symptom-related and health-related quality-of-life questionnaire was then sent to FH patients to assess the long-term outcome. RESULTS:Forty patients fulfilled the criteria for FH, representing 8.5% of the referred population. Twenty-two months after initial testing, 66% of patients still suffered from heartburn. The rate of mixed reflux (liquid/gas) was higher in patients with persisting heartburn at the final evaluation (63 vs. 50%, P=0.04). Sixty-six per cent of patients had one or more manometric abnormalities. Acid clearance time in MII-pH was significantly higher in patients with weak peristalsis than patients with normal peristalsis (60 ± 45 vs. 31 ± 19 s, P=0.03). A high rate of mixed reflux and/or a manometric abnormality were associated with a higher risk of persistent heartburn. CONCLUSION:FH is a chronic disorder with persisting symptoms in two-thirds of patients. An increased rate of mixed reflux and/or the presence of manometric abnormalities are associated with a higher risk of persisting symptoms and may help to identify the population with unmet therapeutic needs.

背景与目标： 目的：患有胃灼热和正常上消化道内窥镜检查，正常食道酸暴露，无症状-反流关联且对质子泵抑制剂无反应的患者被归类为功能性胃灼热（FH）。这项研究旨在（i）表征FH患者的症状和功能异常，以及（ii）描述其临床结局。
材料与方法：在所有接受24 h多通道管腔内阻抗pH（MII-pH）治疗的患者中，均鉴定出FH患者。在24小时MII-pH测试时分析了FH患者的临床特征和高分辨率的食管压力地形图记录。然后将症状相关和健康相关的生活质量调查表发送给FH患者，以评估其长期预后。
结果：40例患者符合FH标准，占推荐人群的8.5％。初始测试后的22个月，仍有66％的患者患有胃灼热。在最终评估中，持续性烧心患者的混合反流（液体/气体）比率更高（63％vs. 50％，P = 0.04）。 66％的患者有一个或多个测压异常。蠕动较弱的患者在MII-pH中的酸清除时间明显长于正常蠕动的患者（60±45 vs. 31±19 s，P = 0.03）。混合反流率高和/或测压异常与持续性烧心的风险较高相关。
结论：FH是一种慢性疾病，在三分之二的患者中持续存在症状。混合反流率的增加和/或压力异常的存在与持续存在症状的风险较高有关，可能有助于确定治疗需求未得到满足的人群。

BACKGROUND & AIMS: :HMGB1 is a nuclear protein that is released or secreted following trauma or severe cellular stress. Extracellular HMGB1 triggers inflammation and recruits leukocytes to the site of tissue damage. We review recent evidence that the ability of HMGB1 to recruit leukocytes may be entirely due to the formation of a heterocomplex with the homeostatic chemokine CXCL12. The HMGB1-CXCL12 heterocomplex acts on the CXCR4 receptor more potently than CXCL12 alone. Notably, only one of the redox forms of HMGB1, the one where all cysteines are reduced (all-thiol), can bind CXCL12. Both HMGB1 containing a disulfide bond between C23 and C45, which induces chemokine and cytokine release by activating TLR4, and HMGB1 terminally oxidized to contain a cysteine sulfonate are inactive in recruiting leukocytes. Thus, the chemoattractant and cytokine-inducing activities of HMGB1 are separable, and we propose that they appear sequentially during the development of inflammation and its resolution. The HMGB1-CXCL12 heterocomplex constitutes a specific target that may hold promise for the treatment of several pathologies.

背景与目标： ：HMGB1是一种核蛋白，在外伤或严重的细胞应激后会释放或分泌。细胞外HMGB1引发炎症，并将白细胞募集到组织损伤部位。我们审查了最近的证据，HMGB1募集白细胞的能力可能完全是由于与稳态趋化因子CXCL12形成异源复合体。 HMGB1-CXCL12异源复合物比单独的CXCL12更有效地作用于CXCR4受体。值得注意的是，HMGB1的一种氧化还原形式（所有半胱氨酸都被还原的形式（全硫醇））可以结合CXCL12。 HMGB1在C23和C45之间包含二硫键，可通过激活TLR4诱导趋化因子和细胞因子释放，而HMGB1最终被氧化以包含半胱氨酸磺酸盐，在募集白细胞方面均无活性。因此，HMGB1的趋化性和细胞因子诱导活性是可分离的，我们建议它们在炎症发展和消退过程中依次出现。 HMGB1-CXCL12异源复合物构成了一个特定的靶标，有望为多种病理学的治疗带来希望。

BACKGROUND & AIMS: :Second generation biofuel production has been appeared as a sustainable and alternative energy option. The ultimate aim is the development of an industrially feasible and economic conversion process of lignocellulosic biomass into biofuel molecules. Since, cellulose is the most abundant biopolymer and also represented as the photosynthetically fixed form of carbon, the efficient hydrolysis of cellulose is the most important step towards the development of a sustainable biofuel production process. The enzymatic hydrolysis of cellulose by suites of hydrolytic enzymes underlines the importance of cellulase enzyme system in whole hydrolysis process. However, the selection of the suitable cellulolytic enzymes with enhanced activities remains a challenge for the biorefinery industry to obtain efficient enzymatic hydrolysis of biomass. The present review focuses on deciphering the novel and effective cellulases from different environmental niches by unculturable metagenomic approaches. Furthermore, a comprehensive functional aspect of cellulases is also presented and evaluated by assessing the structural and catalytic properties as well as sequence identities and expression patterns. This review summarizes the recent development in metagenomics based approaches for identifying and exploring novel cellulases which open new avenues for their successful application in biorefineries.

背景与目标： ：第二代生物燃料生产已被视为一种可持续的替代能源选择。最终目的是开发一种工业上可行且经济的木质纤维素生物质转化为生物燃料分子的方法。由于纤维素是最丰富的生物聚合物，并且也表现为碳的光合作用固定形式，因此纤维素的有效水解是朝着可持续生物燃料生产工艺发展的最重要步骤。一系列水解酶对纤维素的酶促水解强调了纤维素酶系统在整个水解过程中的重要性。然而，选择具有增强活性的合适的纤维素分解酶对于生物精炼工业获得有效的生物质的酶水解仍然是一个挑战。目前的审查侧重于通过不可培养的宏基因组学方法从不同的环境利基破译新颖和有效的纤维素酶。此外，还介绍了纤维素酶的综合功能方面，并通过评估其结构和催化特性以及序列同一性和表达模式来对其进行评估。这篇综述总结了基于宏基因组学的方法的最新发展，该方法用于鉴定和探索新型纤维素酶，为它们在生物精炼厂的成功应用开辟了新途径。