The First Case of a Class I Glucose-6-phosphate Dehydrogenase Deficiency, G6PD Santiago de Cuba (1339 GA), in a Chinese Population as Found in a Survey for G6PD Deficiency in Northeastern and Central China

In Liaoning Province in northeastern China, we found a G6PD-deficient patient at the age of 3. By the classification of the World Health Organization, this patient was categorized as class I (very severe G6PD deficiency). When we investigated the G6PD gene of the patient, we found that he had a replacement of G to A at nucleotide 1339. As a result, the amino acid at position 447 should change from Gly to Arg. This replacement is known as G6PD Santiago de Cuba, because it was first discovered in a Cuban boy who showed heavy chronic anemia. Today, 28 G6PD variants have been reported in the Chinese population, and all are categorized as class II (severe deficiency) or class III (mild deficiency);in class II or III deficiency, anemia is not present in daily life, but hemolytic attack can occur when the carrier ingests certain oxidative medicines or foods. This is the first report of a G6PD-deficient Chinese patient in the category of class I. We intended to find other G6PD-deficient cases in northeastern China and tested several hundred blood samples, but no cases of G6PD deficiency were found (0/414). In central China, where falciparum malaria was endemic from the 1950s to 1970s, we found two G6PD-deficient cases (2/27) and the other members from their families whose variant type was G6PD Kaiping (1388GT), which is a common variant in the Chinese population.</p

The anti-resection activity of the X protein encoded by Hepatitis Virus B

Chronic infection of hepatitis virus B (HBV) is associated with an increased incidence of hepatocellular carcinoma (HCC). HBV encodes an oncoprotein (HBx) that is crucial for viral replication and interferes with multiple cellular activities including gene expression, histone modifications and genomic stability. To date, it remains unclear how disruption of these activities contributes to hepatocarcinogenesis. Here, we report that HBV exhibits a novel anti‐resection activity by disrupting DNA end resection, thus impairing the initial steps of homologous recombination (HR). This anti‐resection activity occurs in primary human hepatocytes (PHHs) undergoing a natural viral infection‐replication cycle, as well as in cells with integrated HBV genomes. Among the seven HBV‐encoded proteins, we identified HBx as the sole viral factor that inhibits resection. By disrupting an evolutionarily conserved Cullin4A‐DDB1‐RING type of E3 ligase, CRL4WDR70, via its H‐box, we show that HBx inhibits H2B monoubiquitylation at lysine 120 (uH2B) at double strand breaks, thus reducing the efficiency of long‐range resection. We further show that directly impairing H2B monoubiquitylation elicited tumorigenesis upon engraftment of deficient cells in athymic mice, confirming that the impairment of CRL4WDR70 function by HBx is sufficient to promote carcinogenesis. Finally, we demonstrated that lack of H2B monoubiquitylation is manifest in human HBV‐associated HCC (HBVHCC) when compared with HBV‐free HCC, implying corresponding defects of epigenetic regulation and end resection. We conclude that the anti‐resection activity of HBx induces an HR defect and genome instability and contributes to tumorigenesis of host hepatocytes

A Biomimetic Membrane Device That Modulates the Excessive Inflammatory Response to Sepsis

OBJECTIVE: Septic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host's response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis. DESIGN: Laboratory investigation. SETTING: University of Michigan Medical School. SUBJECTS: Pigs weighing 30-35 kg. INTERVENTIONS: To assess the effect of the SCD in septic shock, pigs were administered 30×10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD. MEASUREMENTS AND MAIN RESULTS: In this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation. CONCLUSIONS: These preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway

CRL4Wdr70 regulates H2B monoubiquitination and facilitates Exo1-dependent resection

Double strand breaks repaired by homologous recombination (HR) are first resected to form single stranded DNA which binds replication protein A (RPA). RPA attracts mediators which load the Rad51 filament to promote strand invasion, the defining feature of HR. How the resection machinery navigates nucleosome-packaged DNA is poorly understood. Using Schizosaccharomyces pombe we report that a conserved DDB1-CUL4-associated factor (DCAF), Wdr70, is recruited to DSBs as part of the Cullin4-DDB1 ubiquitin ligase (CRL4Wdr70) and stimulates distal H2B lysine 119 monoubiquitination(uH2B). Wdr70 deletion, or uH2B loss, results in increased loading of the checkpoint adaptor and resection inhibitor Crb253BP1, decreased Exo1 association and delayed resection. Wdr70 is dispensable for resection upon Crb253BP1 loss, or when the Set9 methyltransferase that creates docking sites for Crb2 is deleted. Finally we establish that this histone regulatory cascade similarly controls DSB resection in human cells

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial

Background: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. Methods: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. Results: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95% CI − 4.3% to 1.2%]; P = 0.42) between groups. Conclusions: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. Trial registration: ISRCTN, ISRCTN12233792. Registered November 20th, 2017

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial.

BackgroundPrevious cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes.MethodsWe conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment.ResultsForty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups.ConclusionsIn this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness.Trial registrationISRCTN, ISRCTN12233792 . Registered November 20th, 2017

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial (vol 26, 46, 2022)

BackgroundPrevious cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes.MethodsWe conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment.ResultsForty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups.ConclusionsIn this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness.Trial registrationISRCTN, ISRCTN12233792 . Registered November 20th, 2017

rutheniumiicomplexcatalystsbearinga26bistetrazolylpyridineligandforthetransferhydrogenationofketones

含氮配体具有稳定性好、易于合成等优点,而且其过渡金属配合物表现出较高的催化活性,因而在配位化学和均相催化等研究领域受到了广泛关注.基于吡啶骨架的三齿NNN配体具有良好的配位能力和丰富的配位模式，如吡啶桥联的对称配体2,2':6',2''-三吡啶、2,6-双噁唑啉基吡啶、2,6-双亚胺基吡啶和2,6-双吡唑基吡啶等在有机合成及配合物催化剂制备等方面得到广泛应用.2,6-双四唑基吡啶也是基于吡啶的多齿配体,已被用于合成发光材料或高效回收次锕系元素等,但是其在催化领域的应用较少.过渡金属催化的不饱和化合物的转移氢化反应具有反应条件温和、不直接使用氢气等优点,因而受到越来越多的关注.一系列优异的配体及配合物在转移氢化反应中脱颖而出,如对甲苯磺酰手性二胺配体、2-甲胺基吡啶钌配合物、配体中含有NH官能团的过渡金属配合物等.我们也报道了几种吡啶基桥联的含氮配体及其钌配合物,并应用于催化酮的转移氢化反应.在此基础上,本文合成了三种连有不同膦配体的2,6-双四唑基吡啶钌配合物,并用于催化酮的转移氢化反应.从N2,N6-二对甲苯基-2,6-吡啶二甲酰胺(1)出发,经氯代/环化两步反应合成4-氯吡啶基桥联双四唑化合物(2),配体2与RuCl2(PPh3)3在对应的反应条件下制得三种连有不同膦配体的2,6-双四唑基吡啶钌配合物(3),其分子结构通过核磁共振波谱和X射线单晶晶体结构测定得到确认.将这三种钌配合物应用于催化酮的转移氢化反应,当催化剂用量为0.5mol%时,在异丙醇回流条件下,比较连有不同膦配体的2,6-双四唑基吡啶钌配合物的催化活性.膦配体为1,4-双(二苯基膦)丁烷的钌配合物3b表现出更高的催化活性,含有双三苯基膦的钌配合物3a则表现出与3b相当或略低的催化活性,含有1,5-双(二苯基膦)戊烷的钌配合物3c活性最差.以3b为催化剂拓展了一系列酮底物,取代的芳香酮、链状和环状的脂肪酮都可以高效地被还原,大部分酮底物以>95%的转化率还原成相应的醇.含有氯取代基的苯乙酮对反应有较大的加速作用,反应时间更短,转化率更高.由于羰基环的张力,1-四氢萘酮与9-芴酮转化率略低.结合实验结果与相关文献,提出了一条基于Ru-H活性中间体的内层反应机理:钌配合物在iPrOK作用下生成Ru(II)-烷氧基中间体I,随后发生β-H消除反应脱去一分子丙酮得到Ru-H配合物,Ru-H配合物与酮底物作用经过渡态II生成另一分子Ru(II)-烷氧基中间体III,随后异丙醇与烷氧基发生交换生成目标产物,同时生成中间体I完成催化循环