Room-temperature half-metals induced via chemical surface modification: 2D Mn2Se2 monolayer.

Compared with various antiferromagnetic (AFM) materials, two-dimensional (2D) room-temperature ferromagnetic (FM) materials are rarely discovered because of the geometrically determined spin interactions. Since 2D FM materials have shown great potential in the next-generational information devices, it is quite important to design new FM materials based on the reported AFM materials. Here, in this study, we found that the Mn2Se2 monolayer can be converted to half-metal from AFM semiconductor at room temperature by edge modification of certain chemical groups (such as -Cl, -Br, -I, and -S) based on systematical first-principles calculations. Our results show that the adsorbed chemical groups significantly modify the electronic states of Mn ions and the resulting spin interactions. Moreover, our results indicate that the Curie temperatures (Tc) of some Mn2Se2 monolayer derivatives approach or even exceed room temperature, among which Curie temperatures after chemical modification by -Cl, -Br, -I, -S are 290 K, 320 K, 400 K, and 1050 K, respectively. Thus, chemical modifications can be one of the effective methods to construct 2D FM materials in experiments.

A case of IgG4-related interstitial nephritis with ureteral obstruction: case report and literature review.

BACKGROUND: IgG4-related disease (IgG4-RD) is a newly discovered systemic disease that can affect any organ or tissue in the body. IgG4-related kidney disease (IgG4-RKD) is relatively rare but essential to IgG4-RD. However, there are few reports of IgG4-RD mimicking malignant ureteral tumors leading to hydronephrosis. We report here a rare case of IgG4-RD involving the ureter. CASE PRESENTATION: An 87-year-old man presented to our nephrology department with anorexia, nausea, and acute kidney injury in November 2020. Urinary computed tomography (CT) examination revealed a right lower ureter mass with right renal and ureter hydronephrosis. The serum level of IgG4 was 1890 mg/dL, and the concurrently renal biopsy revealed extensive infiltration of IgG4-positive plasma cells in renal interstitium, which was diagnosed as IgG4-associated tubule-interstitial nephritis(IgG4-TIN). The renal function improved significantly after double-J tube implantation of the right ureter and moderate-dose hormone therapy. The serum IgG4 decreased to the normal range, and the right lower ureter mass almost disappeared after one year of low-dose hormone maintenance therapy. CONCLUSION: IgG4-RD can present as a mass in the renal pelvis and (or) ureter, leading to hydronephrosis. Therefore, early recognition of this disease is significant. Most patients respond well to hormonal therapy to avoid surgical treatment due to misdiagnosis as malignant tumors, causing secondary harm to patients.

Identification of a novel ene reductase from Pichia angusta with potential application in (R)-levodione production.

Asymmetric reduction of electronically activated alkenes by ene reductases (ERs) is an attractive approach for the production of enantiopure chiral products. Herein, a novel FMN-binding ene reductase (PaER) from Pichia angusta was heterologously expressed in Escherichia coli BL21(DE3), and the recombinant enzyme was characterized for its biocatalytic properties. PaER displayed optimal activity at 40 °C and pH 7.5, respectively. The purified enzyme was quite stable below 30 °C over a broad pH range of 5.0-10.0. PaER was identified to have a good ability to reduce the C[double bond, length as m-dash]C bond of various α,ß-unsaturated compounds in the presence of NADPH. In addition, PaER exhibited a high reduction rate (k cat = 3.57 s-1) and an excellent stereoselectivity (>99%) for ketoisophorone. Engineered E. coli cells harboring PaER and glucose dehydrogenase (for cofactor regeneration) were employed as biocatalysts for the asymmetric reduction of ketoisophorone. As a result, up to 1000 mM ketoisophorone was completely and enantioselectively converted to (R)-levodione with a >99% ee value in a space-time yield of 460.7 g L-1 d-1. This study provides a great potential biocatalyst for practical synthesis of (R)-levodione.

IL-17A in diabetic kidney disease: protection or damage.

The effect of IL-17A in diabetic kidney disease (DKD) has received increasing attention. Interleukin (IL)-17A promotes renal inflammation and the progression of DKD, and IL-17A deficiency improves experimental DKD. However, recent studies have found that the effect of IL-17A on DKD is more complicated than the negative impact. IL-17A alleviates renal inflammation and fibrosis via regulating autophagy or the macrophage phenotype. Moreover, paradoxical expression of IL-17A has been reported in human DKD. This review focuses on how IL-17A affects the progression of DKD and the resulting opportunities and challenges.

Design and engineering of whole-cell biocatalyst for efficient synthesis of (R)-citronellal.

Bioproduction of optical pure (R)-citronellal from (E/Z)-citral at high substrate loading remains challenging. Low catalytic efficiency of (R)-stereoselective ene reductases towards crude citral mixture is one of the major bottlenecks. Herein, a structure-based engineering strategy was adopted to enhance the catalytic efficiency and stereoselectivity of an ene reductase (OYE2p) from Saccharomyces cerevisiae YJM1341 towards (E/Z)-citral. On basis of homologous modelling, molecular docking analysis and alanine scanning at the binding pocket of OYE2p, a mutant Y84A was obtained with simultaneous increase in catalytic efficiency and stereoselectivity. Furthermore, site-saturation mutagenesis of Y84 yielded seven mutants with improved activity and stereoselectivity in the (E/Z)-citral reduction. Among them, the variant Y84V exhibited an 18.3% and 71.3% rise in catalytic efficiency (kcat /Km ) for (Z)-citral and (E)-citral respectively. Meanwhile, the stereoselectivity of Y84V was improved from 89.2% to 98.0% in the reduction in (E/Z)-citral. The docking analysis and molecular dynamics simulation of OYE2p and its variants revealed that the substitution Y84V enabled (E)-citral and (Z)-citral to bind with a smaller distance to the key hydrogen donors at a modified (R)-selective binding mode. The variant Y84V was then co-expressed with glucose dehydrogenase from Bacillus megaterium in E. coli D4, in which competing prim-alcohol dehydrogenase genes were deleted to prevent the undesired reduction in the aldehyde moiety of citral and citronellal. Employing this biocatalyst, 106 g l-1 (E/Z)-citral was completely converted into (R)-citronellal with 95.4% ee value and a high space-time yield of 121.6 g l-1  day-1 . The work highlights the synthetic potential of Y84V, which enabled the highest productivity of (R)-citronellal from (E/Z)-citral in high enantiopurity so far.

Clinical features of velamentous umbilical cord insertion and vasa previa: A retrospective analysis based on 501 cases.

ABSTRACT: To identify the risk factors associated with velamentous cord insertion (VCI) and investigate the association between adverse pregnancy outcomes and VCI in singleton pregnancies and those with vasa previa.A total of 59,976 single cases admitted from Qinhuangdao Maternal and Child Health Hospital and Qinhuangdao Beidaihe Hospital from January 2004 to January 2014 were included in this study. We retrospectively analyzed the perinatal complications, neonatal complications, and the clinical features, as well as the Color Doppler ultrasonography findings of the velamentous placenta and placenta previa.We reviewed the clinical data of 59,976 women with singleton pregnancies delivered in Qinhuangdao Maternal and Child Health Hospital and Qinhuangdao Beidaihe Hospital from January 2004 to January 2014. Risk factors and the risks of adverse pregnancy outcomes including admission to a neonatal unit, fetal death, preterm delivery, low birth weight of <2500 g, the infant being small for its gestation age, low Apgar scores (<7) at 1 and 5 minute were evaluated separately among women with and without VCI by means of logistic regression analyses.The prevalence of velamentous umbilical cord insertion was 0.84%, and the prevalence of vasa previa was 0.0017%. The independent risk factors for VCI were nulliparity, obesity, fertility problems, placenta previa, and maternal smoking. VCI was associated with a 1.83-, 2.58-, 3.62-, and 1.41-fold increase in the risk of retention in the neonatal unit, preterm delivery (<37 gestation weeks), low birth weight, and small-for-gestational age, compared to pregnancies involving normal cord insertion. Of the women with VCI, 16.1% underwent emergency cesarean section compared to 8.9% (P < .001) of women without VCI.The prevalence of VCI was 0.84% in singletons. The results suggest that VCI is a moderate risk condition resulted in increased risks of prematurity and impairment of fetal growth.

Cross-Sectional Imaging Evaluation of Vascular Lesions in the Gastrointestinal Tract and Mesentery.

Gastrointestinal (GI) tract and mesenteric vascular lesions can have various clinical presentations, of which GI bleeding is the most common. This collection of pathology is highly variable in etiology ranging from occlusive disease to vascular malformations to trauma to neoplasms which makes for a challenging workup and diagnosis. The advent of multiple imaging modalities and endoscopic techniques makes the diagnosis of these lesions more achievable, and familiarity with their various imaging findings can have a significant impact on patient management. In this article, we review the gamut of GI tract and mesenteric vascular lesions and their associated imaging findings.

Wenxin Granule Ameliorates Hypoxia/Reoxygenation-Induced Oxidative Stress in Mitochondria via the PKC-δ/NOX2/ROS Pathway in H9c2 Cells.

Myocardial infarction and following reperfusion therapy-induced myocardial ischemia/reperfusion (I/R) injury have been recognized as an important subject of cardiovascular disease with high mortality. As the antiarrhythmic agent, Wenxin Granule (WXG) is widely used to arrhythmia and heart failure. In our pilot study, we found the antioxidative potential of WXG in the treatment of myocardial I/R. This study is aimed at investigating whether WXG could treat cardiomyocyte hypoxia/reoxygenation (H/R) injury by inhibiting oxidative stress in mitochondria. The H9c2 cardiomyocyte cell line was subject to H/R stimuli to mimic I/R injury in vitro. WXG was added to the culture medium 24 h before H/R exposing as pretreatment. Protein kinase C-δ (PKC-δ) inhibitor rottlerin or PKC-δ lentivirus vectors were conducted on H9c2 cells to downregulate or overexpress PKC-δ protein. Then, the cell viability, oxidative stress levels, intracellular and mitochondrial ROS levels, mitochondrial function, and apoptosis index were analyzed. In addition, PKC-δ protein expression in each group was verified by western blot analysis. Compared with the control group, the PKC-δ protein level was significantly increased in the H/R group, which was remarkably improved by WXG or rottlerin. PKC-δ lentivirus vector-mediated PKC-δ overexpression was not reduced by WXG. WXG significantly improved H/R-induced cell injury, lower levels of SOD and GSH/GSSG ratio, higher levels of MDA, intracellular and mitochondrial ROS content, mitochondrial membrane potential and ATP loss, mitochondrial permeability transition pore opening, NOX2 activation, cytochrome C release, Bax/Bcl-2 ratio and cleaved caspase-3 increasing, and cell apoptosis. Similar findings were obtained from rottlerin treatment. However, the protective effects of WXG were abolished by PKC-δ overexpression, indicating that PKC-δ was a potential target of WXG treatment. Our findings demonstrated a novel mechanism by which WXG attenuated oxidative stress and mitochondrial dysfunction of H9c2 cells induced by H/R stimulation via inhibitory regulation of PKC-δ/NOX2/ROS signaling.

IgG4-related disease in the abdomen and pelvis: atypical findings, pitfalls, and mimics.

IgG4-related disease (IgG4-RD) is a systemic, autoimmune, fibroinflammatory disease that can cause multi-organ damage. Although there have been many trials and studies since its recognition in 2003, there is still much that is unknown. Furthermore, IgG4-RD can affect any organ in the body and often has many mimics and alternative diagnoses, which can make for a challenging workup. Imaging plays a substantial role in the diagnosis of IgG4-RD and is often the first occasion where IgG4-RD comes into consideration. Thus, knowledge about the imaging findings of various manifestations of IgG4-RD can aid in the diagnosis and have a significant impact on patient management. In this article, we review the wide array of imaging findings, both typical and atypical, as well as possible mimics of IgG4-RD in the abdomen and pelvis.

[Effects of nitrogen level on growth of Tetrastigma hemsleyanum and phytochemical content and antioxidant activity in stems and leaves].

As a rare endangered medical plant that newly cultivated,little experimental information is available for growth and metabolites of Tetrastigma hemsleyanum in response to nitrogen( N). The effects of different levels of N on growth of T. hemsleyanum and the content of phytochemicals( polysaccharide,total flavonoids and phenolics) and antioxidant activity( ABTS and FRAP) in stems and leaves were investigated in this study. A certain amount of N had positive effects on most of biological traits,and excessive dose of N went against growth of T. hemsleyanum. With N levels decreased,the polysaccharide content in stems and leaves had no significant change,while the total flavonoid and phenolic content,and antioxidant activities increased steadily. Antioxidant activities and total flavonoid and phenolic content had significant positive correlation. Excessive N fertilizer should be avoided by cultivation.

NLRP3 (Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3)-Caspase-1 Inflammasome Degrades Contractile Proteins: Implications for Aortic Biomechanical Dysfunction and Aneurysm and Dissection Formation.

OBJECTIVE: Increasing evidence suggests that contractile dysfunction in smooth muscle cells (SMCs) plays a critical role in aortic biomechanical dysfunction and aortic aneurysm and dissection (AAD) development. However, the mechanisms underlying SMC contractile dysfunction in sporadic AAD are poorly understood. In this study, we examined the role of the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome, a key inflammatory cascade, in SMC contractile dysfunction in AAD. APPROACH AND RESULTS: We observed significant SMC contractile protein degradation in aortas from patients with sporadic thoracic AAD. The contractile protein degradation was associated with activation of the NLRP3-caspase-1 inflammasome cascade. In SMCs, caspase-1 bound and directly cleaved and degraded contractile proteins, leading to contractile dysfunction. Furthermore, Nlrp3 or caspase-1 deficiency in mice significantly reduced angiotensin II-induced contractile protein degradation, biomechanical dysfunction, and AAD formation in both thoracic and abdominal aortas. Finally, blocking this cascade with the inflammasome inhibitor, glyburide (an antidiabetic medication), reduced angiotensin II-induced AAD formation. CONCLUSIONS: Inflammasome-caspase-1-mediated degradation of SMC contractile proteins may contribute to aortic biomechanical dysfunction and AAD development. This cascade may be a therapeutic target in AAD formation. In addition, glyburide may have protective effects against AAD development.

The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function.

Haploinsufficiency of Progranulin (PGRN), a gene encoding a secreted glycoprotein, is a major cause of frontotemporal lobar degeneration with ubiquitin (FTLD-U) positive inclusions. Single nucleotide polymorphisms in the TMEM106B gene were recently discovered as a risk factor for FTLD-U, especially in patients with PGRN mutations. TMEM106B is also associated with cognitive impairment in amyotrophic lateral sclerosis patients. Despite these studies, little is known about TMEM106B at molecular and cellular levels and how TMEM106B contributes to FTLD. Here, we show that TMEM106B is localized in the late endosome/lysosome compartments and TMEM106B levels are regulated by lysosomal activities. Ectopic expression of TMEM106B induces morphologic changes of lysosome compartments and delays the degradation of endocytic cargoes by the endolysosomal pathway. Furthermore, overexpression of TMEM106B correlates with elevated levels of PGRN, possibly by attenuating lysosomal degradation of PGRN. These results shed light on the cellular functions of TMEM106B and the roles of TMEM106B in the pathogenesis of FTLD-U with PGRN mutations.

Co-inhibition of HSP70/HSP90 synergistically sensitizes nasopharyngeal carcinoma cells to thermotherapy.

The upregulation of both HSP70 and HSP90 frequently compromises the effects of thermotherapy. The co-inhibition of HSP70/HSP90 may be preferable to enhance the effects of thermotherapy on nasopharyngeal carcinoma cells. The changes of HSP70 and HSP90 were detected after thermotherapy in human nasopharyngeal cancer cell HNE1. 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) and quercetin were used to inhibit the activity of HSP90 and HSP70. The enhanced effects were evaluated in vitro and in vivo. Both HSP70 and HSP90 were upregulated promptly in HNE1 after thermotherapy. Single inhibition of HSP70 resulted in overexpression and delayed descent of HSP90. The co-inhibition of HSP70/HSP90 with quercetin plus 17-DMAG significantly increased apoptosis in hyperthermia-treated HNE1 cells both in vitro and in vivo. The co-inhibition of HSP70/HSP90 synergistically sensitizes nasopharyngeal carcinoma cells to hyperthermia.

C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking.

Progranulin haplo-insufficiency is a main cause of frontotemporal lobar degeneration (FTLD) with TDP-43 aggregates. Previous studies have shown that sortilin regulates progranulin trafficking and is a main determinant of progranulin level in the brain. In this study, we mapped the binding site between progranulin and sortilin. Progranulin binds to the beta-propeller region of sortilin through its C-terminal tail. The C-terminal progranulin fragment is fully sufficient for sortilin binding and progranulin C-terminal peptide displaces progranulin binding to sortilin. Deletion of the last 3 residues of progranulin (QLL) abolishes its binding to sortilin and also sortilin dependent regulation of progranulin trafficking. Since progranulin haplo-insufficiency results in FTLD, these results may provide important insights into future studies of progranulin trafficking and signaling and progranulin based therapy for FTLD.

Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1.

TAR DNA-binding protein-43 (TDP-43) proteinopathy has been linked to several neurodegenerative diseases, such as frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Phosphorylated and ubiquitinated TDP-43 C-terminal fragments have been found in cytoplasmic inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis patients. However, the factors and pathways that regulate TDP-43 aggregation are still not clear. We found that the C-terminal 15 kDa fragment of TDP-43 is sufficient to induce aggregation but the aggregation phenotype is modified by additional sequences. Aggregation is accompanied by phosphorylation at serine residues 409/410. Mutation of 409/410 to phosphomimetic aspartic acid residues significantly reduces aggregation. Inhibition of either proteasome or autophagy dramatically increases TDP-43 aggregation. Furthermore, TDP-43 aggregates colocalize with markers of autophagy and the adaptor protein p62/SQSTM1. Over-expression of p62/SQSTM1 reduces TDP-43 aggregation in an autophagy and proteasome-dependent manner. These studies suggest that aggregation of TDP-43 C-terminal fragments is regulated by phosphorylation events and both the autophagy and proteasome-mediated degradation pathways.

Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin.

VIDEO ABSTRACT: The most common inherited form of Frontotemporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation and exhibits TDP-43 plus ubiquitin aggregates. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons via its C terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1⁻/⁻ neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/⁻ mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology.

[In vitro study of expression and effects of HSP70/HSP90 in nasopharyngeal carcinoma cells after thermotherapy].

OBJECTIVE: To investigate the changes and effects of HSP70/HSP90 of in nasopharyngeal carcinoma cells HNE1 after thermotherapy. METHODS: HNE1 cells were incubated at 42 degrees C for 2 h. The changes of mRNA and protein level of HSP70/HSP90 were detected by real-time PCR and western-blot at different intervals. HNE1 cells were pretreated with quercetin, geldanamycin or quercetin plus geldanamycin, respectively, before heat treatment. Flow cytometry assay was applied to determine the apoptosis of HNE1 cells before thermotherapy and at 2 h, 4 h, 6 h, 8 h, 12 h and 24 h after thermotherapy. RESULTS: HSP70/HSP90 expression was up regulated at 2 h, reached to its peak at 4 h, descended at 8 h and returned to the normal level at 24 h after thermotherapy. The inhibition of HSP70 through quercetin induced up-regulation and delayed descent of HSP90. Combined pretreatment with quercetin and geldanamycin could significantly induce HNE1 apoptosis when compared with pretreatment with quercetin or geldanamycin alone (P<0.05). CONCLUSION: HSP70/HSP90 expression in HNE1 up regulated promptly after thermotherapy. Inhibition of expression and activity of HSP70/HSP90 before thermotherapy can increase sensitivity of the tumor cell to heat treatment.