Microsporidian Nosema bombycis hijacks host vitellogenin and restructures ovariole cells for transovarial transmission.

Microsporidia are a group of obligate intracellular parasites that infect almost all animals, causing serious human diseases and major economic losses to the farming industry. Nosema bombycis is a typical microsporidium that infects multiple lepidopteran insects via fecal-oral and transovarial transmission (TOT); however, the underlying TOT processes and mechanisms remain unknown. Here, we characterized the TOT process and identified key factors enabling N. bombycis to invade the ovariole and oocyte of silkworm Bombyx mori. We found that the parasites commenced with TOT at the early pupal stage when ovarioles penetrated the ovary wall and were exposed to the hemolymph. Subsequently, the parasites in hemolymph and hemolymph cells firstly infiltrated the ovariole sheath, from where they invaded the oocyte via two routes: (I) infecting follicular cells, thereby penetrating oocytes after proliferation, and (II) infecting nurse cells, thus entering oocytes following replication. In follicle and nurse cells, the parasites restructured and built large vacuoles to deliver themselves into the oocyte. In the whole process, the parasites were coated with B. mori vitellogenin (BmVg) on their surfaces. To investigate the BmVg effects on TOT, we suppressed its expression and found a dramatic decrease of pathogen load in both ovarioles and eggs, suggesting that BmVg plays a crucial role in the TOT. Thereby, we identified the BmVg domains and parasite spore wall proteins (SWPs) mediating the interaction, and demonstrated that the von Willebrand domain (VWD) interacted with SWP12, SWP26 and SWP30, and the unknown function domain (DUF1943) bound with the SWP30. When disrupting these interactions, we found significant reductions of the pathogen load in both ovarioles and eggs, suggesting that the interplays between BmVg and SWPs were vital for the TOT. In conclusion, our study has elucidated key aspects about the microsporidian TOT and revealed the key factors for understanding the molecular mechanisms underlying this transmission.

Rational Design of Activatable Lanthanide NIR-IIb Emissive Nanoprobe for In Situ Specific Imaging of HOCl In Vivo.

Hypochlorous acid (HOCl), as an indispensable signaling molecule in organisms, is one of the key members of reactive oxygen species (ROS). However, in vivo, real-time dynamic near-infrared fluorescence imaging of HOCl levels in the 1400-1700 nm sub-window (NIR-IIb) remains a major challenge due to the lack of suitable detection methods. Herein, a general design of HOCl-responsive NIR-IIb fluorescence nanoprobe is proposed by integrating NaLuF4Yb/Er@NaLuF4 downshift nanoparticles (DSNPs) and HOCl recognition/NIR-IIb emissive modulation unit of M2-xS (M = Cu, Co, Pb) nanodots for real-time monitoring of HOCl levels. The fluorescence modulation unit of M2-xS nanodots presents remarkably enhanced absorption than Yb sensitizer at 980 nm and greatly inhibits the NIR-IIb fluorescence emission via competitive absorption mechanism. While, the M2-xS nanodots are easily degraded after triggering by HOCl, resulting in HOCl responsive turn-on (≈ten folds) NIR-IIb emission at 1532 nm. More importantly, in vivo highly precise and specific monitoring of inflammatory with abnormal HOCl expression is successfully achieved. Thus, the explored competitive absorption mediated quenching-activation mechanism provides a new general strategy of designing HOCl-responsive NIR-IIb fluorescence nanoprobe for highly specific and sensitive HOCl detection.

The SUMO E3 ligase activity of ORF45 determines KSHV lytic replication.

RSK1, an essential cellular kinase for Kaposi's sarcoma-associated herpesvirus (KSHV) replication, is highly phosphorylated and SUMOylated during KSHV lytic cycle, which determine the substrate phosphorylation and specificity of RSK1, respectively. However, the SUMO E3 ligase responsible for attaching SUMO to RSK1 has not yet been identified. By genome-wide screening, we found that KSHV ORF45 is necessary and sufficient to enhance RSK1 SUMOylation. Mechanistically, KSHV ORF45 binds to SUMOs via two classic SUMO-interacting motifs (SIMs) and functions as a SIM-dependent SUMO E3 ligase for RSK1. Mutations on these ORF45 SIMs resulted in much lower lytic gene expressions, viral DNA replication, and mature progeny virus production. Interestingly, KSHV ORF45 controls RSK1 SUMOylation and phosphorylation via two separated functional regions: SIMs and amino acid 17-90, respectively, which do not affect each other. Similar to KSHV ORF45, ORF45 of Rhesus Macaque Rhadinovirus has only one SIM and also increases RSK1 SUMOylation in a SIM-dependent manner, while other ORF45 homologues do not have this function. Our work characterized ORF45 as a novel virus encoded SUMO E3 ligase, which is required for ORF45-RSK1 axis-mediated KSHV lytic gene expression.

Label-free Colorimetric Detection of Viral RNA Based on Clustered Regularly Interspaced Short Palindromic Repeats and Gold Nanoparticles with a Portable Device.

Viral infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are some of the most dangerous threats to humans. SARS-CoV-2 has caused a global pandemic, highlighting the unprecedented demand for rapid and portable diagnostic methods. To meet these requirements, we designed a label-free colorimetric platform that combines the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) 12a system for naked-eye detection (named LFP). This method utilizes reverse transcription loop-mediated isothermal amplification (RT-LAMP) and the trans-cleavage activity of the CRISPR/Cas12a system to increase the sensitivity and specificity of the reaction. This platform can detect as few as 4 copies/µL of RNA and produces no false positive results when tested against the influenza virus. To better meet the requirements of point-of-care (POC) detection, we developed a portable device that can be applied in resource-poor and densely populated regions. The LFP assay holds great potential for application in resource-limited settings, and the label-free gold nanoparticle (AuNPs) probe can reduce costs, making it suitable for large-scale screening. We expect that the LFP assay will be promising for the POC screening of COVID-19.

An Activated Structure Transformable Ratiometric Photoacoustic Nanoprobe for Real-Time Dynamic Monitoring of H2S In Vivo.

H2S has emerged as a promising biomarker for many diseases such as colon cancer and metformin-induced hepatotoxicity. Real-time monitoring of H2S levels in vivo is significant for early accurate diagnosis of these diseases. Herein, a new accurate and reliable nanoprobe (Au NRs@Ag) was designed for real-time dynamic ratiometric photoacoustic (PA) imaging of H2S in vivo based on the endogenous H2S-triggered local surface plasmon resonance (LSPR) red-shift. The Au NRs@Ag nanoprobe can be readily converted into Au NRs@Ag2S via the endogenous H2S-activated in situ sulfurative reaction, subsequently leading to a significant red-shift of the LSPR wavelength from 808 to 980 nm and enabling accurate ratiometric PA (PA980/PA808) imaging of H2S. Moreover, dynamic ratiometric PA imaging of metformin-induced hepatotoxicity was also successfully achieved by the designed PA imaging strategy. These findings provide the possibility of designing a new ratiometric PA imaging strategy for dynamic in situ monitoring of H2S-related diseases.

ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.

Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis.

Shaping Sulfur Precursors to Low Dimensional (0D, 1D and 2D) Sulfur Nanomaterials: Synthesis, Characterization, Mechanism, Functionalization, and Applications.

Low-dimensional sulfur nanomaterials featuring with 0D sulfur nanoparticles (SNPs), sulfur nanodots (SNDs) and sulfur quantum dots (SQDs), 1D sulfur nanorods (SNRs), and 2D sulfur nanosheets (SNSs) have emerged as an environmentally friendly, biocompatible class of metal-free nanomaterials, sparking extensive interest in a wide range application. In this review, various synthetic methods, precise characterization, creative formation mechanism, delicate functionalization, and versatile applications of low dimensional sulfur nanomaterials over the last decades are systematically summarized. Initially, it is striven to summarize the progress of low dimensional sulfur nanomaterials from versatile precursors by using different synthetic approaches and various characterization. Then, a multi-faceted proposed formation mechanism with emphasis on how these different precursors produce corresponding SNPs, SNDs, SQDs, SNRs, and SNSs is highlighted. Besides, it is essential to fine-tune the surface functional groups of low dimensional sulfur nanomaterials to form new complex nanomaterials. Finally, these sulfur nanomaterials are being investigated in bio-sensing, bio-imaging, lithium-sulfur batteries, antibacterial activities, plant growth along with future perspective and challenges in emerging fields. The purpose of this review is to tailor low dimensional nanomaterials through accurately selecting precursors or synthetic approach and provide a foundation for the formation of versatile sulfur nanostructure.

RSK1 SUMOylation is required for KSHV lytic replication.

RSK1, a downstream kinase of the MAPK pathway, has been shown to regulate multiple cellular processes and is essential for lytic replication of a variety of viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV). Besides phosphorylation, it is not known whether other post-translational modifications play an important role in regulating RSK1 function. We demonstrate that RSK1 undergoes robust SUMOylation during KSHV lytic replication at lysine residues K110, K335, and K421. SUMO modification does not alter RSK1 activation and kinase activity upon KSHV ORF45 co-expression, but affects RSK1 downstream substrate phosphorylation. Compared to wild-type RSK1, the overall phosphorylation level of RxRxxS*/T* motif is significantly declined in RSK1K110/335/421R expressing cells. Specifically, SUMOylation deficient RSK1 cannot efficiently phosphorylate eIF4B. Sequence analysis showed that eIF4B has one SUMO-interacting motif (SIM) between the amino acid position 166 and 170 (166IRVDV170), which mediates the association between eIF4B and RSK1 through SUMO-SIM interaction. These results indicate that SUMOylation regulates the phosphorylation of RSK1 downstream substrates, which is required for efficient KSHV lytic replication.

ldi-miR396-LdPMaT1 enhances reactive oxygen species scavenging capacity and promotes drought tolerance in Lilium distichum Nakai autotetraploids.

Drought is a key environmental stress that inhibits plant growth, development, yield and quality. Whole-genome replication is an effective method for breeding drought resistant cultivars. Here, we evaluated the tolerance of Lilium distichum Nakai diploids (2n = 2× = 24) and artificially induced autotetraploids (2n = 4× = 48) to drought simulated by polyethylene glycol (PEG) stress. Autotetraploids showed stronger drought tolerance than diploids, and high-throughput sequencing during PEG stress identified five differentially expressed miRNAs. Transcriptome analysis revealed significantly different reactive oxygen species (ROS)-scavenger expression levels between diploids and autotetraploids, which increased the drought tolerance of autotetraploids. Specifically, we identified ldi-miR396b and its only target gene (LdPMaT1) for further study based on its expression level and ROS-scavenging ability in response to drought stress (DS). Autotetraploids showed higher expression of LdPMaT1 and significantly downregulated expression of ldi-miR396b under DS compared with diploids. Through a short tandem target mimic (STTM) in transgenic lilies, functional studies revealed that miR396b silencing promotes LdPMaT1 expression and the DS response. Under PEG stress, STTM393 transgenic lines showed improved drought resistance mediated by lowered MDA content but exhibited high antioxidant enzyme activity, consistent with the autotetraploid results. Collectively, these findings suggest that ldi-miR396b-LdPMaT1 potentially enhances ROS-scavenging ability, which contributes to improved stress adaptation in autotetraploid lilies.

The novel biomarkers for assessing clinical benefits of continuous renal replacement therapy in pediatric sepsis: a pilot study.

BACKGROUND: Continuous renal replacement therapy (CRRT) has been considered as an adjuvant therapy for sepsis. However, the novel biomarker to evaluate the benefits of CRRT is limited. The aim of this study was to explore the novel biomarkers involved in the impact of CRRT in pediatric sepsis. METHODS: The serum proteomic profiles on the 7th day after CRRT (CRRT 7th day) compared with before CRRT (CRRT 1st day) was determined in 3 children with sepsis as a discovery set. The screened candidates were confirmed in the validation cohort including patients received CRRT (CRRT group) and without CRRT (non-CRRT group). We defined that pediatric sequential organ failure assessment score (pSOFA) in pediatric patients with sepsis decreased by 2 points or more on the CRRT 1st day compared with CRRT initiation as CRRT responders. The changes of serum biomarkers were compared between CRRT responders and CRRT non-responders. Moreover, correlation analysis was further conducted in pediatric sepsis. RESULTS: A total of 145 differentially expressed proteins were found according to the serum proteomics profiles. By visualizing the interaction between the differential proteins, 6 candidates (Lysozyme C [LYZ], Leucine-rich alpha-2-glycoprotein [LRG1], Fibromodulin [FMOD], Alpha-1-antichymotrypsin [SERPINA3], L-selectin [SELL], Monocyte differentiation antigen CD14 [CD14]) were screened. In the validation cohort, serum levels of LYZ and LRG1 showed a higher trend on the CRRT 7th day than that on the 1st day in the non-CRRT group. However, the changes in levels of LYZ and LRG1 on the 7th day was significant in the CRRT group (p = 0.016, p = 0.009, respectively). Moreover, the levels of LYZ and LRG1 on the CRRT 7th day in the CRRT group were significantly higher than that in the non-CRRT group (p < 0.001, p = 0.025). Decreased levels of CD14 were associated with sepsis recovery, but not associated with CRRT. There were no significantly difference in serum FMOD, SERPINA3, and SELL levels. Importantly, serum LYZ and LRG1 levels changed in CRRT responders, but not CRRT non-responders. Further analysis indicated that serum LYZ levels were correlated to total platelet counts, aspartate aminotransferase (ALT), alanine aminotransferase (AST), and albumin levels, and serum LRG1 level were correlated to total platelet count and TBIL levels on the 1st day in the CRRT group. Protein-protein interaction network analysis displayed that serum LYZ and LRG1 were involved in the process of inflammatory response, leucocytes adhesion to vascular endothelial cell, as well as complement activation. CONCLUSION: Elevated serum LYZ and LRG1 levels are associated with clinical benefits of CRRT during sepsis.

RAGE inhibition alleviates lipopolysaccharides-induced lung injury via directly suppressing autophagic apoptosis of type II alveolar epithelial cells.

BACKGROUND: Advanced glycation end product receptor (RAGE) acts as a receptor of pro-inflammatory ligands and is highly expressed in alveolar epithelial cells (AECs). Autophagy in AECs has received much attention recently. However, the roles of autophagy and RAGE in the pathogenesis of acute lung injury remain unclear. Therefore, this study aimed to explore whether RAGE activation signals take part in the dysfunction of alveolar epithelial barrier through autophagic death. METHODS: Acute lung injury animal models were established using C57BL/6 and Ager gene knockout (Ager -/- mice) mice in this study. A549 cells and primary type II alveolar epithelial (ATII) cells were treated with siRNA to reduce Ager gene expression. Autophagy was inhibited by 3-methyladenine (3-MA). Lung injury was assessed by histopathological examination. Cell viability was estimated by cell counting kit-8 (CCK-8) assay. The serum and bronchoalveolar lavage fluid (BALF) levels of interleukin (IL)-6, IL-8 and soluble RAGE (sRAGE) were evaluated by Enzyme-linked immunosorbent assay (ELISA). The involvement of RAGE signals, autophagy and apoptosis was assessed using western blots, immunohistochemistry, immunofluorescence, transmission electron microscopy and TUNEL test. RESULTS: The expression of RAGE was promoted by lipopolysaccharide (LPS), which was associated with activation of autophagy both in mice lung tissues and A549 cells as well as primary ATII cells. sRAGE in BALF was positively correlated with IL-6 and IL-8 levels. Compared with the wild-type mice, inflammation and apoptosis in lung tissues were alleviated in Ager-/- mice. Persistently activated autophagy contributed to cell apoptosis, whereas the inhibition of autophagy by 3-MA protected lungs from damage. In addition, Ager knockdown inhibited LPS-induced autophagy activation and attenuated lung injury. In vitro, knockdown of RAGE significantly suppressed the activation of LPS-induced autophagy and apoptosis of A549 and primary ATII cells. Furthermore, RAGE activated the downstream STAT3 signaling pathway. CONCLUSION: RAGE plays an essential role in the pathogenesis of ATII cells injury. Our results suggested that RAGE inhibition alleviated LPS-induced lung injury by directly suppressing autophagic apoptosis of alveolar epithelial cells.

Treg cell: Critical role of regulatory T-cells in depression.

Depression is a highly prevalent disorder of the central nervous system. The neuropsychiatric symptoms of clinical depression are persistent and include fatigue, anorexia, weight loss, altered sleep patterns, hyperalgesia, melancholia, anxiety, and impaired social behaviours. Mounting evidences suggest that neuroinflammation triggers dysregulated cellular immunity and increases susceptibility to psychiatric diseases. Neuroimmune responses have transformed the clinical approach to depression because of their roles in its pathophysiology and their therapeutic potential. In particular, activated regulatory T (Treg) cells play an increasingly evident role in the inflammatory immune response. In this review, we summarized the available data and discussed in depth the fundamental roles of Tregs in the pathogenesis of depression, as well as the clinical therapeutic potential of Tregs. We aimed to provide recent information regarding the potential of Tregs as immune-modulating biologics for the treatment and prevention of long-term neuropsychiatric symptoms of depression.

A Cas12a-based platform combined with gold nanoparticles for sensitive and visual detection of Alternaria solani.

Alternaria solani (A. solani), the causal agent of early blight in potatoes, poses a serious and persistent threat to potato production worldwide. Therefore, developing a method that can accurately detect A. solani in the early stage to avoid further spread is urgent. However, the conventional PCR-based method is not appropriate for application in the fields. Recently, the CRISPR-Cas system has been developed for nucleic acids analysis at point-of-care. Here, we propose a gold nanoparticles-based visual assay combining loop-mediated isothermal amplification with CRISPR-Cas12a to detect A. solani. After optimization, the method could detect 10-3 ng/µL genomic gene of A. solani. The specificity of the method was confirmed by discriminating A. solani from other three highly homologous pathogens. We also developed a portable device that could be used in the fields. By integrating with the smartphone readout, this platform holds significant potential in high-throughput detection of multiple pathogens in the fields.

Titanium alloys with varying surface micro-area potential differences have antibacterial abilities and a favorable cellular response.

OBJECTIVES: Surface micro-area potential difference (MAPD) can achieve bacteriostatic performance independent of metal ion dissolution. To study the influence of MAPD on antibacterial properties and the cellular response, Ti-Ag alloys with different surface potentials were designed and prepared by changing the preparation and heat treatment processes. MATERIALS AND METHODS: Ti-Ag alloys (T4, T6, and S) were prepared by vacuum arc smelting, water quenching, and sintering. Cp-Ti was set as a control group in this work. The microstructures and surface potential distributions of the Ti-Ag alloys were analyzed by SEM and energy dispersive spectrometry. Plate counting and live/dead staining methods were used to evaluate the antibacterial properties of the alloys, and the mitochondrial function, ATP levels, and apoptosis were assessed in MC3T3-E1 cells to analyze the cellular response. RESULTS: Due to the formation of the Ti-Ag intermetallic phase in the Ti-Ag alloys, Ti-Ag (T4) without the Ti-Ag phase had the lowest MAPD, Ti-Ag (T6) with a fine Ti2Ag phase had a moderate MAPD, and Ti-Ag (S) with a Ti-Ag intermetallic phase had the highest MAPD. The primary results demonstrated that the Ti-Ag samples with different MAPDs exhibited different bacteriostatic effects, ROS expression levels, and apoptosis-related protein expression levels in cells. The alloy with a high MAPD exhibited a strong antibacterial effect. A moderate MAPD stimulated cellular antioxidant regulation (GSH/GSSG) and downregulated the expression of intracellular ROS. MAPD could also promote the transformation of the inactive mitochondria to biologically active mitochondria by increasing the ΔΨm and reducing apoptosis. CONCLUSION: The results here indicated that moderate MAPD not only had bacteriostatic effects but also promoted mitochondrial function and inhibited cell apoptosis, which provides a new strategy to improve the surface bioactivity of titanium alloys and a new idea for titanium alloy design. CLINICAL RELEVANCE: There are some limitations of the mechanism of MAPD. However, researchers will become increasingly aware of the advantages and disadvantages of MAPD and MAPD might provide an affordable solution of peri-implantitis.

Sustainable recovery of titanium from secondary resources: A review.

The exploitation and utilization of secondary resources have the social benefits of saving resources, reducing pollution, and reducing production costs. Currently, less than 20% of titanium secondary resources can be recycled, and there are few reviews on titanium secondary resources recovery, which cannot fully reveal the technical information and progress of titanium secondary resources recovery. This work presents the current global distribution of titanium resources and market supply and demand, then focuses on an overview of technical studies on titanium extraction from different titanium-bearing secondary slags. The following types of titanium secondary resources are mainly available: sponge titanium production, the production of titanium ingot, titanium dioxide production, red mud, titanium-bearing blast furnace slag, spent SCR catalyst, and lithium titanate waste. The various methods of secondary resource recovery are compared, including the advantages and disadvantages, and the future development direction of the titanium recycling process is pointed out. On the one hand, recycling companies can classify and recover each type of residual waste according to its characteristics. On the other hand, solvent extraction technology can be the direction of attention due to the increased requirement for the purity of recovered materials. Meanwhile, the attention to lithium titanate waste recycling should also be enhanced.

Periodic subcellular structures undergo long-range synchronized reorganization during C. elegans epidermal development.

Periodic pattern formation on the cellular and tissue scale is an important process and has been extensively studied. However, periodic pattern formation at the subcellular level still remains poorly understood. The C. elegans epidermis displays a highly ordered parallel stripe pattern as part of its subcellular structure, making it an ideal model to study the formation and reorganization of periodic patterns within cells. Here, we show that the initial formation of periodic striped patterns in the C. elegans epidermis is dependent on actin and spectrin, and requires the apical membrane attachment structures for maintenance. The periodic subcellular structures do not accommodate cell growth by continuously making new stripes. Instead, they increase the number of stripes by going through one round of uniform duplication, which is independent of the increasing epidermal length or the developmental cycles. This long-range synchronized reorganization of subcellular structures is achieved by physical links established by extracellular collagens together with extension forces generated from epidermal cell growth. Our studies uncover a novel strategy employed by evenly spaced and interlinked subcellular structures to maintain their integrity and equidistribution during cell growth and tissue development.

Analysis of the Clinical Characteristics of Dipeptidyl Peptidase-4 Inhibitor-Induced Bullous Pemphigoid.

OBJECTIVE: To analyze and discuss the clinical characteristics of dipeptidyl peptidase-4 inhibitor (DPP4i)-induced bullous pemphigoid (BP). DATA SOURCES: We collected case reports of DPP4i-induced BP by searching databases from 2006 to mid-May 2021, as a retrospective analysis. STUDY SELECTION AND DATA EXTRACTION: Relevant case reports and case analyses of DPP4i-induced BP were included. DATA SYNTHESIS: The median time of symptom onset was 9 months (range 0.5-59 months). BP most often occurred in patients receiving vildagliptin (52.63%) followed by linagliptin (27.19%) and sitagliptin (17.54%). Tense bullae and blisters (85.51%) and erythema (82.61%) on the extremities and trunk were the most common presenting symptoms. In total, 64.06% of BP patients were anti-BP180 autoantibody positive, 58.97% were BP180NC16a autoantibody positive, and 31.25% were anti-BP230 autoantibody positive. Skin biopsy revealed subepidermal bulla eosinophil infiltration in 93.85% of BP patients, lymphocyte infiltration in 56.93%, and neutrophil infiltration in 44.62%. Direct immunofluorescence was positive in 98.94% of BP patients with linear deposition of IgG (97.80%) and/or complement C3 (98.94%) along the basement membrane zone. Indirect immunofluorescence was positive in 87.88% of BP patients. Complete remission of BP was achieved in 83.64% of patients on DPP4i withdrawal and after 4 months (range 0.13-72 months) of follow-up. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review analyzes and discusses the clinical characteristics of DPP4i-induced BP and provides a reference for the safe and reasonable clinical application of DPP4i. CONCLUSIONS: DPP4i drugs are related to the occurrence of BP in diabetic patients, especially elderly men taking vildagliptin.

Adipose-specific knockout of Protein Kinase D1 suppresses de novo lipogenesis in mice via SREBP1c-dependent signaling.

Having healthy adipose tissue is essential for metabolic health, as excessive adipose tissue in the body can cause its dysregulation and driving chronic metabolic diseases. Protein kinase D1 (PKD1) is considered to be a key kinase in signal transduction, which regulates multiple cellular functions, but its physiological functions in adipose are still not fully understood. This study aimed at elucidating the function of adipocyte PKD1 on lipogenesis. From RNA-Sequencing data, we found that the fatty acid biosynthesis pathway in white adipose tissue lacking PKD1 was significantly affected. Critical rate-limiting enzymes for de novo lipogenesis in adipocytes, such as FASN, ACCα, and SCD1, were significantly repressed after deleting PKD1 in vivo and in vitro. Further studies revealed that blockade of PKD1 significantly increased phosphorylation of SREBP1c at serine 372 site. Co-immunoprecipitation analysis showed that PKD1 interacts with SREBP1c in vitro and in vivo. Importantly, overexpression of SREBP1c reversed the inhibition of FASN and ACCα expression caused by PKD1 silencing. Together, adipocyte PKD1 promotes de novo lipogenesis via SREBP1c-dependent manner in visceral white adipose tissue and might provide a new target for the development of anti-obesity therapies.

Transcriptome Profiling of 'Candidatus Liberibacter asiaticus' in Citrus and Psyllids.

'Candidatus Liberibacter asiaticus' (Las) is an emergent bacterial pathogen that is associated with the devastating citrus huanglongbing (HLB). Vectored by the Asian citrus psyllid, Las colonizes the phloem tissue of citrus, causing severe damage to infected trees. So far, cultivating pure Las culture in axenic media has not been successful, and dual-transcriptome analyses aiming to profile gene expression in both Las and its hosts have a low coverage of the Las genome because of the low abundance of bacterial RNA in total RNA extracts from infected tissues. Therefore, a lack of understanding of the Las transcriptome remains a significant knowledge gap. Here, we used a bacterial cell enrichment procedure and confidently determined the expression profiles of approximately 84% of the Las genes. Genes that exhibited high expression in citrus include transporters, ferritin, outer membrane porins, specific pilins, and genes involved in phage-related functions, cell wall modification, and stress responses. We also found 106 genes to be differentially expressed in citrus versus Asian citrus psyllids. Genes related to transcription or translation and resilience to host defense response were upregulated in citrus, whereas genes involved in energy generation and the flagella system were expressed to higher levels in psyllids. Finally, we determined the relative expression levels of potential Sec-dependent effectors, which are considered as key virulence factors of Las. This work advances our understanding of HLB biology and offers novel insight into the interactions of Las with its plant host and insect vector.

Sequential Blood Purification for Pediatric Fatal Toxic Epidermal Necrolysis: A Case Series.

BACKGROUND: Extracorporeal therapy that included therapeutic plasma exchange (TPE) or continuous hemofiltration (CHF) for toxic epidermal necrolysis (TEN) syndrome was used in small number of patients. We aimed to describe the sequential mode of combined application of CHF and TPE in 3 TEN patients with multiple organ dysfunction (MODS) in pediatric intensive care unit. METHODS: Three patients with fatal TEN received sequential CHF and TPE due to unsatisfactorily conventional treatments. CHF was initiated and performed on a daily basis with 35-50 mL/kg.h replacement fluid at the rate of 3-5 mL/kg.min blood flow. CHF was temporarily interrupted for TPE, which was performed with exchange 1-1.5-fold of one body calculated plasma volume in each section. RESULTS: All 3 fatal TEN (with >30% involvement of body surface and MODS) following unsuccessful treatment with corticosteroids and intravenous immunoglobulin. Antibiotics were suspected in the TEN-triggered drugs. The range number of TPE sessions was 3-5 and the duration of CHF was from 120 h to 202 h. After initiation of TPE and CHF, blistering with extensive epidermal necrosis halted and the skin re-epithelialized within 2 weeks. Serum C-reactive protein, procalcitonin, tumor necrosis factor-α , and interlukin-6 decreased and percentage of natural killer cells increased in surviving children. Two patients survived to discharge and one case died due to nosocomial infection with multidrug-resistant Acinetobacter baumannii. CONCLUSION: After sequential TPE and CHF, skin lesions and inflammatory response improved in TEN. Our result indicates extracorporeal therapy could be used as an alternative modality for fatal pediatric TEN.