bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulinotropic Effects of Neprilysin and/or Angiotensin Receptor Inhibition in Mice
Authors: Esser Nathalie , Schmidt Christine , Barrow Breanne M. , Cronic Laura , Hackney Daryl J. , Mongovin Stephen M. , Hogan Meghan F. , Templin Andrew T. , Castillo Joseph J. , Hull Rebecca L. , Zraika Sakeneh
Published: June 2022

Treatment of heart failure with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan improved glycemic control in individuals with type 2 diabetes. The relative contribution of neprilysin inhibition versus angiotensin II receptor antagonism to this glycemic benefit remains unknown. Thus, we sought to determine the relative effects of the neprilysin inhibitor sacubitril versus the angiotensin II receptor blocker valsartan on beta-cell function and glucose homeostasis in a mouse model of reduced first-phase insulin secretion, and whether any beneficial effects are additive/synergistic when combined in sacubitril/valsartan. High fat-fed C57BL/6J mice treated with low-dose streptozotocin (or vehicle) were followed for eight weeks on high fat diet alone or supplemented with sacubitril, valsartan or sacubitril/valsartan. Body weight and fed glucose levels were assessed weekly. At the end of the treatment period, insulin release in response to intravenous glucose, insulin sensitivity, and beta-cell mass were determined. Sacubitril and valsartan, but not sacubitril/valsartan, lowered fasting and fed glucose levels and increased insulin release in diabetic mice. None of the drugs altered insulin sensitivity or beta-cell mass, but all reduced body weight gain. Effects of the drugs on insulin release were reproduced in angiotensin II-treated islets from lean C57BL/6J mice, suggesting the insulin response to each of the drugs is due to a direct effect on islets and mechanisms therein. In summary, sacubitril and valsartan each exert beneficial insulinotropic, glycemic and weight-reducing effects in obese and/or diabetic mice when administered alone; however, when combined, mechanisms within the islet contribute to their inability to enhance insulin release.
Automatic Grading of Disc Herniation, Central Canal Stenosis and Nerve Roots Compression in Lumbar Magnetic Resonance Image Diagnosis
Authors: Su Zhi-Hai , Liu Jin , Yang Min-Sheng , Chen Zi-Yang , You Ke , Shen Jun , Huang Cheng-Jie , Zhao Qing-Hao , Liu En-Qing , Zhao Lei , Feng Qian-Jin , Pang Shu-Mao , Li Shao-Lin , Lu Hai
Published: June 2022

Aim

Accurate severity grading of lumbar spine disease by magnetic resonance images (MRIs) plays an important role in selecting appropriate treatment for the disease. However, interpreting these complex MRIs is a repetitive and time-consuming workload for clinicians, especially radiologists. Here, we aim to develop a multi-task classification model based on artificial intelligence for automated grading of lumbar disc herniation (LDH), lumbar central canal stenosis (LCCS) and lumbar nerve roots compression (LNRC) at lumbar axial MRIs.

Methods

Total 15254 lumbar axial T2W MRIs as the internal dataset obtained from the Fifth Affiliated Hospital of Sun Yat-sen University from January 2015 to May 2019 and 1273 axial T2W MRIs as the external test dataset obtained from the Third Affiliated Hospital of Southern Medical University from June 2016 to December 2017 were analyzed in this retrospective study. Two clinicians annotated and graded all MRIs using the three international classification systems. In agreement, these results served as the reference standard; In disagreement, outcomes were adjudicated by an expert surgeon to establish the reference standard. The internal dataset was randomly split into an internal training set (70%), validation set (15%) and test set (15%). The multi-task classification model based on ResNet-50 consists of a backbone network for feature extraction and three fully-connected (FC) networks for classification and performs the classification tasks of LDH, LCCS, and LNRC at lumbar MRIs. Precision, accuracy, sensitivity, specificity, F1 scores, confusion matrices, receiver-operating characteristics and interrater agreement (Gwet k) were utilized to assess the model’s performance on the internal test dataset and external test datasets.

Results

A total of 1115 patients, including 1015 patients from the internal dataset and 100 patients from the external test dataset [mean age, 49 years ± 15 (standard deviation); 543 women], were evaluated in this study. The overall accuracies of grading for LDH, LCCS and LNRC were 84.17% (74.16%), 86.99% (79.65%) and 81.21% (74.16%) respectively on the internal (external) test dataset. Internal and external testing of three spinal diseases showed substantial to the almost perfect agreement (k, 0.67 - 0.85) for the multi-task classification model.

Conclusion

The multi-task classification model has achieved promising performance in the automated grading of LDH, LCCS and LNRC at lumbar axial T2W MRIs.
Effects of Total Flavonoids of Epimedium on Bone Marrow Adipose Tissue in Ovariectomized Rats
Authors: Chen Lei , Ma Rui , Luo Peng , Shi Dan , Shi Xiao , Nian Hua , Chang Shi-Xin , Yuan Wei , Li Guan-Wu
Published: June 2022

Bone marrow adipose tissue has brown fat characteristics. Several studies have demonstrated that total flavonoids of Epimedium (TFE) could prevent bone loss and reduce the white adiposity in bone marrow induced by ovariectomy (OVX) in rats. However, the effects of TFE on marrow brown fat in OVX rats remain unclear. In this word, we addressed this question expected to provide a new target for preventing and treating osteoporosis. Thirty-six 3-month-old female Sprague-Dawley rats were equally divided into Sham controls, OVX controls, and OVX treated with TFE. Chemical shift coding magnetic resonance was performed to detect marrow fat fraction at the left femur at baseline, 6 and 12 weeks post-OVX. Bone mineral density at the lumbar spine and femur was measured by dual-energy x-ray absorptiometry. Serum bone biomarkers by ELISA, trabecular bone microarchitecture at the proximal tibia by micro-CT, quantitative parameters of marrow adipocyte by hematoxylin, and eosin staining were evaluated. The marrow adipocyte gene and protein expressions profile were determined by real-time quantitative PCR and immunostaining in whole tibiae. We found that TFE treatment could decrease bone turnover rate and improved bone mineral density and trabecular microarchitecture in OVX rats. OVX resulted in marrow adipogenesis as evidenced by increased marrow fat fraction, larger marrow adipocyte size, increased adipocyte number and percentage of adipocyte area, marrow white adipocyte gene, and protein expression, including PPARγ2 and FABP4. These pathological changes induced by estrogen deficiency were restored by TFE treatment. TFE also increased brown adipocyte expressions of the transcription factor Ucp1 and Prdm16 in whole tibiae. There was no detectible protein expression of brown adipocyte markers in the proximal tibia. Taken together, TFE regulation of bone marrow adiposity in OVX rats is mediated, at least in part, via maintaining the reciprocity of white and brown adipose tissue.
An IPAVSG Control Strategy for Microgrid With Multi-Parallel VSG System
Authors: Song Xinqing , Zhu Fanglin , Cao Xingchen , Liu Jiawei , Wang Rui , Zhang Yi , Liu Yao
Published: June 2022

Virtual synchronous generator (VSG) is widely used in various distributed power generation systems due to great simulated inertia and damping support performance. However, when the microgrid (MG) composed of multi-parallel VSG is in both grid-connected and islanded modes with various large disturbances, the control strategy with fixed parameters cannot guarantee the stable operation of the MG under all disturbances. To this end, an improved parameter-adaptive virtual synchronous generator (IPAVSG) control strategy is proposed in this paper to ensure that the virtual inertia and damping are adaptively optimized with the system operating state during the disturbance process. Therefore, the dynamic performance of the power frequency regulation and transient stability are significantly improved. Meanwhile, in order to realize the output active power of each VSG is distributed among the loads according to the ratio of its rated capacity, the active power decoupling control is designed to eliminate the influence of the virtual damping on the output active power of the VSG in islanded MG. The effectiveness and practicability of the proposed control strategy are verified through several experiments.
Unexpected Methane Emissions From Old Small Fishing Vessels in China
Authors: Wang Lizhi , Du Wei , Shen Huizhong , Chen Yuanchen , Zhu Xi , Yun Xiao , Shen Guofeng , Chen Yilin , Liu Junfeng , Wang Xuejun , Tao Shu
Published: June 2022

Diesel-fueled ships have long been considered to contribute a marginal fraction of the global methane (CH4) emission budget compared to liquified natural gas (LNG)-fueled ships. Here, based on real-world measurements, we find that a specific yet-overlooked group of diesel-fueled ships–the old small fishing vessels (OSFVs)–is associated with high levels of CH4 emissions. The emission factors of CH4 from OSFVs is on average 5.2 ± 6.4 g CH4 per 1 kg fuel consumed, approaching EFCH4 of LNG-fueled ships (5.3–30.1 g/kg) and being at least six times EFCH4 of other types of diesel-fueled ships (0.0–0.9 g/kg). We estimate that CH4 emissions from OSFVs in China amount to 570–2,240 t per year, which is comparable to the total CH4 emission from all LNG-fueled ships worldwide. Our results thus call for revision of the global CH4 emission inventory for shipping.
Sustainable Research of Land Optimization in a Semiarid Sandy Area Based on Soil Moisture Characteristics
Authors: Zhang Hongfei , Cai Zhaoyang , Chen Jingyuan , Xu Yan , Zhang Fengrong
Published: June 2022

Land optimization is a necessary means to improve the land use efficiency and promote the sustainable use of land resources. How to fully consider the regional background conditions and scientifically and comprehensively achieve the sustainable and optimal utilization of land resources is a necessary means to promote the sustainable utilization of land resources, especially in semiarid sandy areas with fragile ecological environments. Therefore, based on the characteristics of a semiarid sandy area and by using existing research, with important water resources as the core, this study constructed an optimal land allocation method in a semiarid sandy area based on the soil moisture characteristics. By taking the Horqin Zuoyihou Banner in the semiarid sandy area of China as a typical case, we explored its soil moisture characteristics and influencing factors and put forward the distribution patterns and suggestions for optimal land use. The results show that it is effective to optimize the land space allocation in semiarid sandy areas based on the soil moisture characteristics, and the corresponding land use activities should be arranged according to the moisture conditions of each region, which is beneficial to achieve sustainable semiarid sandy land use. We hope that this study can provide valuable sustainable land optimization solutions for the efficient, sustainable use and protection of land resources in semiarid regions.
Individual Network Topology of Patch Selection Under Influence of Drifting Site Fidelity
Authors: Gautestad Arild O.
Published: June 2022

Network theory has led to important insight into statistical-mechanical aspects of systems showing scaling complexity. I apply this approach to simulate the behavior of animal space use under the influence of memory and site fidelity. Based on the parsimonious Multi-scaled random walk model (MRW) an emergent property of self-reinforcing returns to a subset of historic locations shows how a network of nodes grows into an increased hierarchical depth of site fidelity. While most locations along a movement path may have a low revisit probability, habitat selection is maturing with respect to utilization of the most visited patches, in particular for patches that emerge during the early phase of node development. Using simulations with default MRW properties, which have been shown to produce space use in close statistical compliance with utilization distributions of many species of mammals, I illustrate how a shifting spatio-temporal mosaic of habitat utilization may be described statistically and given behavioral-ecological interpretation. The proposed method is illustrated with a pilot study using black bearUrsus americanustelemetry fixes. One specific parameter, the Characteristic Scale of Space Use, is here shown to express strong resilience against shifting site fidelity. This robust result may seem counter-intuitive, but is logical under the premise of the MRW model and its relationship to site fidelity, whether stable or shifting spatially over time. Thus, spatial analysis of the dynamics of a gradually drifting site fidelity using simulated scenarios may indirectly cast light on the dynamics of movement behavior as preferred patches are shifting over time. Both aspects of complex space use, network topology and dynamically drifting dispersion of site fidelity, provide in tandem important descriptors of behavioral ecology with relevance to habitat selection.
The Value of Hazard Quotients in Honey Bee (Apis mellifera) Ecotoxicology: A Review
Authors: Carlson Emily A. , Melathopoulos Andony , Sagili Ramesh
Published: June 2022

Estimates of pesticide application hazards have grown to be one of the most common methodologies for evaluating the impact of pest management practices on honey bees. Typically, hazards are estimated by calculating a Hazard Quotient (HQ), which is based on acute toxicity data for different pesticides and the quantity of those pesticides applied to a field or detected on bees and matrices associated with their hive (honey, wax, pollen, and/or bee bread). Although use of HQ is widespread, there have been few reviews of this methodology, particularly with focus on how effective this method is at predicting effects of pesticides on hives. We evaluated 36 relevant papers, containing calculations of HQ to estimate hazards to honey bees. We observed that HQ was primarily calculated using two different approaches: (1) from the concentration of pesticides in the food, hive, or tissues of honey bees or (2) using the field application rate of the active ingredient as the estimation of pesticide hazard. Within and between HQ calculation methods, thresholds vary widely with some HQ thresholds set below 1 and others set at 10,000. Based on our review we identify key weakness with current HQ methodology and how studies relate HQ to honey bee health endpoints. First, HQ thresholds from studies of pesticides in hives are not based on the same pesticide consumption models from the EPA, potentially overestimating the risk of impacts to colonies. Conversely, HQ estimates calculated from field application rates are not based on eco-toxicological estimates of field exposure, resulting in an overestimation of pesticide reaching colonies. We suggest it is for these reasons that there is poor correspondence between HQ and field-level honey bee health endpoints. Considering these challenges, HQ calculations should be used cautiously in future studies and more research should be dedicated to field level exposure models.
Tree Growth, Foliar Nutrition, and Soil Properties in Mixtures of Lodgepole Pine and Sitka Alder in the Central Interior of British Columbia, Canada: 25-Year Results
Authors: Sanborn Paul , Ott Peter K.
Published: June 2022

Densities of naturally regenerated mixtures of lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia Engelm.) and Sitka alder [Alnus viridis subsp. sinuata (Regel) Á. Löve & D. Löve] were manipulated in 1995 at a site logged in 1987 in the central interior of British Columbia, Canada. Four levels of alder retention (0, 500, 1,000, and 2,000 clumps/ha) were combined with a uniform lodgepole pine density of 1,000 stems/ha across all treatments. After 25 years, effects of alder retention on lodgepole pine growth consisted of modest reductions in height and diameter increment, and treatment effects on soil nitrogen were confined to the forest floor organic horizons. Nutritional benefits of alder retention for lodgepole pine were not detected after year 6. The operational silvicultural implication of these findings is that only limited intervention to control Sitka alder in similar stands can be justified.
Novel Insight Into the Role of ACSL1 Gene in Milk Production Traits in Buffalo
Authors: Lin Yuxin , Sun Hui , Shaukat Aftab , Deng Tingxian , Abdel-Shafy Hamdy , Che Zhaoxuan , Zhou Yang , Hu Changmin , Li Huazhao , Wu Qipeng , Yang Liguo , Hua Guohua
Published: June 2022

Understanding the genetic mechanisms underlying milk production traits contribute to improving the production potential of dairy animals. Long-chain acyl-CoA synthetase 1 (ACSL1) plays a key role in fatty acid metabolism and was highly expressed in the lactating mammary gland epithelial cells (MGECs). The objectives of the present study were to detect the polymorphisms within ACSL1 in Mediterranean buffalo, the genetic effects of these mutations on milk production traits, and understand the gene regulatory effects on MGECs. A total of twelve SNPs were identified by sequencing, including nine SNPs in the intronic region and three in the exonic region. Association analysis showed that nine SNPs were associated with one or more traits. Two haplotype blocks were identified, and among these haplotypes, the individuals carrying the H2H2 haplotype in block 1 and H5H1 in block 2 were superior to those of other haplotypes in milk production traits. Immunohistological staining of ACSL1 in buffalo mammary gland tissue indicated its expression and localization in MGECs. Knockdown of ACSL1 inhibited cell growth, diminished MGEC lipid synthesis and triglyceride secretion, and downregulated CCND1, PPARγ, and FABP3 expression. The overexpression of ACSL1 promoted cell growth, enhanced the triglyceride secretion, and upregulated CCND1, PPARγ, SREBP1, and FABP3. ACSL1 was also involved in milk protein regulation as indicated by the decreased or increased β-casein concentration and CSN3 expression in the knockdown or overexpression group, respectively. In summary, our present study depicted that ACSL1 mutations were associated with buffalo milk production performance. This may be related to its positive regulation roles on MGEC growth, milk fat, and milk protein synthesis. The current study showed the potential of the ACSL1 gene as a candidate for milk production traits and provides a new understanding of the physiological mechanisms underlying milk production regulation.
Cladribine Treatment for MS Preserves the Differentiative Capacity of Subsequently Generated Monocytes, Whereas Its Administration In Vitro Acutely Influences Monocyte Differentiation but Not Microglial Activation
Authors: Medeiros-Furquim Tiago , Ayoub Sinan , Johnson Laura J. , Aprico Andrea , Nwoke Eze , Binder Michele D. , Kilpatrick Trevor J.
Published: June 2022

Cladribine (2-chlorodeoxyadenosine, 2CdA) is one of the most effective disease-modifying drugs for multiple sclerosis (MS). Cladribine is a synthetic purine nucleoside analog that induces cell death of lymphocytes and oral cladribine treatment leads to a long-lasting disease stabilization, potentially attributable to immune reconstitution. In addition to its effects on lymphocytes, cladribine has been shown to have immunomodulatory effects on innate immune cells, including dendritic cells and monocytes, which could also contribute to its therapeutic efficacy. However, whether cladribine can modulate human macrophage/microglial activation or monocyte differentiation is currently unknown. The aim of this study was to determine the immunomodulatory effects of cladribine upon monocytes, monocyte-derived macrophages (MDMs) and microglia. We analyzed the phenotype and differentiation of monocytes from MS patients receiving their first course of oral cladribine both before and three weeks after the start of treatment. Flow cytometric analysis of monocytes from MS patients undergoing cladribine treatment revealed that the number and composition of CD14/CD16 monocyte subsets remained unchanged after treatment. Furthermore, after differentiation with M-CSF, such MDMs from treated MS patients showed no difference in gene expression of the inflammatory markers compared to baseline. We further investigated the direct effects of cladribine in vitro using human adult primary MDMs and microglia. GM-CSF-derived MDMs were more sensitive to cell death than M-CSF-derived MDMs. In addition, MDMs treated with cladribine showed increased expression of costimulatory molecules CD80 and CD40, as well as expression of anti-inflammatory, pro-trophic genes IL10 and MERTK, depending on the differentiation condition. Cladribine treatment in vitro did not modulate the expression of activation markers in human microglia. Our study shows that cladribine treatment in vitro affects the differentiation of monocytes into macrophages by modulating the expression of activation markers, which might occur similarly in tissue after their infiltration in the CNS during MS.
Neutrophil-Specific Knockdown of β2 Integrins Impairs Antifungal Effector Functions and Aggravates the Course of Invasive Pulmonal Aspergillosis
Authors: Haist Maximilian , Ries Frederic , Gunzer Matthias , Bednarczyk Monika , Siegel Ekkehard , Kuske Michael , Grabbe Stephan , Radsak Markus , Bros Matthias , Teschner Daniel
Published: June 2022

β2-integrins are heterodimeric surface receptors that are expressed specifically by leukocytes and consist of a variable α (CD11a-d) and a common β-subunit (CD18). Functional impairment of CD18, which causes leukocyte adhesion deficiency type-1 results in an immunocompromised state characterized by severe infections, such as invasive pulmonary aspergillosis (IPA). The underlying immune defects have largely been attributed to an impaired migratory and phagocytic activity of polymorphonuclear granulocytes (PMN). However, the exact contribution of β2-integrins for PMN functionsin-vivohas not been elucidated yet, since the mouse models available so far display a constitutive CD18 knockout (CD18-/-or CD18hypo). To determine the PMN-specific role of β2-integrins for innate effector functions and pathogen control, we generated a mouse line with a Ly6G-specific knockdown of the common β-subunit (CD18Ly6GcKO). We characterized CD18Ly6GcKO micein-vitroto confirm the PMN-specific knockdown of β2-integrins. Next, we investigated the clinical course of IPA inA. fumigatusinfected CD18Ly6GcKO mice with regard to the fungal burden, pulmonary inflammation and PMN response towardsA. fumigatus. Our results revealed that the β2-integrin knockdown was restricted to PMN and that CD18Ly6GcKO mice showed an aggravated course of IPA. In accordance, we observed a higher fungal burden and lower levels of proinflammatory innate cytokines, such as TNF-α, in lungs of IPA-infected CD18Ly6GcKO mice. Bronchoalveolar lavage revealed higher levels of CXCL1, a stronger PMN-infiltration, but concomitantly elevated apoptosis of PMN in lungs of CD18Ly6GcKO mice. Ex-vivoanalysis further unveiled a strong impairment of PMN effector function, as reflected by an attenuated phagocytic activity, and a diminished generation of reactive oxygen species (ROS) and neutrophil-extracellular traps (NET) in CD18-deficient PMN. Overall, our study demonstrates that β2-integrins are required specifically for PMN effector functions and contribute to the clearance ofA. fumigatusby infiltrating PMN, and the establishment of an inflammatory microenvironment in infected lungs.
Renal Endothelial Cytotoxicity Assay to Diagnose and Monitor Renal Transplant Recipients for Anti-Endothelial Antibodies
Authors: Lammerts Rosa G. M. , Born Jacob van den , Huberts-Kregel Magdalena , Gomes-Neto Antonio W. , Daha Mohammed R. , Hepkema Bouke G. , Sanders Jan-Stephan , Pol Robert A. , Diepstra Arjan , Berger Stefan P.
Published: June 2022

Tissue-specific nonhuman leukocyte antigen (HLA) antigens can play crucial roles in allograft immunity and have been shown to trigger humoral responses leading to rejection of HLA-matched kidney allografts. Interest in the role of endothelial-specific antigens has grown over the past years, and several case reports have been described in which antibodies reacting with endothelial cells (ECs) are associated with rejection. Such antibodies escape the detection in conventional crossmatch tests as they do not react with lymphocytes. However, due to the heterogeneity of endothelial cells from different vascular beds, it remains difficult to draw organ-specific conclusions from studies describing endothelial crossmatch assays. We present a case of a 69-year-old male patient whose kidney allograft was rejected as hyperacute, despite the absence of pretransplant HLA-specific antibodies. To place findings from previous studies in a kidney-related context, we performed crossmatch assays with primary renal endothelial cells. The patient’s serum was reactive with primary renal ECs, demonstrated by antibody binding and complement-dependent cytotoxicity. Antibodies from this patient did not react with lymphocytes nor were HLA donor-specific antibodies (DSAs) found. Two years later, the patient successfully received a second kidney transplant after treatment with rituximab and plasmapheresis before and after transplantation. We demonstrated that the removal of antibodies against non-HLA EC-specific molecules can be monitored using a primary renal EC crossmatch test, possibly contributing to a successful transplantation outcome.
The Internal Conduit System of the Swine Inverted Lymph Node
Authors: Dubreil Laurence , Ledevin Mireille , Hervet Caroline , Menard Déborah , Philippe Claire , Michel François J. , Larcher Thibaut , Meurens François , Bertho Nicolas
Published: June 2022

Lymph nodes (LN) are the crossroad where naïve lymphocytes, peripheral antigens and antigen presenting cells contact together in order to mount an adaptive immune response. For this purpose, LN are highly organized convergent hubs of blood and lymphatic vessels that, in the case of B lymphocytes, lead to the B cell follicles. Herein take place the selection and maturation of B cell clones producing high affinity antibodies directed against various antigens. Whereas the knowledge on the murine and human LN distribution systems have reached an exquisite precision those last years, the organization of the antigens and cells circulation into the inverted porcine LN remains poorly described. Using up to date microscopy tools, we described the complex interconnections between afferent lymphatics and blood vessels, perifollicular macrophages, follicular B cells and efferent blood vessels. We observed that afferent lymphatic sinuses presented an asymmetric Lyve-1 expression similar to the one observed in murine LN, whereas specialized perifollicular sinuses connect the main afferent lymphatic sinus to the B cell follicles. Finally, whereas it was long though that mature B cells egress from the inverted LN in the T cell zone through HEV, our observations are in agreement with mature B cells accessing the efferent blood circulation in the efferent, subcapsular area. This understanding of the inverted porcine LN circuitry will allow a more accurate exploration of swine pathogens interactions with the immune cells inside the LN structures. Moreover, the mix between similarities and differences of porcine inverted LN circuitry with mouse and human normal LN shall enable to better apprehend the functions and malfunctions of normal LN from a new perspective.
CaMK4 Promotes Acute Lung Injury Through NLRP3 Inflammasome Activation in Type II Alveolar Epithelial Cell
Authors: Zhang Tengyue , Li Mengyuan , Zhao Siyuan , Zhou Mianjing , Liao Huai , Wu Haiyan , Mo Xinyue , Wang Hongxing , Guo Chaohuan , Zhang Hui , Yang Niansheng , Huang Yuefang
Published: June 2022

Background

Type II alveolar epithelial cell (AEC II), in addition to its roles in maintaining lung homeostasis, takes an active role in inflammatory response during acute lung injury (ALI). Ca2+/calmodulin-dependent protein kinase IV (CaMK4) activated by Ca2+/calmodulin signaling, has been implicated in immune responses. This study was to investigate the roles of CaMK4 in the development of ALI and the underlying mechanisms.

Methods

CaMK4 inhibitor KN-93 was used to investigate the effects of CaMK4 on NLRP3 inflammasome activation. The effects of KN-93 on disease development of lipopolysaccharide (LPS)-induced ALI were also evaluated. The role of CaMK4 on NLRP3 inflammasome activation was explored in human AEC II cell line A549 using KN-93 or CaMK4 siRNA. NLRP3 inflammasome activation was measured by histology immunofluorescence and Western blot. IL-1β and IL-18 were measured by ELISA.

Results

Phosphorylation of CaMK4 and the expression of NLRP3 and Caspase-1 p20 were increased in the lungs of LPS-induced ALI mice, which was suppressed by KN-93 as measured by Western blot. Further, the activation of NLRP3 inflammasome was detected in AEC II from patients with acute respiratory distress syndrome (ARDS) and LPS-induced ALI mice. In vitro, inhibition or silencing CaMK4 in AEC II significantly inhibited NLRP3 inflammasome activation, resulting in reduced IL-1β production. The inhibition of NLRP3 inflammasome and decreased IL-1β/IL-18 production by KN-93 led to reduced inflammatory infiltration and ameliorated lung injury in LPS-induced ALI mice.

Conclusion

CaMK4 controls the activation of NLRP3 inflammasome in AEC II during LPS-induced ALI. CaMK4 inhibition could be a novel therapeutic approach for the treatment of ALI.
Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Response After Heterologous Immunizations With ChAdOx1/BNT162b2 in End-Stage Renal Disease Patients on Hemodialysis
Authors: Kim Dae Kyu , Jung Su Woong , Moon Ju-Young , Jeong Kyung Hwan , Hwang Hyeon Seok , Kim Jin Sug , Lee Sang-Ho , Kang So-Young , Kim Yang Gyun
Published: June 2022

The Korean government decided to schedule heterologous vaccinations on dialysis patients for early achievement of immunization against Coronavirus disease 2019(COVID-19). However, the effects of heterologous immunizations in hemodialysis (HD) patients are unclear. One hundred (HD) patients from Gangdong Kyung Hee University Hospital and Kyung Hee Medical Center and 100 hospital workers from Gangdong Kyung Hee University Hospital were enrolled in this study. The HD patients received the mixing schedule of ChAdOx1/BNT162b2 vaccinations at 10-week intervals, while hospital workers received two doses of ChAdOx1 vaccines at 12-week intervals. Serum IgG to a receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 was measured 1 month after the first dose, 2 months and 4 months after the second dose. The median [interquartile range] anti-RBD IgG was 82.1[34.5, 176.6] AU/ml in HD patients and 197.1[124.0, 346.0] AU/ml in hospital workers (P < 0.001) after the first dose. The percentage of positive responses (IgG > 50 AU/ml) was 65.0% and 96.0% among the both group, respectively (P < 0.001). The anti-RBD IgG levels increased significantly by 2528.8 [1327.6, 5795.1] AU/ml with a 100.0% positive response rate in HD patients 2 months after the second dose, which was higher than those in hospital workers 981.4[581.5, 1891.4] AU/ml (P < 0.001). Moreover, anti-RBD IgG remains constantly high, and positive response remains 100% in HD patients 4 months after the second dose. This study suggests that heterologous vaccinations with ChAdOx1/BNT162b2 can be an alternative solution on HD patients for early and strong induction of humoral response.
Lung Epithelial CYP1 Activity Regulates Aryl Hydrocarbon Receptor Dependent Allergic Airway Inflammation
Authors: Alessandrini Francesca , de Jong Renske , Wimmer Maria , Maier Ann-Marie , Fernandez Isis , Hils Miriam , Buters Jeroen T. , Biedermann Tilo , Zissler Ulrich M. , Hoffmann Christian , Esser-von-Bieren Julia , Schmidt-Weber Carsten B. , Ohnmacht Caspar
Published: June 2022

The lung epithelial barrier serves as a guardian towards environmental insults and responds to allergen encounter with a cascade of immune reactions that can possibly lead to inflammation. Whether the environmental sensor aryl hydrocarbon receptor (AhR) together with its downstream targets cytochrome P450 (CYP1) family members contribute to the regulation of allergic airway inflammation remains unexplored. By employing knockout mice for AhR and for single CYP1 family members, we found that AhR-/- and CYP1B1-/- but not CYP1A1-/- or CYP1A2-/- animals display enhanced allergic airway inflammation compared to WT. Expression analysis, immunofluorescence staining of murine and human lung sections and bone marrow chimeras suggest an important role of CYP1B1 in non-hematopoietic lung epithelial cells to prevent exacerbation of allergic airway inflammation. Transcriptional analysis of murine and human lung epithelial cells indicates a functional link of AhR to barrier protection/inflammatory mediator signaling upon allergen challenge. In contrast, CYP1B1 deficiency leads to enhanced expression and activity of CYP1A1 in lung epithelial cells and to an increased availability of the AhR ligand kynurenic acid following allergen challenge. Thus, differential CYP1 family member expression and signaling via the AhR in epithelial cells represents an immunoregulatory layer protecting the lung from exacerbation of allergic airway inflammation.
New Avenues to Design Toxoplasma Vaccines Based on Oocysts and Cysts
Authors: Arranz-Solís David , Saeij Jeroen P. J.
Published: June 2022

Toxoplasmosis is a worldwide disease affecting all warm-blooded animals, including humans. Vaccination strategies aimed at inducing an efficient immune response while preventing transmission have been attempted in the past. While many different approaches can partially protect immunized animals against subsequent infections, full and lasting protection is rarely attained and only with live-attenuated vaccines. In addition, vaccines based on mutant strains that are deficient in forming the chronic phase of the parasite (such as Toxovax™) cannot be extensively used due to their zoonotic potential and the possibility of reversion to virulent phenotypes. An increasing number of studies using emerging genetic-engineering tools have been conducted to design novel vaccines based on recombinant proteins, DNA or delivery systems such as nanoparticles. However, these are usually less efficient due to their antigenic simplicity. In this perspective article we discuss potential target genes and novel strategies to generate live-attenuated long-lasting vaccines based on tissue cysts and oocysts, which are the environmentally resistant chronic forms ofToxoplasma. By selectively disrupting genes important for parasite dissemination, cyst formation and/or sporozoite invasion, alone or in combination, a vaccine based on a live-attenuated strain that elicits a protective immune response while preventing the transmission ofToxoplasmacould be created. Finally, further improvements of protocols to generateToxoplasmasexual stagesin vitromight lead to the production of oocysts from such a strain without the need for using mice or cats.
Novel Alloy Design Concepts Enabling Enhanced Mechanical Properties of High Entropy Alloys
Authors: Kumar Jitesh , Jha Saumya , Raturi Abheepsit , Bajpai Anurag , Sonkusare Reshma , Gurao N. P. , Biswas Krishanu
Published: June 2022

The emergence of High Entropy Alloys (HEAs) in the world of materials has shifted the alloy design strategy based on a single principal element to the multi-principal elements where compositional space can cover almost the entire span of the higher dimensional phase diagrams. This approach can provide advanced materials with unique properties, including high strength with sufficient ductility and fracture toughness and excellent corrosion and wear resistance for a wide range of temperatures due to the concentrated alloying that cannot be obtained by traditional microalloying based on a single principal element. In addition, the alloy design approach provides new alloy systems in astronomical numbers with variety of microstructural attributes that can yield different properties, and hence conventional trial and error experimental methods for alloy development are redundant. With the help of high throughput experiments along with efficient computational tools, and artificial intelligence, mechanisms based mechanistic development of the multi-principal element alloys with tailored solid solution strengthening, stacking fault energy and microstructure is possible. The current review discusses the various design strategies based on multi-principal elements alloys in semblance with the desired mechanical properties dictated by the micro mechanisms associated with them to overcome the bottlenecks presented by the conventional approaches with possible breakthrough applications. The article will shed light on the current status as well as the future prospects of using these approaches to design novel HEAs.
Impact of Carbapenem Peri-Transplant Prophylaxis and Risk of Extended-Spectrum Cephalosporin-Resistant Enterobacterales Early Urinary Tract Infection in Kidney Transplant Recipients: A Propensity Score-Matched Analysis
Authors: Aramwittayanukul Suwadee , Malathum Kumthorn , Kantachuvesiri Surasak , Arpornsujaritkun Nuttapon , Chootip Patumsri , Bruminhent Jackrapong
Published: June 2022

Background

Urinary tract infection (UTI) is the most common bacterial infection after kidney transplantation (KT), leading to unfavorable clinical and allograft outcomes. Gram-negative uropathogenic bacteria are frequently encountered especially extended-spectrum cephalosporin-resistant (ESC-R) Enterobacterales (EB), causing UTI early after KT.

Methods

A retrospective single transplant study was conducted between January 2016 and December 2019. We performed 1:1 nearest-neighbor propensity score matching without replacement using recipient age, recipient sex, induction, transplant year, human leukocyte antigen, cold ischemia time, and panel-reactive antibody before analyses. Cumulative incidence of ESC-R EB early (within 14 days after KT) UTI was estimated by the Kaplan–Meier method. Risk factors for ESC-R EB early UTI were analyzed by a Cox proportional hazards model. Variables measured after transplantation were considered time-dependent covariates.

Results

We included 620 KT recipients (37% women; mean age ± SD, 43 ± 11 years). Overall, 64% and 76% received deceased-donor allograft and induction therapy. Sixty-five (10%) and 555 (90%) received carbapenems and cefuroxime peri-transplant prophylaxis, respectively. Early UTI occurred in 183 (30%) patients, 52% caused by ESC-R EB. Propensity score matching produced 65 well-balanced pairs. During a 14-day follow-up, the cumulative incidence of ESC-R EB early UTI was 5 and 28% in the carbapenems and cefuroxime groups, respectively (log-rank test = 0.003). Peri-transplant carbapenems prophylaxis was a protective factor against ESC-R EB after KT (hazard ratio, 0.19; 95% confidence interval, 0.05–0.64;p= 0.008). Clinical and allograft outcomes did not differ significantly between the groups.

Conclusions

In the setting where ESC-R EB UTI is common among KT recipients, carbapenems peri-transplant prophylaxis could protect against the occurrence of early ESC-R EB UTI after KT. Further prospective studies should focus on this specific infection prevention strategy.
Mechanisms of Tumor Necrosis Factor-Alpha Inhibitor-Induced Systemic Lupus Erythematosus
Authors: Yen Chung-Yang , Yu Sheng-Jie , Chen Yi-Ming , Lai Kuo-Lung , Wu Yi-Da , Liao En-Chih , Hsieh Ching-Liang
Published: June 2022

Systemic lupus erythematosus induced by biologics mainly results from tumor necrosis factor-alpha remains unclear. The objectives of the study were to investigate the mechanisms of tumor necrosis factor-alpha inhibitor-induced systemic lupus erythematosus. Peripheral blood mononuclear cells obtained from thirteen psoriasis patients were cultured and treated with the following: untreated control, Streptococcus pyogenes with or without different biologics. The supernatants were collected for cytokines assay. Analysis of cytokine expression revealed that IL-2 and IL-10 levels decreased only in the TNF-α inhibitor-treated groups but not in the groups treated with biologics involving IL-17, IL-12/IL-23 or IL-23 inhibitor mechanisms (p < 0.001, p < 0.05). The IFN-γ/IL-13 ratio increased significantly in patients with SLE inducing biologics to S. pyogenes induction only compared with non-SLE inducing biologics to S. pyogenes induction only (p = 0.001). IL-2 and IL-10 depletion and a shift to the Th-1 pathway in the innate response are the correlated mechanism for tumor necrosis factor-alpha inhibitor-induced systemic lupus erythematosus.
Challenges in Age-Related Macular Degeneration: From Risk Factors to Novel Diagnostics and Prevention Strategies
Authors: Lombardo Marco , Serrao Sebastiano , Lombardo Giuseppe
Published: June 2022

Age-related macular degeneration (AMD) is a chronic multifactorial eye disease representing the primary cause of vision loss in people aged 60 years and older. The etiopathogenesis of the disease remains uncertain, with several risk factors contributing to its onset and progression, such as genotype, aging, hypertension, smoking, overweight, and low dietary intake of carotenoids. Since the aging populations of the industrialized world are increasing rapidly, the impact of AMD in the socio-economical life-developed countries is expected to increase dramatically in the next years. In this context, the benefits of prevention and early disease detection for prompt and effective treatment can be enormous to reduce the social and economic burden of AMD. Nutritional and lifestyle changes, including dietary intake of xanthophyll pigments, such as lutein and zeaxanthin, no smoking, and regular exercise, are known to protect from risk of AMD progression from early to advanced disease stages. In this review, we present the clinical outcomes of a pilot study on trans-scleral iontophoresis delivery of lutein in patients with AMD. Topical delivery of lutein directly to the macula may provide a more efficient method for enriching the macular pigment and for achieving greater patient compliance to therapy than oral administration and thus enhancing prevention strategies. Modern diagnostic methodologies shall address the major problem of accurately detecting the risk of transition from intermediate AMD to advanced AMD stages. Adaptive optics retinal imaging and resonance Raman spectroscopy are two highly promising technologies for the objective assessment of patients with AMD. In this review, we present some of their clinical applications for collecting quantitative measurements of retinal cellular changes and macular content of xanthophyll pigments, respectively. In conclusion, there is great expectation that technological advancements in AMD management will deliver improved screening, therapeutic prevention, and diagnostic systems in the coming decade through a pro-active strategy of “treatment for prevention” that will aim to reduce the global burden of vision loss caused by AMD in the elderly.
Improvement of Pancreatic Steatosis and Indices of Insulin Resistance After Metabolic Surgery
Authors: Salman Ahmed Abdallah , Salman Mohamed Abdalla , Said Mostafa , El Sherbiny Mohammad , Elkassar Hesham , Hassan Mohamed Badr , Marwan Ahmed , Morad Mohamed Abdelkader , Ashoush Omar , Labib Safa , Aon Mohamed H. , Awad Abeer , Sayed Mohamed , Taha Ahmed E. , Moustafa Ahmed , Shaaban Hossam El-Din , Khater Amir , Elewa Ahmed , Khalaf Adel M. , Mostafa Ahmed A. , Matter Mohamed , Youssef Ahmed
Published: June 2022

Purpose

Obesity is associated with fat accumulation in ectopic sites such as the pancreas, the so-called pancreatic steatosis (PS). Bariatric surgery has been shown to be associated with reducing pancreatic fat. This study investigated the effect of laparoscopic sleeve gastrectomy (LSG) on pancreatic volume and its fat content and glucose homeostasis.

Methods

The study enrolled 54 patients subjected to LSG. Metabolic variables and pancreatic exocrine function were assessed immediately before surgery and 12 months after. MRI of the abdomen was performed to measure pancreatic fat content and its total volume and visceral adipose tissue (VAT).

Results

Surgery resulted in a significant reduction in body weight and BMI. HbA1c, fasting insulin, C-peptide levels, HOMA-IR, and Hs-CRP levels decreased significantly. Surgery resulted in significant improvement in lipid profile except for HDL-cholesterol and liver function tests. Total VAT volume decreased significantly. Total pancreas volume decreased by a mean of 9.0 cm3 (95% CI: 6.6–11.3). The median change of pancreatic fat was −26.1% (range: −55.6 to 58.3%). Pancreatic lipase decreased significantly (P < 0.001). There was a positive correlation between the percentage of total weight loss and decrease in pancreatic fat volume (r = 0.295, P = 0.030).

Conclusion

Weight loss after LSG is associated with a reduction of total VAT volume, total pancreatic volume, and pancreatic fat content. These changes are associated with improved glucose homeostasis, reduced systemic inflammation, and decreased pancreatic lipase secretion.
The Type I Interferon Pathway Is Upregulated in the Cutaneous Lesions and Blood of Multibacillary Leprosy Patients With Erythema Nodosum Leprosum
Authors: Rosa Thabatta Leal Silveira Andrezo , Mendes Mayara Abud , Linhares Natasha Ribeiro Cardoso , Rodrigues Thais Fernanda , Dias André Alves , Leal-Calvo Thyago , Gandini Mariana , Ferreira Helen , Costa Fabrício da Mota Ramalho , Sales Anna Maria , Amadeu Thaís Porto , Schmitz Veronica , Pinheiro Roberta Olmo , Rodrigues Luciana Silva , Moraes Milton Ozório , Pessolani Maria Cristina Vidal
Published: June 2022

In leprosy patients, acute inflammatory episodes, known as erythema nodosum leprosum (ENL), are responsible for high morbidity and tissue damage that occur during the course of Mycobacterium leprae infection. In a previous study, we showed evidence implicating DNA-sensing via TLR9 as an important inflammatory pathway in ENL. A likely important consequence of TLR9 pathway activation is the production of type I interferons (IFN-I) by plasmacytoid dendritic cells (pDCs), also implicated in the pathogenesis of several chronic inflammatory diseases. In this study, we investigated whether the IFN-I pathway is activated during ENL. Blood samples and skin lesions from multibacillary patients diagnosed with ENL were collected and the expression of genes of the IFN-I pathway and interferon-stimulated genes were compared with samples collected from non-reactional multibacillary (NR) patients. Whole blood RNAseq analysis suggested higher activation of the IFN-I pathway in ENL patients, confirmed by RT-qPCR. Likewise, significantly higher mRNA levels of IFN-I-related genes were detected in ENL skin biopsies when compared to NR patient lesions. During thalidomide administration, the drug of choice for ENL treatment, a decrease in the mRNA and protein levels of some of these genes both in the skin and blood was observed. Indeed, in vitro assays showed that thalidomide was able to block the secretion of IFN-I by peripheral blood mononuclear cells in response to M. leprae sonicate or CpG-A, a TLR9 ligand. Finally, the decreased frequencies of peripheral pDCs in ENL patients, along with the higher TLR9 expression in ENL pDCs and the enrichment of CD123+ cells in ENL skin lesions, suggest the involvement of these cells as IFN-I producers in this type of reaction. Taken together, our data point to the involvement of the pDC/type I IFN pathway in the pathogenesis of ENL, opening new avenues in identifying biomarkers for early diagnosis and new therapeutic targets for the better management of this reactional episode.