bluuebunny/crossref_metadata_2025 huggingface dataset:
Surveying After a Disaster: Capturing Elements of Vulnerability, Risk and Lessons Learned from a Household Survey in the Case Study of Hurricane Irma in Sint Maarten
Authors: Medina Neiler , Abebe Yared Abayneh , Sanchez Arlex , Vojinovic Zoran , Nikolic Igor
Published: August 2019

On September 5 2017, a Category 5 Hurricane, named Irma, struck the Caribbean island of Sint Maarten causing destruction and loss of life across the territory. This paper presents a household survey and the main findings related to vulnerability and risk to extreme weather events in the aftermath of Hurricane Irma. The post-disaster context posed challenges in relation to data collection, determination of sample size and timing of the fieldwork. The survey was conducted using a combination of face-to-face interviews and web-administered questionnaires. This method proved useful in achieving a better coverage of the study area as well as obtaining a greater overall response rate. With regards to the timing of the survey, it was found that a period of six months between Hurricane Irma’s landfall and the field data campaign was adequate in terms of availability of resources and emotional distress of respondents. Data collected in the survey was categorized into general household information, hurricane preparedness and reaction, and risk perception/awareness. Survey findings show that the factors that increased vulnerability and risk on the island include a high tenancy rate, low insurance coverage, lack of house maintenance, disregard to building regulations (particularly on leased lands), low evacuation rate, not receiving a clear warning, and lack of preparation. The factors that reduce vulnerability include high hurricane awareness at a household level and high tendency of rebuilding houses with comparable quality to houses that can sustain hurricanes. Finally, recommendations are provided that could potentially reduce communities’ vulnerability and risk to hurricanes, and lessons learned in conducting household surveys after disasters.
Geochronological and geochemical constraints on the subduction-modified lithospheric origin of the early Cretaceous volcanic rocks, in the western North Huaiyang Belt of Dabie Orogen, China
Authors: Zhang Feifei , Cawood Peter A. , Dong Yunpeng
Published: August 2019

Geochronological, elemental and Sr–Nd–Hf isotopic data for intermediate–acid volcanic sequences from the western North Huaiyang Belt of the Dabie Orogen, China, provide new constraints for the nature of the lithosphere and the potential involvement of subducted Yangtze crust. These rocks are calc-alkaline andesite, trachyandesite and dacite. They yield ages of 129
–
127 Ma and show a geochemical affinity to arc volcanic rocks. (
87
Sr/
86
Sr)
i
ratios and
ε
Nd
(
t
) values range from 0.7065 to 0.7080 and −16.9 to −13.2, respectively. Zircon
in situ ε
Hf
(
t
) values range from −29.4 to −20.2 and Hf model ages from 3.03 to 2.46 Ga. These volcanic rocks were likely derived from a hybridized source involving enriched lithosphere of the North China Craton (NCC) and deep-recycled continental crust of Yangtze Block. Our data, along with geological observations from early Cretaceous igneous rocks, suggest an east–west extensional magmatic pulse at 130–120 Ma along the entire North Huaiyang Belt. The extent of involvement of the Yangtze continental crust with the lithosphere of the NCC decreases from East to West. This reflects along strike changes in Triassic northward deep subduction and subsequent exhumation of the Yangtze crust. Further lithospheric extension in the early Cretaceous led to unrooting of the thickened lithosphere and generation of Cretaceous volcanic rocks along the North Huaiyang Belt.

Supplementary material:
Microprobe data for all samples are available at
https://doi.org/10.6084/m9.figshare.c.4611911
Joint Neural Collaborative Filtering for Recommender Systems
Authors: Chen Wanyu , Cai Fei , Chen Honghui , Rijke Maarten De
Published: August 2019

We propose a Joint Neural Collaborative Filtering (J-NCF) method for recommender systems. The J-NCF model applies a joint neural network that couples deep feature learning and deep interaction modeling with a rating matrix. Deep feature learning extracts feature representations of users and items with a deep learning architecture based on a user-item rating matrix. Deep interaction modeling captures non-linear user-item interactions with a deep neural network using the feature representations generated by the deep feature learning process as input. J-NCF enables the deep feature learning and deep interaction modeling processes to optimize each other through joint training, which leads to improved recommendation performance. In addition, we design a new loss function for optimization that takes both implicit and explicit feedback, point-wise and pair-wise loss into account.

Experiments on several real-world datasets show significant improvements of J-NCF over state-of-the-art methods, with improvements of up to 8.24% on the MovieLens 100K dataset, 10.81% on the MovieLens 1M dataset, and 10.21% on the Amazon Movies dataset in terms of HR@10. NDCG@10 improvements are 12.42%, 14.24%, and 15.06%, respectively. We also conduct experiments to evaluate the scalability and sensitivity of J-NCF. Our experiments show that the J-NCF model has a competitive recommendation performance with inactive users and different degrees of data sparsity when compared to state-of-the-art baselines.
Mechanics of Anteroposterior Axis Formation in Vertebrates
Authors: Mongera Alessandro , Michaut Arthur , Guillot Charlène , Xiong Fengzhu , Pourquié Olivier
Published: August 2019

The vertebrate anteroposterior axis forms through elongation of multiple tissues during embryogenesis. This process is based on tissue-autonomous mechanisms of force generation and intertissue mechanical coupling whose failure leads to severe developmental anomalies such as body truncation and spina bifida. Similar to other morphogenetic modules, anteroposterior body extension requires both the rearrangement of existing materials—such as cells and extracellular matrix—and the local addition of new materials, i.e., anisotropic growth, through cell proliferation, cell growth, and matrix deposition. Numerous signaling pathways coordinate body axis formation via regulation of cell behavior during tissue rearrangements and/or volumetric growth. From a physical perspective, morphogenesis depends on both cell-generated forces and tissue material properties. As the spatiotemporal variation of these mechanical parameters has recently been explored in the context of vertebrate body elongation, the study of this process is likely to shed light on the cross talk between signaling and mechanics during morphogenesis.
Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies
Authors: Mar Philip L. , Raj Satish R.
Published: August 2019

Postural orthostatic tachycardia syndrome (POTS) is a clinically heterogeneous disorder with multiple contributing pathophysiologic mechanisms manifesting as symptoms of orthostatic intolerance in the setting of orthostatic tachycardia (increase in heart rate by at least 30 beats per minute upon assuming an upright position) without orthostatic hypotension. The three major pathophysiologic mechanisms include partial autonomic neuropathy, hypovolemia, and hyperadrenergic state. Patients often will exhibit overlapping characteristics from more than one of these mechanisms. The approach to the treatment of POTS centers on treating the underlying pathophysiologic mechanism. Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. Exercise and volume expansion are the main treatment strategies for hypo-volemic POTS. For hyperadrenergic POTS, beta-blockers and avoidance of norepinephrine reuptake inhibitors is important. Attempts should be made to discern which pathophysiologic mechanism(s) may be afflicting patients so that treatment regimens can be individualized.
CD40 Agonist Antibodies in Cancer Immunotherapy
Authors: Vonderheide Robert H.
Published: August 2019

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 antibodies of varying formulations have been evaluated in the clinic and found to be tolerable and feasible. Administration is associated with mild to moderate (but transient) cytokine release syndrome, readily managed in the outpatient setting. Antitumor activity with or without anti-CTLA4 monoclonal antibody (mAb) therapy has been observed in patients with melanoma, and major tumor regressions have been observed in patients with pancreatic cancer, mesothelioma, and other tumors in combination with chemotherapy. In a recent study of chemotherapy plus CD40 mAb, with or without PD-1 mAb, the objective response rate in patients with untreated, metastatic pancreatic cancer was >50%. Mechanistically, the combination of chemotherapy followed by CD40 mAb functions as an in situ vaccine; in addition, destruction of stroma by CD40-activated macrophages may enhance chemotherapy delivery. Evidence to date suggests that CD40 activation is a critical and nonredundant mechanism to convert so-called cold tumors to hot ones (with prominent tumor infiltration of T cells), sensitizing them to checkpoint inhibition.
Inhibition of the ubiquitous calpains protects complex I activity and enables improved mitophagy in the heart following ischemia-reperfusion
Authors: Chen Qun , Thompson Jeremy , Hu Ying , Dean Joseph , Lesnefsky Edward J.
Published: August 2019

Activation of calpain 1 (CPN1) and calpain 2 (CPN2) contributes to cardiac injury during ischemia (ISC) and reperfusion (REP). Complex I activity is decreased in heart mitochondria following ISC-REP. CPN1 and CPN2 are ubiquitous calpains that exist in both cytosol (cs)-CPN1 and 2 and mitochondria (mit)-CPN1 and 2. Recent work shows that the complex I subunit (NDUFS7) is a potential substrate of the mit-CPN1. We asked whether ISC-REP led to decreased complex I activity via proteolysis of the NDUFS7 subunit via activation of mit-CPN1 and -2. Activation of cs-CPN1 and -2 decreases mitophagy in hepatocytes following ISC-REP. We asked whether activation of cs-CPN1 and -2 impaired mitophagy in the heart following ISC-REP. Buffer-perfused rat hearts underwent 25 min of global ISC and 30 min of REP. MDL-28170 (MDL; 10 µM) was used to inhibit CPN1 and -2. Cytosol, subsarcolemmal mitochondria (SSM), and interfibrillar mitochondria (IFM) were isolated at the end of heart perfusion. Cardiac ISC-REP led to decreased complex I activity with a decrease in the content of NDUFS7 in both SSM and IFM. ISC-REP also resulted in a decrease in cytosolic beclin-1 content, a key component of the autophagy pathway required to form autophagosomes. MDL treatment protected the contents of cytosolic beclin-1 and mitochondrial NDUFS7 in hearts following ISC-REP. These results support that activation of both cytosolic and mitochondrial calpains impairs mitochondria during cardiac ISC-REP. Mitochondria-localized calpains impair complex I via cleavage of a key subunit. Activation of cytosolic calpains contributes to mitochondrial dysfunction by impairing removal of the impaired mitochondria through depletion of a key component of the mitophagy process.
Cytokine and inflammatory mediator effects on TRPV4 function in choroid plexus epithelial cells
Authors: Simpson Stefanie , Preston Daniel , Schwerk Christian , Schroten Horst , Blazer-Yost Bonnie
Published: August 2019

The choroid plexus (CP), composed of capillaries surrounded by a barrier epithelium, is the main producer of cerebrospinal fluid (CSF). The CP epithelium regulates the transport of ions and water between the blood and the ventricles, contributing to CSF production and composition. Several studies suggest a connection between the cation channel transient receptor potential vanilloid-4 (TRPV4) and transepithelial ion movement. TRPV4 is a nonselective, calcium-permeable cation channel present in CP epithelia reported to be activated by cytokines and inflammatory mediators. Utilizing the PCP-R (porcine choroid plexus-Riems) cell line, we investigated the effects of various cytokines and inflammatory mediators on TRPV4-mediated activity. Select proinflammatory cytokines (TNF-α, IL-1β, TGF-β1) had inhibitory effects on TRPV4-stimulated transepithelial ion flux and permeability changes, whereas anti-inflammatory cytokines (IL-10, IL-4, and IL-6) had none. Quantitative mRNA analysis showed that these cytokines had no effect on TRPV4 transcription levels. Inhibition of the transcription factor NF-κB, involved in the production and regulation of several inflammatory cytokines, inhibited TRPV4-mediated activity, suggesting a link between TRPV4 and cytokine production. Contrary to published studies, the proinflammatory mediator arachidonic acid (AA) had inhibitory rather than stimulatory effects on TRPV4-mediated responses. However, inhibition of AA metabolism also caused inhibitory effects on TRPV4, suggesting a complex interaction of AA and its metabolites in the regulation of TRPV4 activity. Together these data imply that TRPV4 activity is involved in the inflammatory response; it is negatively affected by proinflammatory mediators. Furthermore, arachidonic acid metabolites, but not arachidonic acid itself, are positive regulators of TRPV4.
Exosomes secreted from osteocalcin-overexpressing endothelial progenitor cells promote endothelial cell angiogenesis
Authors: Yi Ming , Wu Ye , Long Jun , Liu Fei , Liu Zhi , Zhang Ying-Hua , Sun Xi-Peng , Fan Zhen-Xing , Gao Jing , Si Jin , Zuo Xue-Bing , Zhang Lei-Min , Shi Ning , Miao Zu-Pei , Bai Zhao-Run , Liu Bin-Yu , Liu Hui-Rong , Li Jing
Published: August 2019

Exosome secretion is an important paracrine way of endothelial progenitor cells (EPCs) to modulate resident endothelial cells. The osteocalcin (OCN)-expressing EPCs have been found to be increased in cardiovascular disease patients and are considered to be involved in the process of coronary atherosclerosis. Since OCN has been proven to prevent endothelial dysfunction, this study aimed to evaluate the effect of exosomes derived from OCN-overexpressed EPCs on endothelial cells. Exosomes derived from EPCs (Exos) and OCN-overexpressed EPCs (OCN-Exos) were isolated and incubated with rat aorta endothelial cells (RAOECs) with or without the inhibition of OCN receptor G protein-coupled receptor family C group 6 member A (GPRC6A). The effects of exosomes on the proliferation activity of endothelial cells were evaluated by CCK-8 assay, and the migration of endothelial cells was detected by wound healing assay. A tube formation assay was used to test the influence of exosomes on the angiogenesis performance of endothelial cells. Here, we presented that OCN was packed into Exos and was able to be transferred to the RAOECs via exosome incorporation, which was increased in OCN-Exos groups. Compared with Exos, OCN-Exos had better efficiency in promoting RAOEC proliferation and migration and tube formation. The promoting effects were impeded after the inhibition of GPRC6A expression in RAOECs. These data suggest that exosomes from OCN-overexpressed EPCs have a beneficial regulating effect on endothelial cells, which involved enhanced OCN-GPRC6A signaling.
Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation
Authors: Zhao Peng , Han Sheng-Na , Arumugam Suyavaran , Yousaf Muhammad Nadeem , Qin Yanqin , Jiang Joy X. , Torok Natalie Julia , Chen Yonglin , Mankash Mohd Salah , Liu Junbao , Li Jiansheng , Iwakiri Yasuko , Ouyang Xinshou
Published: August 2019

The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH.

NEW & NOTEWORTHY This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.
Moderate hyperoxia induces senescence in developing human lung fibroblasts
Authors: You Kai , Parikh Pavan , Khandalavala Karl , Wicher Sarah A. , Manlove Logan , Yang Binxia , Roesler Annie , Roos Ben B. , Teske Jacob J. , Britt Rodney D. , Pabelick Christina M. , Prakash Y. S.
Published: August 2019

Hyperoxia exposure in premature infants increases the risk of subsequent lung diseases, such as asthma and bronchopulmonary dysplasia. Fibroblasts help maintain bronchial and alveolar integrity. Thus, understanding mechanisms by which hyperoxia influences fibroblasts is critical. Cellular senescence is increasingly recognized as important to the pathophysiology of multiple diseases. We hypothesized that clinically relevant moderate hyperoxia (<50% O2) induces senescence in developing fibroblasts. Using primary human fetal lung fibroblasts, we investigated effects of 40% O2 on senescence, endoplasmic reticulum (ER) stress, and autophagy pathways. Fibroblasts were exposed to 21% or 40% O2 for 7 days with etoposide as a positive control to induce senescence, evaluated by morphological changes, β-galactosidase activity, and DNA damage markers. Senescence-associated secretory phenotype (SASP) profile of inflammatory and profibrotic markers was further assessed. Hyperoxia decreased proliferation but increased cell size. SA-β-gal activity and DNA damage response, cell cycle arrest in G2/M phase, and marked upregulation of phosphorylated p53 and p21 were noted. Reduced autophagy was noted with hyperoxia. mRNA expression of proinflammatory and profibrotic factors (TNF-α, IL-1, IL-8, MMP3) was elevated by hyperoxia or etoposide. Hyperoxia increased several SASP factors (PAI-1, IL1-α, IL1-β, IL-6, LAP, TNF-α). The secretome of senescent fibroblasts promoted extracellular matrix formation by naïve fibroblasts. Overall, we demonstrate that moderate hyperoxia enhances senescence in primary human fetal lung fibroblasts with reduced autophagy but not enhanced ER stress. The resulting SASP is profibrotic and may contribute to abnormal repair in the lung following hyperoxia.
Surfactant protein-D modulation of pulmonary macrophage phenotype is controlled byS-nitrosylation
Authors: Guo Chang-Jiang , Atochina-Vasserman Elena N. , Abramova Elena , Smith Ley Cody , Beers Michael F. , Gow Andrew J.
Published: August 2019

Surfactant protein-D (SP-D) is a regulator of pulmonary innate immunity whose oligomeric state can be altered through S-nitrosylation to regulate its signaling function in macrophages. Here, we examined how nitrosylation of SP-D alters the phenotypic response of macrophages to stimuli both in vivo and in vitro. Bronchoalveolar lavage (BAL) from C57BL6/J and SP-D-overexpressing (SP-D OE) mice was incubated with RAW264.7 cells ± LPS. LPS induces the expression of the inflammatory genes Il1b and Nos2, which is reduced 10-fold by SP-D OE-BAL. S-nitrosylation of the SP-D OE-BAL (SNO-SP-D OE-BAL) abrogated this inhibition. SNO-SP-D OE-BAL alone induced Il1b and Nos2 expression. PCR array analysis of macrophages incubated with SP-D OE-BAL (±LPS) shows increased expression of repair genes, Ccl20, Cxcl1, and Vcam1, that was accentuated by LPS. LPS increases inflammatory gene expression, Il1a, Nos2, Tnf, and Ptgs2, which was accentuated by SNO-SP-D OE-BAL but inhibited by SP-D OE-BAL. The transcription factor NF-κB was identified as a target for SNO-SP-D by IPA, which was confirmed by Trans-AM ELISA in vitro. In vivo, SP-D overexpression increases the burden of infection in a Pneumocystis model while increasing cellular recruitment. Expression of iNOS and the production of NO metabolites were significantly reduced in SP-D OE mice relative to C57BL6/J. Inflammatory gene expression was increased in infected C57BL6/J mice but decreased in SP-D OE. SP-D oligomeric structure was disrupted in C57BL6/J infected mice but unaltered within SP-D OE. Thus SP-D modulates macrophage phenotype and the balance of multimeric to trimeric SP-D is critical to this regulation.
Role of TRPP2 in mouse airway smooth muscle tension and respiration
Authors: Sang Dacheng , Bai Suwen , Yin Sheng , Jiang Sen , Ye Li , Hou Wenxuan , Yao Yanheng , Wang Haoran , Shen Yonggang , Shen Bing , Du Juan
Published: August 2019

The transient receptor potential polycystin-2 (TRPP2) is encoded by the Pkd2 gene, and mutation of this gene can cause autosomal dominant polycystic kidney disease (ADPKD). Some patients with ADPKD experience extrarenal manifestations, including radiologic and clinical bronchiectasis. We hypothesized that TRPP2 may regulate airway smooth muscle (ASM) tension. Thus, we used smooth muscle- Pkd2 conditional knockout ( Pkd2SM-CKO) mice to investigate whether TRPP2 regulated ASM tension and whether TRPP2 deficiency contributed to bronchiectasis associated with ADPKD. Compared with wild-type mice, Pkd2SM-CKOmice breathed more shallowly and faster, and their cross-sectional area ratio of bronchi to accompanying pulmonary arteries was higher, suggesting that TRPP2 may regulate ASM tension and contribute to the occurrence of bronchiectasis in ADPKD. In a bioassay examining isolated tracheal ring tension, no significant difference was found for high-potassium-induced depolarization of the ASM between the two groups, indicating that TRPP2 does not regulate depolarization-induced ASM contraction. By contrast, carbachol-induced contraction of the ASM derived from Pkd2SM-CKOmice was significantly reduced compared with that in wild-type mice. In addition, relaxation of the carbachol-precontracted ASM by isoprenaline, a β-adrenergic receptor agonist that acts through the cAMP/adenylyl cyclase pathway, was also significantly attenuated in Pkd2SM-CKOmice compared with that in wild-type mice. Thus, TRPP2 deficiency suppressed both contraction and relaxation of the ASM. These results provide a potential target for regulating ASM tension and for developing therapeutic alternatives for some ADPKD complications of the respiratory system or for independent respiratory disease, especially bronchiectasis.
Skeletal muscles induce recruitment of Ly6C+macrophage subtypes and release inflammatory cytokines 3 days after downhill exercise
Authors: Minari André Luis Araujo , Avila Felipe , Oyama Lila Missae , Thomatieli-Santos Ronaldo Vagner
Published: August 2019

Macrophages are one of the most versatile cells of the immune system that can express distinct subtypes and functions depending on the physiological challenge. After skeletal muscle damage, inflammatory macrophage subtypes aid muscles to regenerate and are implicated in physical training adaption. Based on this information, this study aimed to evaluate two classic mice macrophage subtypes and determine whether some inflammatory cytokines might be involved in the muscle adaption process after exercise. For this purpose, mice were exposed to an intermittent experimental protocol of downhill exercise (18 bouts of running, each bout 5 min with a 2-min rest interval, slope −16°) and were euthanized before [control (CTRL)] and 1, 2 (D2), and 3 (D3) days after exercise. After euthanasia, the triceps brachii was harvested and submitted to protein extraction, immunostaining, and mononuclear digestion procedures. The muscle size, macrophage accumulation, and cytokines were determined. We observed an increase in the Ly6C+macrophage subtype ( P ≤ 0.05) in D2 and D3 compared with CTRL, as well as a significant inverse correlation coefficient (−0.52; P ≤ 0.05) between Ly6C+and Ly6C−macrophage subtypes. Moreover, we also observed elevation in several cytokines (IL-1β, IFN-γ, TNF-α, IL-6, and IL-13) at D3, although not IL-4, which tended to decrease at this time point ( P = 0.06). Downhill exercises preferentially recruited Ly6C+macrophages with important proinflammatory cytokine elevation at D3. Moreover, despite the elevation of several cytokines involved with myogenesis, an increase in IL-6 and IL-13, which potentially involve muscle adaption training after acute exercise, was also observed.
Sonic hedgehog selectively promotes lymphangiogenesis after kidney injury through noncanonical pathway
Authors: Zhuo Hui , Zhou Dong , Wang Yuanyuan , Mo Hongyan , Yu Ying , Liu Youhua
Published: August 2019

Kidney fibrosis is associated with an increased lymphangiogenesis, characterized by the formation and expansion of new lymphatic vessels. However, the trigger and underlying mechanism responsible for the growth of lymphatic vessels in diseased kidney remain poorly defined. Here, we report that tubule-derived sonic hedgehog (Shh) ligand is a novel lymphangiogenic factor that plays a crucial role in mediating lymphatic endothelial cell proliferation and expansion. Shh was induced in renal tubular epithelium in various models of fibrotic chronic kidney disease, and this was accompanied by an expansion of lymphatic vessels in adjacent areas. In vitro, Shh selectively promoted the proliferation of human dermal lymphatic endothelial cells (HDLECs) but not human umbilical vein endothelial cells, as assessed by cell counting, MTT assay, and bromodeoxyuridine incorporation. Shh also induced the expression of vascular endothelial growth factor receptor-3, cyclin D1, and proliferating cell nuclear antigen in HDLECs. Shh did not affect the expression of Gli1, the downstream target and readout of canonical hedgehog signaling, but activated ERK-1/2 in HDLECs. Inhibition of Smoothened with small-molecule inhibitor or blockade of ERK-1/2 activation abolished the lymphatic endothelial cell proliferation induced by Shh. In vivo, inhibition of Smoothened also repressed lymphangiogenesis and attenuated renal fibrosis. This study identifies Shh as a novel mitogen that selectively promotes lymphatic, but not vascular, endothelial cell proliferation and suggests that tubule-derived Shh plays an essential role in mediating lymphangiogenesis after kidney injury.
Kidney dopamine D1-like receptors and angiotensin 1–7 interaction inhibits renal Na+ transporters
Authors: Banday Anees A. , Diaz Andrea Diaz , Lokhandwala Mustafa
Published: August 2019

The role of dopamine D1-like receptors (DR) in the regulation of renal Na+ transporters, natriuresis, and blood pressure is well established. However, the involvement of the angiotensin 1–7 (ANG 1−7)-Mas receptor in the regulation of Na+ balance and blood pressure is not clear. The present study aimed to investigate the hypothesis that ANG 1–7 can regulate Na+ homeostasis by modulating the renal dopamine system. Sprague-Dawley rats were infused with saline alone (vehicle) or saline with ANG 1–7, ANG 1–7 antagonist A-779, DR agonist SKF38393, and antagonist SCH23390. Infusion of ANG 1–7 caused significant natriuresis and diuresis compared with saline alone. Both natriuresis and diuresis were blocked by A-779 and SCH23390. SKF38393 caused a significant, SCH23390-sensitive natriuresis and diuresis, and A-779 had no effect on the SKF38393 response. Concomitant infusion of ANG 1–7 and SKF38393 did not show a cumulative effect compared with either agonist alone. Treatment of renal proximal tubules with ANG 1–7 or SKF38393 caused a significant decrease in Na+-K+-ATPase and Na+/H+ exchanger isoform 3 activity. While SCH23390 blocked both ANG 1–7- and SKF38393-induced inhibition, the DR response was not sensitive to A-779. Additionally, ANG 1–7 activated PKG, enhanced tyrosine hydroxylase activity via Ser40 phosphorylation, and increased renal dopamine production. These data suggest that ANG 1–7, via PKG, enhances tyrosine hydroxylase activity, which increases renal dopamine production and activation of DR and subsequent natriuresis. This study provides evidence for a unidirectional functional interaction between two G protein-coupled receptors to regulate renal Na+ transporters and induce natriuresis.
Timing of sacral neurostimulation is important for increasing bladder capacity in the anesthetized rat
Authors: Potts Bradley A. , Degoski Danielle J. , Brooks Jillene M. , Peterson Andrew C. , Nelson Dwight E. , Brink Thaddeus S. , Fraser Matthew O.
Published: August 2019

We assessed the effects of limited application of sacral neurostimulation (SNS) during bladder filling on bladder capacity using our previously published SNS model in rats. Female Sprague-Dawley rats ( n = 24) were urethane anesthetized (1.2 g/kg sc) and implanted with jugular venous and transvesical bladder catheters. L6/S1 nerve trunks were isolated bilaterally, and two electrodes were placed on each exposed nerve. True bladder capacity (TBC) was determined using stable single-fill cystometrograms. In the first series of experiments, SNS was applied at the onset of bladder filling for 25%, 50%, 75%, and 100% of the previous control filling cycle duration ( n = 10). In the second series of experiments, SNS was applied during the first, second, third, and fourth 25% and the first and second 50% of the control fill. In the first series, a significant increase in TBC was observed only when SNS was applied for 75% or 100% of the control fill duration (30% and 35%, respectively, P < 0.05). In the second series, significant increases in TBC only occurred during the fourth 25% period and second 50% period (32% and 43%, respectively, P < 0.001). Results from the second series also revealed an increase in subsequent single-fill bladder capacities (TBC) only when SNS was applied during the second 50% of the prior fill cycle. These data indicate that the application of SNS during the final 50% of the bladder fill cycle is necessary and sufficient for increasing bladder capacity.
Multiple doses of stem cells maintain urethral function in a model of neuromuscular injury resulting in stress urinary incontinence
Authors: Janssen Kristine , Lin Dan Li , Hanzlicek Brett , Deng Kangli , Balog Brian M. , van der Vaart Carl H. , Damaser Margot S.
Published: August 2019

Stress urinary incontinence (SUI) is more prevalent among women who deliver vaginally than women who have had a cesarean section, suggesting that tissue repair after vaginal delivery is insufficient. A single dose of mesenchymal stem cells (MSCs) has been shown to partially restore urethral function in a model of SUI. The aim of the present study was to determine if increasing the number of doses of MSCs improves urethral and pudendal nerve function and anatomy. We hypothesized that increasing the number of MSC doses would accelerate recovery from SUI compared with vehicle treatment. Rats underwent pudendal nerve crush and vaginal distension or a sham injury and were treated intravenously with vehicle or one, two, or three doses of 2 × 106 MSCs at 1 h, 7 days, and 14 days after injury. Urethral leak point pressure testing with simultaneous external urethral sphincter electromyography and pudendal nerve electroneurography were performed 21 days after injury, and the urethrovaginal complex and pudendal nerve were harvested for semiquantitative morphometry of the external urethral sphincter, urethral elastin, and pudendal nerve. Two and three doses of MSCs significantly improved peak pressure; however, a single dose of MSCs did not. Single, as well as repeated, MSC doses improved urethral integrity by restoring urethral connective tissue composition and neuromuscular structures. MSC treatment improved elastogenesis, prevented disruption of the external urethral sphincter, and enhanced pudendal nerve morphology. These results suggest that MSC therapy for postpartum incontinence and SUI can be enhanced with multiple doses.
The protective effect of klotho against contrast-associated acute kidney injury via the antioxidative effect
Authors: Oh Hyung Jung , Oh Hyewon , Nam Bo Young , You Je Sung , Ryu Dong-Ryeol , Kang Shin-Wook , Chung Yong Eun
Published: August 2019

As oxidative stress is one major factor behind contrast-associated acute kidney injury (CA-AKI), we investigated the protective effect of klotho against CA-AKI via the antioxidative effect. In in vitro experiments, cells (NRK-52E) were divided into the following three groups: control, iopamidol, or iopamidol + recombinant klotho (rKL) groups. Moreover, cell viability was measured with the Cell Counting Kit-8 assay, and oxidative stress was examined with 2',7'-dichlorodihydrofluorescein diacetate fluorescence intensity. RT-PCR and Western blot analysis were performed to assess propidium iodide klotho expression, and Bax-to-Bcl-2 and apoptosis ratios were evaluated with annexin V/Hoechst 33342 staining. Furthermore, we knocked down the klotho gene using siRNA to verify the endogenous effect of klotho. In our in vivo experiments, oxidative stress was evaluated with the thiobarbituric acid-reactive substance assay, and apoptosis was evaluated with the Bax-to-Bcl-2 ratio and cleaved caspase-3 immunohistochemistry. Additionally, cell and tissue morphology were investigated with transmission electron microscopy. In both in vitro and in vivo experiments, mRNA and protein expression of klotho significantly decreased in CA-AKI mice compared with control mice, whereas oxidative stress and apoptosis markers were significantly increased in CA-AKI mice. However, rKL supplementation mitigated the elevated apoptotic markers and oxidative stress in the CA-AKI mouse model and improved cell viability. In contrast, oxidative stress and apoptotic markers were more aggravated when the klotho gene was knocked down. Moreover, we found more cytoplasmic vacuoles in the CA-AKI mouse model using transmission electron microscopy but fewer cytoplasmic vacuoles in rKL-supplemented cells. The present study shows that klotho in proximal tubular cells can protect against CA-AKI via an antioxidative effect.
Long-term outcomes in mouse models of ischemia-reperfusion-induced acute kidney injury
Authors: Scarfe Lauren , Menshikh Anna , Newton Emily , Zhu Yuantee , Delgado Rachel , Finney Charlene , de Caestecker Mark P.
Published: August 2019

Severe acute kidney injury has a high mortality and is a risk factor for progressive chronic kidney disease. None of the potential therapies that have been identified in preclinical studies have successfully improved clinical outcomes. This failure is partly because animal models rarely reflect the complexity of human disease: most preclinical studies are short term and are commonly performed in healthy, young, male mice. Therapies that are effective in preclinical models that share common clinical features seen in patients with acute kidney injury, including genetic diversity, different sexes, and comorbidities, and evaluate long-term outcomes are more likely to predict success in the clinic. Here, we evaluated susceptibility to chronic kidney disease after ischemia-reperfusion injury with delayed nephrectomy by monitoring long-term functional and histological responses to injury. We defined conditions required to induce long-term postinjury renal dysfunction and fibrosis without increased mortality in a reproducible way and evaluate effect of mouse strains, sexes, and preexisting diabetes on these responses.
Mechanical coupling through the skin affects whisker movements and tactile information encoding
Authors: Ego-Stengel Valerie , Abbasi Aamir , Larroche Margot , Lassagne Henri , Boubenec Yves , Shulz Daniel E.
Published: August 2019

Rats use their whiskers to extract sensory information from their environment. While exploring, they analyze peripheral stimuli distributed over several whiskers. Previous studies have reported cross-whisker integration of information at several levels of the neuronal pathways from whisker follicles to the somatosensory cortex. In the present study, we investigated the possible coupling between whiskers at a preneuronal level, transmitted by the skin and muscles between follicles. First, we quantified the movement induced on one whisker by deflecting another whisker. Our results show significant mechanical coupling, predominantly when a given whisker’s caudal neighbor in the same row is deflected. The magnitude of the effect was correlated with the diameter of the deflected whisker. In addition to changes in whisker angle, we observed curvature changes when the whisker shaft was constrained distally from the base. Second, we found that trigeminal ganglion neurons innervating a given whisker follicle fire action potentials in response to high-magnitude deflections of an adjacent whisker. This functional coupling also shows a bias toward the caudal neighbor located in the same row. Finally, we designed a two-whisker biomechanical model to investigate transmission of forces across follicles. Analysis of the whisker-follicle contact forces suggests that activation of mechanoreceptors in the ring sinus region could account for our electrophysiological results. The model can fully explain the observed caudal bias by the gradient in whisker diameter, with possible contribution of the intrinsic muscles connecting follicles. Overall, our study demonstrates the functional relevance of mechanical coupling on early information processing in the whisker system.

NEW & NOTEWORTHY Rodents explore their environment actively by touching objects with their whiskers. A major challenge is to understand how sensory inputs from different whiskers are merged together to form a coherent tactile percept. We demonstrate that external sensory events on one whisker can influence the position of another whisker and, importantly, that they can trigger the activity of mechanoreceptors at its base. This cross-whisker interaction occurs pre-neuronally, through mechanical transmission of forces in the skin.
Low-Temperature Deposition Manufacturing: A Versatile Material Extrusion-Based 3D Printing Technology for Fabricating Hierarchically Porous Materials
Authors: Liu Changyong , Tong Junda , Ma Jun , Wang Daming , Xu Feng , Liu Yanliang , Chen Zhangwei , Lao Changshi
Published: August 2019

Low-temperature deposition manufacturing (LTDM) is a technology that combines material extrusion-based 3D printing and thermally induced phase separation (TIPS) into one process. With this feature, both the merits of 3D printing and TIPS can be incorporated including complex geometries with tailorable ordered macroporous features facilitated by 3D printing and microporous/nanoporous features endowed by TIPS. These macroporous/microporous/nanoporous combined structures are important to some important applications such as tissue engineering scaffolds, porous electrodes for electrochemical energy storage, purification, and filtering applications. However, the unique advantages and potential applications of LTDM have not been fully recognized and exploited yet. In this review, we will discuss the origin, principle, advantages, processes, and machine setup of LTDM technology with an emphasis on its unique advantages in fabricating porous materials. Then, current applications of LTDM including porous tissue engineering scaffolds and emerging porous electrodes for electrochemical storage will be described. The versatility of LTDM including its capability of processing a wide range of materials, multimaterial and gradient structures, and core-shell structures will be introduced. Finally, we will conclude with a perspective and outlook on the future development and applications of LTDM technology.
Novel Gysel Power Dividers with Negative Group Delay Characteristics
Authors: Zhu Zihui , Wang Zhongbao , Zhou Jianhao , Shao Te , Fang Shaojun , Liu Hongmei
Published: August 2019

A novel Gysel power divider with negative group delay (NGD), good matching, and low insertion loss is proposed. Resistors connected with short-circuited coupled lines (RCSCL) are shunted at output ports of the Gysel power divider to obtain NGD characteristics, and another resistor is shunted at the input port to realize perfect input and output matching. To verify the proposed structure, an NGD Gysel power divider is designed and fabricated. At the center frequency of 1.0 GHz, the measured NGD times for different output ports are −1.94 ns and −1.97 ns, the input/output port return loss is greater than 38 dB, the insertion loss is less than 8.3 dB, and the isolation between output ports is higher than 41 dB. To enhance the NGD bandwidth, two RCSCL networks having slightly different center frequencies are connected in parallel, which provides wider bandwidth with good input matching characteristics.
Production Practices, Postharvest Handling, and Quality of Cowpea Seed Used by Farmers in Makueni and Taita Taveta Counties in Kenya
Authors: Njonjo Mary W. , Muthomi James W. , Mwang’ombe Agnes W.
Published: August 2019

Over 80% of farmers in the developing countries use seeds from the informal seed supply that is of unknown quality status with low physical purity, reduced vigour, and contamination with seed-borne pathogens. A survey involving 114 farmers was conducted in Makueni and Taita counties using a semistructured questionnaire to determine cowpea production practices. Forty-seven cowpea seed samples were collected from farmers, and thirty-four were collected from markets and analysed for physical and physiological quality. The data from the questionnaire were analysed using SPSS package. Majority, over 76% of farmers used farm-saved seeds and intercropped cowpea with cereals (56%). The common storage container was polythene bags (56%), and farmers did not treat the seeds. The seed was below the recommended purity standard of 98%. In Taita, farm-saved and market-sourced seeds met the recommended 75% germination at 82.7% and 76.8%, respectively. Even though the germination standard was met, seeds were of low physical purity and reduced vigour. Farmers should be enlightened on recommended production practices, methods of harvesting, and postharvest handling practices to reduce seed quality loss during storage and maximize production.
Minimally Manipulated Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence
Authors: Di Matteo B. , Vandenbulcke F. , Vitale N. D. , Iacono F. , Ashmore K. , Marcacci M. , Kon E.
Published: August 2019

Background. The use of laboratory-expanded mesenchymal stem cells (MSCs) is subject to several restrictions, resulting in “minimal manipulation” methods becoming the current most popular strategy to increase the use of MSCs in an orthopaedic practice. The aim of the present systematic review is to assess the clinical applications of “minimally” manipulated MSCs, either as bone marrow aspirate concentrate (BMAC) or as stromal vascular fraction (SVF), in the treatment of knee osteoarthritis (OA). Methods. A systematic review of three databases (PubMed, ScienceDirect, and Google Scholar) was performed using the following keywords: “Knee Osteoarthritis” with “(Bone marrow aspirate) OR (bone marrow concentrate)” or with “(adipose-derived mesenchymal stem cells) OR (adipose derived stromal cells) OR (stromal vascular fraction) OR (SVF)” as either keywords or MeSH terms. The reference lists of all retrieved articles were further reviewed for identification of potentially relevant studies. Results. Twenty-three papers were included in the final analysis (10 on BMAC and 13 on SVF). Of these, only 4 were randomized controlled trials (RCTs). Bias risk evaluation, performed using a modified Coleman score, revealed an overall poor quality of the studies. In terms of clinical application, despite the apparent safety of minimally manipulated MSCs and the short-term positive clinical outcomes associated with their use, clinicians reported different preparation and administration methods, ranging from single intra-articular injections to intraosseous applications to administration in combination with other surgical procedures. Conclusions. The available literature is undermined by both the lack of high-quality studies and the varied clinical settings and different protocols reported in the few RCTs presently published. This prevents any recommendation on the use of either product in a clinical practice. Nevertheless, the use of minimally manipulated MSCs (in the form of BMAC or SVF) has been shown to be safe and have some short-term beneficial effects.
Association of ESR1 Mutations and Visceral Metastasis in Patients with Estrogen Receptor-Positive Advanced Breast Cancer from Brazil
Authors: Reinert Tomás , Coelho Guilherme Portela , Mandelli Jovana , Zimermann Edinéia , Zaffaroni Facundo , Bines José , Barrios Carlos Henrique , Graudenz Marcia Silveira
Published: August 2019

Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive advanced breast cancer and have been recognized as a prognostic and predictive biomarker as well as a potential therapeutic target. However, the prevalence of ESR1m in real-world patients has not been adequately described. Therefore, we sought to evaluate the prevalence of ESR1m in metastatic samples from Brazilian patients with estrogen receptor-positive (ER+) advanced breast cancer previously treated with endocrine therapy. The presence of ESR1m was evaluated in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue using real-time quantitative polymerase chain reaction (RT-qPCR). Mutations in codons 380, 537, and 538 of the ESR1 gene were analyzed. Out of 77 breast cancer samples, 11 (14.3%) showed mutations in the ESR1 gene. ESR1m were detected in a variety of organs, and the D538G substitution was the most common mutation. In visceral metastasis, ESR1m were detected in 25% (8/32) of the samples, whereas in nonvisceral metastasis, ESR1m were detected in 6.7% (3/45) of the samples. The odds of a sample with visceral metastasis having an ESR1 mutation is 4.66 times the odds of a sample of nonvisceral metastasis having an ESR1 mutation (95% CI: 1.13–19.27; p value = 0.0333). Our study indicates that the prevalence of ESR1m in samples from Brazilian patients with metastatic ER+ breast cancer is similar to that described in patients included in clinical trials. We observed an association of ESR1m with visceral metastasis.